Shizuo Komune

Long Noncoding RNA HOTAIR Regulates Polycomb-Dependent Chromatin Modification and Is Associated with Poor Prognosis in Colorectal Cancers

The functional impact of recently discovered long noncoding RNAs (ncRNAs) in human cancer remains to be clarified. One long ncRNA which has attracted attention is the Hox transcript antisense intergenic RNA termed HOTAIR, a long ncRNA expressed from the developmental HOXC locus located on chromosome 12q13.13. In cooperation with Polycomb complex PRC2, the HOTAIR long ncRNA is reported to reprogram chromatin organization and promote breast cancer metastasis. In this study, we examined the status and function of HOTAIR in patients with stage IV colorectal cancer (CRC) who have liver metastases and a poor prognosis. HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and high HOTAIR expression correlated tightly with the presence of liver metastasis. Moreover, patients with high HOTAIR expression had a relatively poorer prognosis. In a subset of 32 CRC specimens, gene set enrichment analysis using cDNA array data revealed a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Our findings suggest that HOTAIR expression is associated with a genome-wide reprogramming of PRC2 function not only in breast cancer but also in CRC, where upregulation of this long ncRNA may be a critical element in metastatic progression.

Prevalence of mitochondrial gene mutations among hearing impaired patients

The frequency of three mitochondrial point mutations, 1555A→G, 3243A→G, and 7445A→G, known to be associated with hearing impairment, was examined using restriction fragment length polymorphism (RFLP) analysis in two Japanese groups: (1) 319 unrelated SNHL outpatients (including 21 with aminoglycoside antibiotic injection history), and (2) 140 cochlear implantation patients (including 22 with aminoglycoside induced hearing loss). Approximately 3% of the outpatients and 10% of the cochlear implantation patients had the 1555A→G mutation. The frequency was higher in the patients with a history of aminoglycoside injection (outpatient group 33%, cochlear implantation group 59%). One outpatient (0.314%) had the 3243A→G mutation, but no outpatients had the 7445A→G mutation and neither were found in the cochlear implantation group. The significance of the 1555A→G mutation, the most prevalent mitochondrial mutation found in this study of a hearing impaired population in Japan, among subjects with specific backgrounds, such as aminoglycoside induced hearing loss, is evident.

Clinical Significance of miR-146a in Gastric Cancer Cases

Purpose: The profiles of microRNAs change significantly in gastric cancer. MiR-146a is reported to be a tumor suppressor in pancreatic cancer, breast cancer, and prostate cancer. We investigated the clinical significance of miR-146a in gastric cancer, in particular focusing on hypothetical miR-146a target genes, such as epidermal growth factor receptor (EGFR) and interleukin-1 receptor-associated kinase (IRAK1). Experimental Design: We examined miR-146a levels in 90 gastric cancer samples by q-real-time (qRT)–PCR and analyzed the association between miR-146a levels and clinicopathologic factors and prognosis. The regulation of EGFR and IRAK1 by miR-146a was examined with miR-146a–transfected gastric cancer cells. Moreover, we analyzed the association between miR-146a levels and the G/C single nucleotide polymorphism (SNP) within pre-miR-146a seed sequences in 76 gastric cancer samples, using direct sequencing of genomic DNA. Results: In 90 clinical samples of gastric cancer, miR-146a levels in cancer tissues were significantly lower than those in the corresponding noncancerous tissue (P < 0.001). Lower levels of miR-146a were associated with lymph node metastasis and venous invasion (P < 0.05). Moreover, a lower level of miR-146a was an independent prognostic factor for overall survival (P = 0.003). Ectopic expression of miR-146a inhibited migration and invasion and downregulated EGFR and IRAK1 expression in gastric cancer cells. In addition, G/C SNP within the pre-miR-146a seed sequence significantly reduced miR-146a levels in the GG genotype compared with the CC genotype. Conclusions:MiR-146a contains an SNP, which is associated with mature miR-146a expression. MiR-146a targeting of EGFR and IRAK1 is an independent prognostic factor in gastric cancer cases. Clin Cancer Res; 17(13); 4277–84. ©2011 AACR.

Pathophysiology of the Ototoxicity of Cis-Diamminedichloroplatinum

The electrophysiologic and histopathologic changes in the inner ear caused by the administration of cis-diamminedichloroplatinum (CP) were studied in guinea pigs. The endocochlear dc potential (EP) gradually decreased after the intravenous injection of CP and reached approximately 0 mV on the fourth day, but the EP did not become negative. The cochlear microphonics also diminished and could not be recorded on the fourth day. The negative potential of the organ of Corti remained in the normal range during the experiment. A large negative summating potential (SP) was observed one day after injection, but the amplitude of the negative SP became small on the second day. Light microscopic examination demonstrated that the outer hair cells are destroyed in the basal turn of the cochlea and are preserved in the upper turns, while the inner hair cells are almost completely preserved in all turns. The stria vascularis was found to be slightly atrophic. Severe collapse of Reissners membrane was observed in the basal turn.

Calcium channel in isolated outer hair cells of guinea pig cochlea

The physiological and pharmacological properties of the Ca2+ channel in outer hair cells (OHCs) freshly isolated from guinea pig cochlea were investigated using a whole-cell patch-clamp technique. The Ca2+ current (ICa) was activated from a membrane potential of -20 mV and reached peak value around +20 mV in external solution containing 20 mM Ca2+ at a holding potential of -70 mV. The peak amplitude of ICa increased in a hyperbolic manner with increasing extracellular Ca2+ concentration. The ion selectively was Ba2+ much greater than Ca2+ greater than or equal to Sr2+. It was concluded that the Ca2+ channel in OHCs of guinea pig is of the L-type.

Anticardiolipin Antibody-Induced Sudden Profound Sensorineural Hearing Loss

INTRODUCTION A link between sensorineural hearing loss (SNHL) and autoimmune disease is postulated. The association of SNHL in a patient with systemic lupus erythematosus is reported. METHODS An adolescent female with left lateral medullary syndrome and right internuclear ophthalmoplegia was diagnosed with systemic lupus erythematosus. Treatment with prednisolone markedly improved her symptoms. Two years later, profound SNHL developed in the right ear. Extensive serologic testing was undertaken. RESULTS Serologic tests for syphilis were false-positive. Enzyme-linked immunosorbent assay to the immunoglobulin (Ig)G anticardiolipin antibody was positive. The anticardiolipin antibody is strongly correlated with episodes of recurrent venous or arterial thrombosis. CONCLUSIONS It appears that the anticardiolipin antibody may be associated with sudden profound sensorineural hearing loss in patients with autoimmune disease.

Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells

Purpose Recently, it has been reported that angiotensin-I converting enzyme (ACE) inhibitors have anticancer activity. In particular, the ACE inhibitor, perindopril, significantly inhibits tumor growth and angiogenesis in hepatocellular carcinoma cells along with suppression of the VEGF level. However, the mechanisms of suppression of the VEGF level are still unclear, and there are no previous reports on this subject related to head and neck squamous cell carcinoma (HNSCC). In some previous studies, angiotensin II, which is produced from angiotensin I by ACE, directly stimulates VEGF expression.Methods In the present study, we focused upon angiotensin II, and investigated the effect of perindopril on VEGF expression, angiogenesis, and tumor development of HNSCC with in vitro and in vivo studies.Results In the in vitro cell proliferation assays, there was no significant difference between the perindopril-treated group and the control group. However, the perindoprilat-treated group showed a significant reduction in mRNA expression of VEGF and inhibited the induction activity of the VEGF promoter in comparison to the control group. Perindoprilat treatment also significantly suppressed angiotensin II production in vitro. In the in vivo studies, perindopril had a significant inhibitory effect on tumor growth, and reduced blood vessel formation surrounding the tumors.Conclusions Our findings suggest that perindopril has no direct cytotoxicity against tumor cells, but has a potential to inhibit tumor growth due to suppression of VEGF-induced angiogenesis in vivo. Angiotensin II might have an important role in carcinogenesis, and the antiangiogenic activity of perindopril is at least partly mediated by angiotensin II inhibition. The ACE inhibitor perindopril has clinical potential as a useful antitumor agent.

Cisplatin blocks mechano-electric transducer current in chick cochlear hair cells

The effects of cisplatin (cis-dichlorodiammine platinum II, CDDP) on the mechano-electrical transduction (MET) current were investigated with a whole-cell patch-electrode voltage clamp technique in dissociated cochlear hair cells of chicks. CDDP blocked the MET channel in a dose- and voltage-dependent manner. At -50 mV, CDDP blocked the MET channel with a Hill coefficient of approximately 2 and a dissociation constant (KD) of 1.5 x 10(-3) M. The kinetics of CDDP blockade consist of a voltage-independent and a voltage-dependent component.

Lipopolysaccharide inhalation exacerbates allergic airway inflammation by activating mast cells and promoting Th2 responses

Background Bacterial infection occasionally exacerbates asthma, although the cellular and molecular mechanisms have not been well defined. An involvement of mast cells has been suggested, as lipopolysaccharides (LPS)‐induced cytokine production from mast cells in vitro.

Correlation between MRI Findings and Second-Look Operation in Cholesteatoma Surgery

Two-staged intact canal wall tympanoplasty is a common operation for treatment of middle ear cholesteatoma. MRI provides better tissue differentiation of the middle ear and/or mastoid, which often become occupied with soft density tissue after the first operation. If MRI was able to detect the presence of a recurrent or residual cholesteatoma with sufficient sensitivity and specificity, this may facilitate a decrease in the number of second-look procedures. This study compared MRI findings to surgical findings at second-look surgery and calculated the correlation rates between the two sets of findings. Thirty ears having undergone intact canal wall tympanoplasty for cholesteatoma at the initial operation were examined by MRI prior to the second look. Otoscopic findings of the tympanic membrane were nonsuspect in all cases. The true positive rate was 11/30 (37%) and the true negative rate was 10/30 (33%), leading to a radiosurgical correlation of 70%, whereas the false positive rate was 6/30 (20%) and the false negative rate was 3/30 (10%). This indicates that 30% of the MRI findings were incorrect. Therefore, at the present time, MRI does not appear as a likely replacement for second-look surgery in cases of intact canal wall tympanoplasty.