Development of functionalized peptides for efficient inhibition of myostatin by selective photooxygenation.

For the inhibition of myostatin, which is an attractive strategy for the treatment of muscle atrophic disorders including muscular dystrophy, myostatin-binding peptides were synthesized with an on/off-switchable photooxygenation catalyst at different positions on the peptide chain. These functionalized peptides oxygenated and inactivated myostatin upon irradiation with near-infrared light. Among the peptides tested, a peptide (5) with the catalyst moiety at the 16 position induced myostatin-selective photooxygenation, and efficiently inhibited myostatin. These peptides exhibited low phototoxicity. Such functionalized peptides would provide a precedented strategy for myostatin-targeting therapy, in which myostatin is irreversibly and catalytically inactivated by photooxygenation.

Inactivation of myostatin by photo-oxygenation using catalyst-functionalized peptides.

Inhibition of myostatin is an attractive treatment for muscular dystrophy and other amyotrophic diseases. A myostatin-binding peptide was functionalized by equipped with an on/off switchable photo-oxygenation catalyst. This peptide induces a selective oxygenation of myostatin under near-infrared light, resulting in inactivation of myostatin. This peptide shows several orders of magnitude greater inhibitory effect than the original peptide.

Resveratrol­induced REG III expression enhances chemo­ and radiosensitivity in head and neck cancer in xenograft mice.

Identifying the key molecules that enhance chemo­ and radiosensitivity in head and neck squamous cell carcinoma (HNSCC) as well as reliable biomarkers for predicting recurrence and metastasis would be desirable to improve the prognosis of HNSCC. Previously, we have reported that Regenerating gene III (REG III) expression was associated with an improved survival rate for patients with HNSCC. In addition, resveratrol (3,4',5­trihydroxystilbene) significantly increased REG III expression in HNSCC cells, and significantly inhibited cell growth, enhanced chemo­ and radiosensitivity, and blocked the cancer invasion of HNSCC cells in vitro. In the present study, the effect of resveratrol on cancer progression in HNSCC was investigated in vivo using a xenograft nude mouse model. The results revealed that resveratrol increased the mRNA level of REG III in vivo, which was in agreement with our previous in vitro findings. Furthermore, REG III increased the antitumor effect of radiation or cisplatin in vivo, and resveratrol sensitized HNSCC to irradiation and cisplatin in vivo. These results indicated that resveratrol could increase the efficacy of cisplatin and irradiation through the REG III expression pathway, resulting in the inhibition of HNSCC progression in vivo.

Effect of resveratrol on cancer progression through the REG â ¢ expression pathway in head and neck cancer cells.

Identification of reliable markers of chemo- and radiosensitivity and the key molecules that enhance the susceptibility of head and neck squamous cell carcinoma (HNSCC) to anticancer treatments is highly desirable. Previously, we have reported that regenerating gene (REG) â…¢ expression was such a marker associated with an improved survival rate for HNSCC patients. In the present study, we investigated the stimulators for induction of REG â…¢ expression using REG â…¢ promoter assay in HNSCC cells transfected with REG â…¢ promoter vector. We tested inflammatory cytokines, growth factors, polyphenols, PPARγ activator of thiazolidinediones, and histone deacetylase inhibitors, and found that 3,4',5-trihydroxy-trans-stilbene (resveratrol) significantly increased the REG â…¢ promoter activity and the mRNA levels of REG â…¢ in HNSCC cells. Moreover, we demonstrated the effect of resveratrol on cancer cell progression, such as cell proliferation, chemo­ and radiosensitivity and cancer invasion of HNSCC cells. Resveratrol significantly inhibited cell growth, enhanced chemo­ and radiosensitivity, and blocked cancer invasion of HNSCC cells. These data suggested that resveratrol could inhibit cancer progression through the REG â…¢ expression pathway in HNSCC cells.

The effect of prostaglandin E1 on brainstem blood flow disturbance in an animal model of vertebrobasilar insufficiency.

Using an animal model of vertebrobasilar insufficiency (VBI), in which brainstem circulatory disturbance was induced in rats, we examined how prostaglandin E1 (PG-E1) affects brainstem blood flow (BBF) to clarify whether it is effective against VBI. Fifteen healthy male Wister rats that displayed positive responses to Preyer's reflex were used. Their BBF was continuously measured on the left side of the midline of the brainstem using laser Doppler flowmetry. A rat model of VBI, a pathological condition that presents with decreased BBF, was prepared by applying a vertebral artery clamp ipsilateral to the BBF measuring site and inducing hypotension of 60-70 mmHg by blood withdrawal. Saline as a control (n = 5), 5 ng/kg/min (n = 5) or 10 ng/kg/min (n = 5) PG-E1 at a dose was continuously administered to the rats using a motor-driven syringe pump. The effects of the drugs on the rats' BBF were evaluated. BBF, which was decreased by the unilateral vertebral artery clamping combined with blood withdrawal-induced hypotension, recovered in a dose-dependent manner after the administration of 5 or 10 ng/kg/min PG-E1, and complete recovery to the baseline level was achieved by 60 min treatment; however, no such effect was observed for intravenous saline. These results suggest that PG-E1 acts on local vessels and improves blood flow insufficiency in the brainstem in our animal model of VBI. PG-E1 might be useful as a cerebral vasodilator for VBI.

New treatment strategy for cupulolithiasis associated with benign paroxysmal positional vertigo of the lateral canal: the head-tilt hopping exercise.

This study was performed to determine whether a novel treatment was effective against cupulolithiasis associated with benign paroxysmal positional vertigo (BPPV) of the lateral semicircular canal, which is characterized by apogeotropic direction-changing nystagmus. We herein describe our head-tilt hopping (HtH) exercise, which is designed to release otoconial debris strongly adhered to the cupula. The subjects were trained to hop while tilting their heads laterally. They completed 3 to 5 exercise sessions per day over a 4-week period. Each session ended with a 20-hop trial. The HtH exercises were performed by 27 patients with intractable lateral canal BPPV who exhibited positional vertigo and persistent nystagmus beating toward the uppermost ear for more than 4 weeks, despite performing therapeutic head shaking in the horizontal plane maneuver. All the patients were subjected to the supine roll test before and immediately after the first trial as well as after 1 and 4 weeks of the program to evaluate the effect of the treatment on their apogeotropic nystagmus. Nystagmus of 9 (33.3 %) patients disappeared immediately after the first training session. After 1 and 4 weeks of the training, the number of patients that had experienced either of these improvements had increased to 15 (55.6 %) and 19 (70.4 %) subjects, respectively. These results suggest that HtH exercises aimed at releasing otoconial debris from the cupula are feasible as a new therapy for cupulolithiasis associated with intractable lateral canal BPPV. However, further studies for comparison with control are required to confirm these preliminary results.

Efficacy of FDG-PET for defining gross tumor volume of head and neck cancer.

We analyzed the data for 53 patients with histologically proven primary squamous cell carcinoma of the head and neck treated with radiotherapy between February 2006 and August 2009. All patients underwent contrast-enhanced (CE)-CT and (18)F-fluorodeoxyglucose (FDG)-PET before radiation therapy planning (RTP) to define the gross tumor volume (GTV). The PET-based GTV (PET-GTV) for RTP was defined using both CE-CT images and FDG-PET images. The CE-CT tumor volume corresponding to a FDG-PET image was regarded as the PET-GTV. The CE-CT-based GTV (CT-GTV) for RTP was defined using CE-CT images alone. Additionally, CT-GTV delineation and PET-GTV delineation were performed by four radiation oncologists independently in 19 cases. All four oncologists did both methods. Of these, PET-GTV delineation was successfully performed in all 19 cases, but CT-GTV delineation was not performed in 4 cases. In the other 15 cases, the mean CT-GTV was larger than the PET-GTV in 10 cases, and the standard deviation of the CT-GTV was larger than that of the PET-GTV in 10 cases. Sensitivity of PET-GTV for identifying the primary tumor was 96%, but that of CT-GTV was 81% (P < 0.01). In patients with oropharyngeal cancer and tongue cancer, the sensitivity of CT-GTV was 63% and 71%, respectively. When both the primary lesions and the lymph nodes were evaluated for RTP, PET-GTV differed from CT-GTV in 19 cases (36%). These results suggested that FDG-PET is effective for defining GTV in RTP for squamous cell carcinoma of the head and neck, and PET-GTV evaluated by both CE-CT and FDG-PET images is preferable to CT-GTV by CE-CT alone.

Laryngeal carcinoma in a non-smoker female patient with thyroid carcinoma: report of a case.

Laryngeal carcinoma is usually encountered in smoker men, and thyroid carcinoma is sometimes discovered incidentally during treatment for these patients. However, this coexistence of malignancies could occur in non-smoker female. We report an unusual case of multiple primary malignancies in the larynx and the thyroid gland. The laryngeal carcinoma was suspected to be related to the malignant transformation of the papillomas. The case suggests the importance of meticulous examination in the head and neck region for treatment of cervical metastatic lymph nodes with negative cytology in non-smoker female.

Late laryngeal radionecrosis in severe arteriosclerosis.

Laryngeal necrosis is a serious complication that usually occurs within the first year following completion of radiotherapy, although it is reported that cases can develop after a long period of latency. Factors such as dosage and irradiation technique employed, tumour invasion into the laryngeal cartilage, infection, continued smoking, trauma and general vascular condition of the patient have been considered to increase the rate and degree of development of radionecrosis. We report an unusual case of laryngeal radionecrosis in a patient with hypertension, hyperlipidaemia, diabetes and a history of cigarette smoking, which developed 25 years after radiotherapy for laryngeal carcinoma. His systemic illnesses and continued smoking were speculated to have contributed to the progress of the radionecrosis, suggesting that cessation of smoking and control of arteriosclerotic diseases should be considered to decrease its incidence.

[Weekly docetaxel treatment for head and neck cancer].

A pilot study was conducted to evaluate the safety and efficacy of weekly docetaxel(DOC) treatment for head and neck cancer as compared with those of 3-weekly DOC treatment at 60 mg/m(2). Weekly DOC was administered at doses ranging from 25-30 mg/m(2)/wk (mean dosage, 40 mg/body/wk) for 3 weeks followed by a 1-week rest or for 6 weeks followed by a 2-week rest. Weekly DOC was administered to 18 patients (1 of whom received prior chemotherapy), and 3-weekly DOC was administered to 29 patients (10 of whom received prior chemotherapy). The overall response rate was 22.2% in the weekly DOC group and 47.8% in the 3-weekly DOC group. In advanced or recurrent cancer, the overall response rate plus long NC (stable disease for at least 6 months) rate was 40.0% in the weekly DOC group, and 42.9% in the 3-weekly DOC group. Only 1 (5.6%) case of grade 3 mucositis developed in the group receiving weekly DOC, while 12 cases of grade 3 or 4 neutropenia (41.4%) and 2 of grade 3 or 4 thrombopenia (6.9%) developed in the 3-weekly DOC group. Based on these results, weekly DOC treatment appears to be useful and feasible for outpatients with head and neck cancer, even in high-risk and elderly patients.

[The usefulness of TS-1 for the treatment of head and neck cancer].

We investigated the usefulness of TS-1 for the treatment of head and neck carcinoma in 29 patients who received treatment on an outpatient basis at our institution. Among the 29 patients, 22 patients in whom the response was evaluable were included in the efficacy analysis. To assess the safety of TS-1, the severity of adverse events was examined in the 29 patients. Each course of treatment consisted of oral administration of TS-1 at a dose of 80 to 120 mg/day, depending on the body surface area (BSA), for 28 consecutive days, followed by a 14-day rest period. None of the patients showed complete response (CR), 7 showed partial response (PR), 10 showed no change (NC), and 5 showed progressive disease (PD). The response rate was thus 31.8%. Severe adverse events (grades 3 and 4) occurred in 2 patients. One developed grade 3 leukopenia and grade 4 thrombocytopenia. The other developed Stevens-Johnson syndrome that was assessed as grade 4. The findings indicate that TS-1 might be useful for the treatment of patients with head and neck carcinoma on an outpatient basis without affecting their quality of life (QOL), although careful monitoring is essential to watch for the development of severe adverse events.