Impact of metformin on immunological markers: Implication in its anti-tumor mechanism.

Metformin, an anti-hyperglycemic drug, has been known to have antitumor properties for around 15 years. Although there are a number of reports attributing the antitumor function of metformin to its impact on energy homeostasis and oxygen re-distribution in tumor microenvironment, detailed mechanisms remain largely unknown. In the past several years, there is an increasing number of publications indicating that metformin can affect various immunological components including lymphocytes, macrophages, cytokines and several key immunological molecules in both human and animal studies. These interesting results appear to be in line with emerging data that suggest associations between immune responses and energy homeostasis/oxygen re-distribution, which may explain effective impacts of metformin on immunotherapies against autoimmune diseases as well as cancers. This review article is to analyse and discuss recent development in the above areas with aim to justify metformin as a new adjuvant for immunotherapy against human cancers. We hope that our summary will help to optimize the application of metformin for various types of human cancers.

CXCR6 and CCR5 localize T lymphocyte subsets in nasopharyngeal carcinoma.

The substantial T lymphocyte infiltrate found in cases of nasopharyngeal carcinoma (NPC) has been implicated in the promotion of both tumor growth and immune escape. Conversely, because malignant NPC cells harbor the Epstein-Barr virus, this tumor is a candidate for virus-specific T cell-based therapies. Preventing the accumulation of tumor-promoting T cells or enhancing the recruitment of tumor-specific cytotoxic T cells offers therapeutic potential. However, the mechanisms involved in T cell recruitment to this tumor are poorly understood. Comparing memory T cell subsets that have naturally infiltrated NPC tissue with their counterparts from matched blood revealed enrichment of CD8(+), CD4(+), and regulatory T cells expressing the chemokine receptor CXCR6 in tumor tissue. CD8(+) and (nonregulatory) CD4(+) T cells also were more frequently CCR5(+) in tumor than in blood. Ex vivo studies demonstrated that both receptors were functional. CXCL16 and CCL4, unique chemokine ligands for CXCR6 and CCR5, respectively, were expressed by the malignant cells in tumor tissue from the majority of NPC cases, as was another CCR5 ligand, CCL5. The strongest expression of CXCL16 was found on tumor-infiltrating cells. CCL4 was detected on the tumor vasculature in a majority of cases. These findings suggest that CXCR6 and CCR5 play important roles in T cell recruitment and/or retention in NPC and have implications for the pathogenesis and treatment of this tumor.

Combined ultrasound/endoscopy-assisted vocal fold injection for unilateral vocal cord paralysis: a case series.

OBJECTIVE: Transcutaneous vocal cord injection is a popular treatment choice for patients suffering from unilateral vocal cord paralysis. Transcutaneous transcartilaginous (through the thyroid cartilage) approach abolishes any anatomical constraint to reach the vocal cord. However it is a largely blind procedure as the needle should stay submucosal. Herein we report our experience in employing ultrasound guidance to circumvent this problem. METHODS: Retrospective review of a series of 8 patients who underwent combined ultrasound/endoscopy-assisted vocal cord injection for unilateral vocal cord paralysis. RESULTS: Vocal cord injections were successfully completed in all but one patient. There were no associate complications. CONCLUSION: The use of ultrasound in aiding transcutaneous transcartilaginous vocal cord injection is safe and feasible. KEY POINTS: • Vocal cord injection is effective in treating unilateral vocal cord paralysis • A number of transcutaneous approaches with the patient awake have been described • Transcutaneous transcartilaginous approach theoretically has minimal anatomical restraint to reach the vocal cord • Disadvantage of that approach is the difficulty to accurately position the needle • Our experience of using ultrasound to circumvent this problem is positive.

Second branchial fistula with unusual presentation--a case report.

Complete second branchial fistula is a rare clinical entity. The classical presentation of second branchial fistula is recurrent discharge from the external opening with or without recurrent painful neck swelling. We report an unusual case whose presenting symptom was a long-standing history of throat discomfort with recurrent blood stained saliva. Her symptoms resolved after her branchial fistula was excised.

Cantonese tone recognition with enhanced temporal periodicity cues.

This study investigated the contributions of temporal periodicity cues and the effectiveness of enhancing these cues for Cantonese tone recognition in noise. A multichannel noise-excited vocoder was used to simulate speech processing in cochlear implants. Ten normal-hearing listeners were tested. Temporal envelope and periodicity cues (TEPCs) below 500 Hz were extracted from four frequency bands: 60-500, 500-1000, 1000-2000, and 2000-4000 Hz. The test stimuli were obtained by combining TEPC-modulated noise signals from individual bands. For periodicity enhancement, temporal fluctuations in the range 20-500 Hz were replaced by a sinusoid with frequency equal to the fundamental frequency of original speech. Tone identification experiments were carried out using disyllabic word carriers. Results showed that TEPCs from the two high-frequency bands were more important for tone identification than TEPCs from the low-frequency bands. The use of periodicity-enhanced TEPCs led to consistent improvement of tone identification accuracy. The improvement was more significant at low signal-to-noise ratios, and more noticeable for female than for male voices. Analysis of error distributions showed that the enhancement method reduced tone identification errors and did not show any negative effect on the recognition of segmental structures.

Cantonese lexical tone recognition from frequency-specific temporal envelope and periodicity components in the same versus different noise band carriers.

Temporal envelope and periodicity components (TEPCs) in the speech signal offer important cues for speech recognition. A recent study revealed that TEPCs extracted from the high-frequency regions contribute significantly to Cantonese lexical tone recognition at the monosyllabic word level (Yuen et al., 2006). The aim of the current study was to compare the contributions of TEPCs from different frequency regions for Cantonese lexical tone recognition in connected speech, using the same or different noise band carriers and a very limited number of frequency bands. Test stimuli were Cantonese disyllabic word minimal pairs differing from each other only in lexical tone. The test stimuli set exhausted all possible 15 lexical tone-pair contrasts (six lexical tones in total) for the first and the second syllables. The TEPC of the test items were extracted by full-wave rectification and low-pass filtering and were used to modulate a speech-spectrum-shaped noise carrier to create the test stimuli. The stimuli therefore contain only TEPCs but no fine structure components (FSCs) of the original signal. Multiple sets of stimuli were created with different combinations of TEPC-modulated frequency bands. Twenty normal-hearing subjects participated in the study. Even in a single-band condition, much robust lexical tone recognition was obtained with TEPC provided from the high-frequency region than those from the low frequency region. This high frequency region TEPC advantage was consistent using noise band carriers from different frequency regions. The TEPCs in the high-frequency region are more important for Cantonese lexical tone recognition, when FSCs are not available. The results indicate a potential to improve speech recognition in tonal languages by preserving or enhancing the critical TEPCs via new signal-processing algorithms in hearing prosthesis.

Development of the computerized Cantonese disyllabic lexical tone identification test in noise (CANDILET-N).

CANDILET-N is a closed-set speech-recognition test to assess lexical tone recognition in noise for Cantonese speakers. The test consists of 60 test items in a four-alternative forced-choice test paradigm, with male and female speaker versions. Each test plate consists of two disyllabic-word lexical tone minimal pair test items and their respective phonemic distracters. Psychometric performance SNR (signal-to-noise ratio) functions from 26 normal hearing adult subjects were fitted to a logistic regression model to obtain the SNR for 50% correct score (SNR-50%) for individual test items. The mean SNR-50% of the 60 test items for the female and male test sets were -10.3 dB and -11.1 dB, respectively. The SNR-50% varies across test items and their SNR need to be adjusted to improve the homogeneity among them.

Band-specific temporal periodicity enhancement for Cantonese tone perception with noise-excited vocoder.

This paper describes a study on the effectiveness of expanding the temporal envelope and periodicity component (TEPC) for Cantonese tone perception. The ultimate goal is to develop speech processing techniques that can improve speech perception of hearing prosthesis users. Cantonese is a popular Chinese dialect with a complex lexical tone system. TEPCs are extracted from a few predefined frequency bands. A nonlinear expansion method is applied to increase the modulation depth of the TEPCs, in order to make the temporal periodicity information more salient. To simulate the speech processing procedures of a cochlear implant, the TEPC is used to modulate a noise carrier. Psychophysical listening tests on Cantonese lexical tone identification are carried out with expanded and unexpanded TEPCs. The experimental results show that: (1) expansion of TEPC from high-frequency band leads to noticeable improvement on tone identification accuracy; (2) the effectiveness of TEPC expansion is more significant for female voice than male voice; (3) the presence of noise carrier in low-frequency band negatively affects tone identification accuracy.

Frequency-specific temporal envelope and periodicity components for lexical tone identification in Cantonese.

OBJECTIVES: Temporal envelope and periodicity components (TEPC) in the speech signal have potentials to offer important cues for speech recognition especially in tonal languages. The aims of this study are: (i) to investigate the degree of contributions of TEPC to lexical tone identification in Cantonese; and (ii) to investigate whether or not the contributions vary among different frequency bands. The results of these investigations would reveal if there are any frequency-specific TEPC that are important for lexical tone identification. DESIGN: TEPC of monosyllable words carrying different lexical tones, were extracted by the method of full-wave rectification and low-pass filtering. They were used to modulate a speech spectrum noise to create the test stimuli. Thus the stimuli contain only temporal envelope and periodicity components but no temporal fine structures of the original speech signal. Multiple sets of stimuli were created with different combinations of TEPC modulated frequency bands, Eighteen adult subjects with normal hearing participated in the study. RESULTS: Lexical tone identification was the best when only the TEPC from the two high frequency bands (1-2 kHz and 2-4 kHz) of the original signal were provided, but the worst when only the TEPC from the two low frequency bands (60-500 Hz and 500-1000 Hz) were provided. The findings suggested that high frequency bands are carrying TEPC which are important for lexical-tone identification. Lexical tone identification performance was better for the male stimuli than the female ones. CONCLUSIONS: The results indicate the potential on improving speech recognition in tonal languages by manipulating TEPC via new signal processing algorithms in hearing prosthesis.

Patient satisfaction after closed reduction of nasal fractures.

OBJECTIVE: To evaluate the outcome of closed reduction from a patient's point of view, because there is increasing evidence that closed reduction of nasal fractures fails to address deformities of the cartilaginous nasal framework and the septum. METHODS: We performed a retrospective study of 62 patients who underwent a closed reduction of nasal fracture between July 1, 2002, and June 30, 2005. All patients were interviewed regarding the esthetic and functional outcomes after closed reduction. RESULTS: Eighteen patients (29%) expressed dissatisfaction with the esthetic outcome of the reduction, and 18 (29%) said they would consider further surgery to correct the residual nasal deformity. CONCLUSIONS: A stringent preoperative assessment of the nasal fracture, other nasal deformities, and nasal function is essential before offering patients a simple closed reduction of their nasal fractures. A septorhinoplasty, as the definitive procedure, should be offered to patients when a closed reduction is deemed unable to address all deformities.

The expression of Bcl-2 family proteins and spontaneous apoptosis in laryngeal carcinomas.

Bcl-2 family proteins play an important role in the growth and biological behavior of tumors. This study aimed to determine Bcl-2 family proteins in laryngeal carcinoma and to examine their relationship with spontaneous apoptosis. The material studied was from 39 patients with laryngeal carcinoma. It was found that the expression of both Bak and Bax was lower in tumor tissues than in nontumor tissues. However, there was no difference in the expression of Bcl-2 between tumor and nontumor tissues. The frequency of spontaneous apoptosis was lower in tumor tissues than in nontumor tissues but was not significantly related to the expression of Bak, Bax, or Bcl-2. Bak was decreased in moderately differentiated tumors compared to well-differentiated tumors. In contrast to Bak, the expression of Bcl-2 was increased in moderately differentiated tumors compared to well-differentiated tumors. These results indicate that the reduction in Bak may be associated with an increase in tumor grade and dedifferentiation in laryngeal carcinomas. The lack of correlation between apoptosis and the expression of Bcl-2 family proteins suggests that spontaneous apoptosis in laryngeal carcinoma is a complex process and that molecules other than Bak, Bax, and Bcl-2 participate in it.

Effects of the Chinese herbal formula Shi-Bi-Lin on cytokine release from the human mast cell line.

BACKGROUND: The traditional Chinese herbal formula Cang Er Zi San has been used for the treatment of rhinitis, paranasal sinusitis, and allergic rhinitis for several centuries. However, its therapeutic mechanisms remain largely unclear. OBJECTIVE: To study the effects of Shi-Bi-Lin (SBL), a modified Cang Er Zi San formula, on cytokine release from and expressions in the human mast cell line (HMC-1). METHODS: The HMC-1 was preincubated with different concentrations of SBL extract solution 1 hour before being stimulated with 25 ng/mL of phorbol myristate acetate plus 2.5 x 10(-7)M calcium ionophore A23187 and then further incubated for 6, 12, and 24 hours, respectively. The cell culture supernatants were harvested, and the cytokines of interleukin 4 (IL-4), IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) in the supernatants were measured by enzyme-linked immunosorbent assay. Furthermore, the total RNA of the cells was extracted, and the cytokines' messenger RNA expressions were examined using semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: After different incubation periods at different concentrations, SBL could potently inhibit the cytokines of IL-4 and TNF-alpha and modestly affect IL-6 but not obviously affect IL-8 release from the HMC-1. However, no inhibitory effects were detected on the messenger RNA expressions of these cytokines. CONCLUSIONS: These results demonstrate that SBL could modulate the mast cell-mediated hypersensitivity reaction in allergy. Inhibition of mast cell-derived IL-4 and TNF-alpha might explain the efficacy of SBL in treating allergic disease.

Quantitative Epstein-Barr virus DNA analysis and detection of gene promoter hypermethylation in nasopharyngeal (NP) brushing samples from patients with NP carcinoma.

PURPOSE: Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China and characterized by a strong association with EBV. We aimed to detect EBV DNA and cancer-related gene promoter hypermethylation in nasopharyngeal (NP) brushing samples and provide a novel noninvasive approach for NPC detection. EXPERIMENTAL DESIGN: Twenty-eight NPC cases and 26 noncancerous subjects were prospectively recruited. NP brushing samples were subjected to quantitative real-time PCR analysis of EBV DNA and methylation-specific PCR analysis of the DAP-kinase, RASSF1A, and p16 genes. RESULTS: EBV DNA quantity in NP brushing samples from NPC patients (median, 8.94 copies/actin) was significantly higher than that of controls (median, 0 copies/actin; P < 0.0001). Twenty-seven of 28 NPC patients had detectable EBV DNA in NP brushes, whereas 25 of 26 controls had undetectable or very low levels of EBV DNA. Elevated EBV DNA level in brushing samples as a tumor marker had a sensitivity of 96.4% and a specificity of 96.2% for NPC detection. Moreover, T(1) disease had a significantly lower EBV DNA level as compared with locally more advanced disease (P = 0.037). In brushing samples of NPC patients, the frequencies of DAP-kinase, RASSF1A, and p16 promoter hypermethylation were 50.0%, 39.3%, and 46.4%, respectively. Seventy-eight percent of cases showed methylation of at least one gene. No aberrant hypermethylation was detected in control samples. CONCLUSIONS: Our study demonstrated the feasibility of detecting multiple molecular tumor markers in NP brushing samples with a high sensitivity and specificity for NPC detection. It offers a powerful yet noninvasive approach for the diagnosis of NPC in high-risk populations.