Autophagy regulates anti-angiogenic property of lenvatinib in thyroid cancer.

We aimed to explore the role of lenvatinib-mediated autophagy in papillary thyroid cancer (PTC). K1 and BCPAP, were tested for cell viability, proliferation, and apoptosis after treatment with lenvatinib or chloroquine (CQ) or both. The levels of angiogenesis vascular endothelial growth factor A (VEGFA) were measured by ELISA. Transwell and wound-healing assays were performed using endothelial HUVECs cells. The dynamics of microvessels were detected by tubular formation assay. Western blotting was used to determine the expression of LC3-I/II and Atg-7 and alterations in the PI3K/Akt/mTOR and MEK/ERK pathways. In vivo tumor growth assay and immunohistochemical staining (IHC) was also performed. The results showed that lenvatinib inhibited the viability of K1 and BCPAP cells and caused apoptosis. We further showed that lenvatinib also upregulated autophagy levels in thyroid cancer cells in a dose-dependent manner through the PI3K/Akt/mTOR and MEK/ERK pathways. Co-administration of lenvatinib with CQ resulted in a greater decrease of VEGFA in the tumor supernatant than with either lenvatinib or CQ alone. Autophagy inhibition enhanced the cytotoxicity and anti-angiogenic ability of lenvatinib, which was supported by the HUVECs migration, wound healing, and tube formation assays. Inhibiting autophagy chemically or genetically enhanced lenvatinib's cytotoxic effects and anti-angiogenic efficacy in thyroid cancer cells in vitro and in vivo. In conclusion, lenvatinib inhibited cell viability and induced apoptosis and autophagy in human PTC cells. Significantly, the combination of lenvatinib and autophagy inhibition may represent a novel and effective treatment option for PTC, which may be able to overcome drug resistance.

Differential Effects of Estrogen Receptor Alpha and Beta on Endogenous Ligands of Peroxisome Proliferator-Activated Receptor Gamma in Papillary Thyroid Cancer.

Purpose: The inhibition of estrogen receptor alpha (ERα) or the activation of ERß can inhibit papillary thyroid cancer (PTC), but the precise mechanism is not known. We aimed to explore the role of ERα and ERß on the production of endogenous peroxisome proliferator-activated receptor gamma (PPARγ) ligands in PTC. Methods: 2 PTC cell lines, 32 pairs of PTC tissues and matched normal thyroid tissues were used in this study. The levels of endogenous PPARγ ligands 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), and15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) were measured by ELISA. Results: The levels of PGJ2 and 15(S)-HETE were significantly reduced in PTC, but 13(S)-HODE was not changed. Activation of ERα or inhibition of ERß significantly downregulated the production of PGJ2, 15(S)-HETE and 13(S)-HODE, whereas inhibition of ERα or activation of ERß markedly upregulated the production of these three ligands. Application of endogenous PPARγ ligands inhibited growth, induced apoptosis of cancer cells, and promoted the efficacy of chemotherapy. Conclusion: The levels of endogenous PPARγ ligands PGJ2 and 15(S)-HETE are significantly decreased in PTC. The inhibition of ERα or activation of ERß can inhibit PTC by stimulating the production of endogenous PPARγ ligands to induce apoptosis in cancer cells.

Are Vowels Normalized After Maxillary Osteotomy? An Acoustic Study in Cleft Lip and Palate.

BACKGROUND: Maxillary hypoplasia is a common skeletal condition in cleft lip and palate (CLP). Maxillary osteotomy is typically used to reposition the maxilla in CLP with maxillary hypoplasia. Previous studies have suggested that vowel articulations are adjusted postsurgically due to altered vocal tract configuration and articulatory reorganization. This acoustic study aims to investigate whether vowels are normalized postoperatively and to explore the nature of articulatory reorganization. METHODS AND PROCEDURES: A prospective study was conducted to examine the vowel production of a group of individuals with CLP (N = 17) undergoing maxillary osteotomy and a group of normal controls (N = 20), using speech acoustic data. The data were collected at 0 to 3 months presurgery (T1), 3-months (T2), and 12-months (T3) postsurgery. General linear model repeated measures and independent t-tests were undertaken on F1, F2, and vowel space area. RESULTS: General linear model repeated measures revealed no main effects of time for F1 (F [2, 22] = 1.094, P = 0.352), F2 (F [2, 22] = 1.269, P = 0.301), and vowel space area (F [2, 28] = 0.059, P = 0.943). Independent t-tests showed statistically significant differences (P < 0.05) for all acoustic parameters and all vowels between the CLP and the normal groups at all time points. CONCLUSIONS: Vowels were not normalized after maxillary osteotomy despite positive anatomical changes within the oral cavity. Individuals with CLP tended to adjust their vowel articulatory gestures to match presurgical patterns. The nature of articulatory reorganization appears to be prompt, sensory-driven, complete, and permanent.

The Cutoff Point and Diagnostic Accuracy of the Voice Handicap Index in Cantonese-Speaking Population.

BACKGROUND: Voice Handicap Index (VHI) has been used extensively in research and clinical settings. It has been suggested to be used as a diagnostic tool in the literature. However, little is known if it could be applied as a diagnostic tool to the Cantonese-speaking population. The study aims to establish cutoff points and the diagnostic accuracy for VHI-30 and VHI-10 to discriminate between Cantonese-speaking dysphonic and nondysphonic individuals. METHODS: Data from 256 adults from Hong Kong were extracted from a database at a local institution. There were a total of 91 nondysphonic individuals and 165 dysphonic individuals. Receiver operating characteristics curve analysis was conducted to establish cutoff points for VHI-30 and VHI-10. Diagnostic accuracy statistics such as sensitivity, specificity, positive, and negative predicted values (PPV and NPV) and likelihood ratios (LRs) were also reported. RESULTS: The dysphonic group scored higher than the nondysphonic group on the mean scores of both versions of VHI. Receiver operating characteristics curve analysis revealed a moderate to strong area under curve of 0.89 in both VHI-30 and VHI-10. A cutoff point of 18.5 point was yielded for VHI-30 (Sensitivity = 86.1%, Specificity = 81.3%, PPV = 89.3%, NPV = 76.3%, LR+ = 4.60, LR- = 0.17) and a cutoff point of 7.5 point was yielded for VHI-10 (Sensitivity = 80.6%, Specificity = 87.9%, PPV = 92.4%, NPV = 71.4%, LR+ = 6.66, LR- = 0.22). CONCLUSIONS: Both the Chinese VHI-30 and VHI-10 for Cantonese speakers showed promising diagnostic accuracy. VHI can be used as adjunct to clinical diagnosis and treatment outcome measures for voice disorders in the Cantonese-speaking population.

Cochlear implantation in postirradiated ears: A case-control comparative study.

OBJECTIVES: The aim of this study is to investigate the hearing outcomes of cochlear implantation (CI) in patients with hearing loss who had received radiotherapy for nasopharyngeal cancer (NPC). The study compared speech perception in patients who had prior radiotherapy with those who did not receive radiotherapy. METHODS: Eighty-eight Cantonese speaking adult patients who had profound sensorineural hearing loss and received CI from 1995 to 2015 at the Chinese University of Hong Kong CI-center were studied. Twenty-five patients had history of NPC and radiotherapy were determined as the exposed group, while 63 patients of mixed etiologies but with no history of radiotherapy were included in the control group. The Hong Kong Speech Perception Test Manual (HKSPTM) scores preoperatively, at 6, 12, and 24 months postoperatively were used to assess hearing performance. The HKSPTM consisted categories of speech recognition, word recognition, and tone perception. RESULTS: No statistical significance differences were found at the four time-points in the three categories of HKSPTM between the two groups. CONCLUSION: CI is a clinically effective intervention and good rehabilitative option for hearing restoration in NPC patients with hearing impairment. Further studies with greater sample size and additional pathological studies on the pathophysiology of hearing loss in this subgroup of patients may provide supplementary information for clinicians when counseling for CI. LEVEL OF EVIDENCE: 4.

The role of microRNA in cisplatin resistance or sensitivity.

INTRODUCTION: Cisplatin is a chemotherapy drug that has been used to treat a number of cancers for decades, and is still one of the most commonly used anti-cancer agents. However, some patients do not respond to cisplatin while other patients who were originally sensitive to cisplatin eventually develop chemoresistance, leading to treatment failure or/and tumor recurrence. AREAS COVERED: Different mechanisms contribute to cisplatin resistance or sensitivity, involving multiple pathways or/and processes such as DNA repair, DNA damage response, drug transport, and apoptosis. Among the various mechanisms, it appears that microRNAs play an important role in determining the resistance or sensitivity. In this article, we analyzed and summarized recent findings in this area, with the aim that these data can aid further research and understanding, leading to the eventual reduction of cisplatin resistance. EXPERT COMMENTARY: microRNAs can positively or negatively regulate cisplatin resistance by acting on molecules or/and pathways related to apoptosis, autophagy, hypoxia, cancer stem cells, NF-κB, and Notch1. It appears that the modulation of relevant microRNAs can effectively re-sensitize cancer cells to cisplatin regimen in certain types of cancers including breast, colorectal, gastric, liver, lung, ovarian, prostate, testicular, and thyroid cancers.

A meta-analysis of narrow-band imaging for the diagnosis of primary nasopharyngeal carcinoma.

Background: Narrow band imaging (NBI), an endoscopic technique featuring an augmented definition of microvasculature and mucosal patterns. NBI is increasingly advocated as a tool to characterize neoplasia and intestinal metaplasia in endoscopic standards, such as for colorectal polyps and tumors. Recently NBI has also been studied in the detection of Nasopharyngeal Carcinoma (NPC). Here we aimed to assess the diagnostic utility of NBI for the diagnosis of NPC. Methods: A meta-analysis of studies comparing narrow-band imaging and white light endoscopy in the diagnosis of primary nasopharyngeal carcinoma was performed. The review process involved two independent investigators. The databases used were MEDLINE, PubMed, the Cochrane library, Embase, and the Web of Science. Statistical analysis was performed with OpenMetaAnalyst, MetaDiSc version 1.4, and Medcalc version 17.9.7.  Results: Five studies including 2480 patients were included. The sensitivity and specificity for narrow-band imaging were 0.90 (0.73-0.97) and 0.95 (0.81-0.99) respectively. The positive likelihood ratio and negative likelihood ratio were 18.82 (0.31-82.1) and 0.08 (0.02-0.31). For white light endoscopy, the sensitivity and specificity were 0.77 (0.58-0.89) and 0.91 (0.79-0.96). The positive likelihood ratio was 7.61 (3.61-16.04), and the negative likelihood ratio was 0.21 (0.11-0.39). The odds ratio for detection rates between narrow-band imaging and white light endoscopy was 4.29 (0.56-33.03, p = 0.16). Area under the curve for narrow-band imaging was 0.98 (SE: 0.02), and for white light it was 0.93 (SE: 0.03). There was no significant difference in the receiver operating characteristic curves between the two modalities (p = 0.14). Conclusion: Narrow-band imaging showed a higher sensitivity and positive likelihood ratio for the diagnosis of nasopharyngeal carcinoma. However, there was no significant difference in detection rates compared to white light endoscopy. Further investigation with a uniform diagnostic criteria and terminology is needed for narrow-band imaging in the diagnosis of nasopharyngeal carcinoma.

Rhythmic speech and stuttering reduction in a syllable-timed language.

Speaking rhythmically, also known as syllable-timed speech (STS), has been known for centuries to be a fluency-inducing condition for people who stutter. Cantonese is a tonal syllable-timed language and it has been shown that, of all languages, Cantonese is the most rhythmic (Mok, 2009). However, it is not known if STS reduces stuttering in Cantonese as it does in English. This is the first study to investigate the effects of STS on stuttering in a syllable-timed language. Nineteen native Cantonese-speaking adults who stutter were engaged in conversational tasks in Cantonese under two conditions: one in their usual speaking style and one using STS. The speakers' percentage syllables stuttered (%SS) and speech rhythmicity were rated. The rhythmicity ratings were used to estimate the extent to which speakers were using STS in the syllable-timed condition. Results revealed a statistically significant reduction in %SS in the STS condition; however, this reduction was not as large as in previous studies in other languages and the amount of stuttering reduction varied across speakers. The rhythmicity ratings showed that some speakers were perceived to be speaking more rhythmically than others and that the perceived rhythmicity correlated positively with reductions in stuttering. The findings were unexpected, as it was anticipated that speakers of a highly rhythmic language such as Cantonese would find STS easy to use and that the consequent reductions in stuttering would be great, even greater perhaps than in a stress-timed language such as English. The theoretical and clinical implications of the findings are discussed.

Lexical tone and stuttering in Cantonese.

Cantonese is a tone language, in which the variation of the fundamental frequency contour of a syllable can change meaning. There are six different lexical tones in Cantonese. While research with Western languages has shown an association between stuttering and syllabic stress, nothing is known about whether stuttering in Cantonese speakers is associated with one or more of the six lexical tones. Such an association has been reported in conversational speech in Mandarin, which is also a tone language, but which varies markedly from Cantonese. Twenty-four native Cantonese-speaking adults who stutter participated in this study, ranging in age from 18-33 years. There were 18 men and 6 women. Participants read aloud 13 Cantonese syllables, each of which was produced with six contrastive lexical tones. All 78 syllables were embedded in the same carrier sentence, to reduce the influence of suprasegmental or linguistic stress, and were presented in random order. No significant differences were found for stuttering moments across the six lexical tones. It is suggested that this is because lexical tones, at least in Cantonese, do not place the task demands on the speech motor system that typify varying syllabic stress in Western languages: variations not only in fundamental frequency, but also in duration and intensity. The findings of this study suggest that treatments for adults who stutter in Western languages, such as speech restructuring, can be used with Cantonese speakers without undue attention to lexical tone.

The Topography of Stuttering in Cantonese.

OBJECTIVE: This is the first study to investigate the behavioral nature (topography) of stuttering in Cantonese. Cantonese, a Sino-Tibetan language, is both tonal and syllable-timed. Previous studies of stuttering topography have mainly been in Western languages, which are mainly stress-timed. METHODS: Conversational speech samples were collected from 24 native Cantonese-speaking adults who stuttered. Six consecutive stuttering moments from each participant were analyzed using the Lidcombe behavioral data language (LBDL). A complexity analysis based on the LBDL was developed to indicate the proportion of multiple-behavior stuttering moments for each participant. RESULTS: There was no significant difference in the frequency of the 7 LBDL behaviors. Almost half the stuttering moments across participants were reported as complex, containing more than 1 stuttering behavior, and stuttering complexity correlated significantly with stuttering severity. CONCLUSIONS: These preliminary findings require replication because of their important theoretical and clinical implications. Differences in topography across languages have the potential to contribute to our understanding of the nature of stuttering. Clinically, the recognition of such differences may assist practitioners in identifying stuttering, for example when screening for early stuttering. The LBDL complexity score developed in this study has the potential to be used in other languages.

The effectiveness of group voice therapy: a group climate perspective.

OBJECTIVES/HYPOTHESIS: Group therapy has frequently been adopted as a service delivery model for providing voice therapy. However, currently no literature has focused on understanding the underlying processes that are unique to group therapy, which contribute to treatment success. This study aimed at investigating the role of group climate in voice group therapy. STUDY DESIGN: Prospective case series. METHODS: Twelve teachers with hyperfunctional dysphonia attended eight sessions of group voice therapy. Treatment comprised both direct and indirect voice therapy. Therapy techniques were introduced and practiced in a large group and small group format. Outcome measures were taken using perceptual evaluation, videostroboscopy measures, voice-related quality-of-life (V-RQOL) measures, and vocal symptom scores. The Group Climate Questionnaire was used to measure the underlying process of group therapy. Treatment outcome was measured immediately posttreatment and at 6-months posttreatment. RESULTS: Results indicated statistically significant improvement in the participants' V-RQOL measures and the vocal symptom scores. Treatment gain was noted to sustain up to 6-months posttreatment. The Group Climate Questionnaire indicated that the treatment group is considered as "engaging" rather than "conflicting," which is considered to be associated with positive treatment outcome. CONCLUSION: Group therapy as a service delivery model possesses many advantages from the psychosocial, clinical, health resources allocation perspective. This study demonstrated that group climate plays a significant role in determining treatment success in group voice therapy.

The development of Cantonese Lexical Neighborhood Test: a pilot study.

OBJECTIVE: This study aimed at developing a theoretically driven open-set speech recognition test for pediatric clinical population of cochlear implant and/or hearing aid users, with Cantonese Chinese as their first language, to track progress in speech recognition performance as an outcome measurement of their rehabilitation. METHODS: Six monosyllabic and six disyllabic word lists were generated from the Cantonese CHILDES language database, constructed according to the Neighborhood Activation Model. There were three lexically "easy" and three lexically "hard" word lists in each sub-test, with 25 items in each list. Four pediatric cochlear implant users and 10 hearing aid users, with bilateral congenital severe to profound sensorineural hearing impairment and below the age of 10, participated in the study. Their performances on word recognition and phoneme recognition with the new test lists, as well as the inter-list equivalency, inter-rater reliability, and face validity of the new materials, were investigated. RESULTS: Word recognition was higher among disyllables than monosyllables. Lexically "easy" disyllabic words were better recognized than their "hard" counterparts and the monosyllables. No significant difference was noted among the three lists in each combination of syllable structure and lexical property. High inter-rater reliability, as well as high correlation between Cantonese LNT score and a receptive vocabulary test score, were revealed. CONCLUSIONS: These newly developed test lists provided reliable information on spoken word recognition of pediatric hearing prosthesis users with severe to profound hearing impairment. Inter-list equivalency and inter-rater reliability allowed monitoring of rehabilitation progress on such specific pediatric clinical population with this new test. (255).