Induction of synergistic non-apoptotic cell death by simultaneously targeting proteasomes with bortezomib and histone deacetylase 6 with ricolinostat in head and neck tumor cells.

Following surgery and chemoradiation, ~50% of patients with locally advanced head and neck tumors experience relapse within the first two years, with a poor prognosis. Therefore, a novel therapeutic approach is required. The aim of the present study was to investigate the effect of combination treatment with the proteasome inhibitor bortezomib (BTZ), and ricolinostat (RCS), a specific inhibitor of histone deacetylase 6 (HDAC6), on CAL27 and Detroit562 head and neck cancer cells. BTZ and RCS exhibited cytotoxicity in a dose- and time-dependent manner. Simultaneous treatment with BTZ and RCS resulted in the synergistic enhancement of non-apoptotic cell death and autophagy. The receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, necrostatin, but not the autophagy inhibitor, 3-methyladenine, attenuated the cytotoxicity of combined BTZ and RCS treatment. Thus, necroptosis [type-III programmed cell death (PCD)], but not autophagic cell death (type-II PCD), appeared to contribute to the pronounced cytotoxicity. However, no phosphorylation of RIPK1 or mixed lineage kinase domain-like protein was detectable in response to BTZ or RCS. Furthermore, RCS induced α-tubulin acetylation and inhibited BTZ-induced aggresome formation along with endoplasmic reticulum stress loading. Combined treatment with BTZ and RCS enhanced the production of reactive oxygen species (ROS). The ROS scavenger, N-acetyl cysteine, abrogated the increase in cytotoxicity. These results suggest the potential therapeutic value of the dual targeting of the proteasome and HDCA6 for head and neck cancers through the induction of necroptosis-like cell death along with ROS generation.

New Vocal Fold-shortening Procedure: External Approach to Anterior Vocal Fold Plication.

INTRODUCTION: We believe that our new procedure offers a useful external approach to anterior vocal fold plication. Vocal cord shortening by laryngomicrosurgery (LMS) involves plication of the anterior commissure, but this difficult procedure requires high-level skills. Dehiscence of the plicated location may occur postoperatively. METHODS: In the present case, we applied an innovative procedure combining vocal cord shortening by LMS with cervical incision. This facilitated plication, and no postoperative dehiscence was encountered. RESULTS: Speaking fundamental frequency (SFF) was 110 Hz at the first visit, 170 Hz after type 4 thyroplasty, 167 Hz after thyroarytenoid muscle myectomy, and 208 Hz after the present procedure, representing a good outcome. CONCLUSIONS: This procedure could be useful when the SFF is not sufficiently raised by existing procedures. The risk of postoperative dehiscence of the plicated location is low compared with LMS. CASE DETAILS: The patient consulted with a major complaint of low vocal pitch. At the first visit, SFF was 110 Hz, suggesting a male voice. In April 201X, type 4 thyroplasty was performed and successfully raised SFF to 170 Hz. As the patient did not readily pass as a woman, thyroarytenoid muscle myectomy was performed in February 201X +1 but only achieved an SFF of 167 Hz, which was considered unsatisfactory. As a result, the procedure was performed again in September 201X +1.

Aumento de la generación de peróxido de hidrógeno en los neutrófilos de pacientes con inflamación acneic / Increased hydrogen peroxide generation by neutrhophils from patients with acne inflammation

Antecedentes: Las sustancias oxigenadas reactivas generadas por los neutrófilos están estrechamente relacionadas con la patogenia de una variedad de enfermedades inflamatorias de la piel. El objetivo de este estudio fue investigar el papel que desempeñan las sustancias oxigenadas reactivas producidas por los neutrófilos como mediadores de la inflamación debida al acné.Métodos: Se aplicaron estímulos fagocitósicos bacterianos a la sangre, mediados por actividad opsonina, y se midió la producción de peróxido de hidrógeno de los neutrófilos.Resultados: Los pacientes con inflamación acneica mostraron un aumento significativo de la producción de peróxido de hidrógeno en los neutrófilos en comparación con los pacientes con comedones acneicos y con los controles sanos. No se observaron diferencias significativas en la producción de peróxido de hidrógeno de los neutrófilos de pacientes con comedones acneicos y de los controles sanos. Además, los pacientes con inflamación acneica tratados por vía oral con hidrocloruro de minociclina, un fármaco que inhibe la generación de peróxido de hidrógeno en los neutrófilos, tuvieron un descenso significativo en la capacidad de los neutrófilos para producir peróxido de hidrógeno, simultánea al descenso en la actividad inflamatoria de las lesiones de acné.Conclusiones: Este estudio sugiere que la inflamación acneica está mediada en parte por la generación de peróxido de hidrógeno de los neutrófilos (AU)

Increased hydrogen peroxide generation by neutrophils from patients with acne inflammation.

BACKGROUND: Reactive oxygen species generated by neutrophils are closely correlated with the pathogenesis of a variety of inflammatory skin diseases. The aim of this study was to investigate the possible role of reactive oxygen species generated by neutrophils in the mediation of acne inflammation. METHODS: Bacterial phagocytotic stimuli, mediated by opsonin activity, were applied to whole blood, and neutrophil hydrogen peroxide production was measured. RESULTS: Patients with acne inflammation showed a significantly increased level of hydrogen peroxide produced by neutrophils compared to patients with acne comedones and healthy controls. There were no marked differences in the level of hydrogen peroxide produced by neutrophils between patients with acne comedones and healthy controls. In addition, patients with acne inflammation treated by oral administration of minocycline hydrochloride, a drug that inhibits hydrogen peroxide generation by neutrophils, showed a significant decrease in the ability of neutrophils to produce hydrogen peroxide in accordance with a decrease in the inflammatory activity of acne lesions. CONCLUSIONS: The present study seems to suggest that acne inflammation is mediated in part by hydrogen peroxide generation by neutrophils.

[Effects of administration of bifidobacteria on fecal microflora and clinical symptoms in infants with atopic dermatitis].

Fifteen children with atopic dermatitis who had Bifidobacterium-deficient microflora were selected for this study. Eight subjects in the bifidobacteria-administered group were given oral administration of lyophilized bifidobacteria (Bifidobacterium breve M-16V strain). The changes in fecal microflora and clinical symptoms were compared with the control group. In the bifidobacteria-administered group, the proportion of Bifidobacterium in the fecal microflora was increased (P=0.0173) and the proportion of aerobic bacteria was decreased (P=0.0499) after 1 month of administration. Furthermore, significant improvement of allergic symptoms (P=0.0176 in cutaneous symptom score, P=0.0117 in total allergic score) was also observed in the bifidobacteria-administered group. The tendency of allergic symptom improvement in the bifidobacteria-administered group was remarkable compared with the control group; however there was no correlation between changes in fecal microflora and allergic symptoms.