Kunihiko Terauchi

Cancer-associated loss of TARSH gene expression in human primary lung cancer

Purpose: We have previously identified mouse Tarsh as one of the cellular senescence-related genes and showed the loss of expression of TARSH mRNA in four human lung cancer cell lines. TARSH is a presumptive signal transduction molecule interacting with NESH, which is implicated to have some roles in lung cancer metastasis. Methods: The amplification of complete ORF-encoding TARSH cDNA was done with reverse transcription-PCR. Northern blotting was carried out using TARSH cDNA probes. To clarify the relationship between TARSH and lung cancer, we quantified TARSH mRNA expression in 15 human lung cancer cell lines and 32 primary non-small cell lung cancers. Results: We first determined the complete ORF-encoding cDNA sequence which is expressed in the human lung. On the Northern hybridization analysis, TARSH was strongly expressed in the human lung. The expression of TARSH mRNA is remarkably downregulated in all the lung cancer cell lines examined. Furthermore, TARSH expression was significantly low in all of the tumor specimens when compared to the expression in corresponding non-neoplastic lung tissue specimens. Conclusion: The cancer-associated transcriptional inactivation of TARSH suggests that TARSH could be used as a biomarker for lung cancer development as well as a molecular adjunct for lung carcinogenesis in human.

Implication of p53-dependent cellular senescence related gene, TARSH in tumor suppression

A novel target of NESH-SH3 (TARSH) was identified as a cellular senescence related gene in mouse embryonic fibroblasts (MEFs) replicative senescence, the expression of which has been suppressed in primary clinical lung cancer specimens. However, the molecular mechanism underlying the regulation of TARSH involved in pulmonary tumorigenesis remains unclear. Here we demonstrate that the reduction of TARSH gene expression by short hairpin RNA (shRNA) system robustly inhibited the MEFs proliferation with increase in senescence-associated beta-galactosidase (SA-beta-gal) activity. Using p53-/- MEFs, we further suggest that this growth arrest by loss of TARSH is evoked by p53-dependent p21(Cip1) accumulation. Moreover, we also reveal that TARSH reduction induces multicentrosome in MEFs, which is linked in chromosome instability and tumor development. These results suggest that TARSH plays an important role in proliferation of replicative senescence and may serve as a trigger of tumor development.

Drug resistance to paclitaxel is not only associated with ABCB1 mRNA expression but also with drug accumulation in intracellular compartments in human lung cancer cell lines.

In order to clarify the mechanisms of resistance to paclitaxel in lung cancer, three human lung cancer cell lines which exhibit different sensitivity to paclitaxel were investigated from the following viewpoints: overexpression of ATP-binding cassette, sub-family B, member 1 (ABCB1), mutations on paclitaxel binding site of β-tubulin genes, quantity of polymerized tubulin and the intracellular localization of paclitaxel. ABCB1 expression was evaluated by real-time RT-PCR. No correlations were noted between the ABCB1 expression in the sensitive and resistant cell lines at the mRNA level. No mutations on the paclitaxel binding site of the β-tubulin genes were detected in either the resistant or sensitive cells. Live cell images obtained by confocal laser microscopy revealed that the resistant cell line, RERF-LC-KJ, had more accumulation of Oregon Green® 488 conjugated paclitaxel in the lysosomal and extra-lysosomal compartments of cytoplasm than other cell lines. The results obtained in this study indicated that the changes in the subcellular localization could contribute to the production of paclitaxel resistance in lung cancer cell lines. Further studies should be conducted to elucidate the molecular mechanisms that differentiate the intracellular localization of paclitaxel.

Lung metastasis of thymoma manifesting as myasthenia gravis 12 years after thymomectomy: report of a case.

A 51-year-old woman, who had undergone thymomectomy for asymptomatic noninvasive thymoma 12 years before, was admitted to our hospital with blepharoptosis caused by myasthenia gravis. A chest computed tomogram (CT) showed an abnormal shadow in the right lower lung field and CT-guided needle biopsy revealed findings of a thymoma. We performed extended thymectomy and partial resection of the right lung using three different approaches, via a cervical incision and bilateral video-assisted thoracoscopic surgery. The resected specimen was a lung metastasis of thymoma, and the residual mediastinal tissue showed no sign of malignancy. Because thymoma and post-thymomectomy myasthenia gravis can both recur, we recommend performing extended thymectomy or thymothymectomy, even for patients who are asymptomatic.

Improvements in thoracic surgery outcomes: a multi-institutional collaboration study.

BackgroundTreatment protocols (including those for thoracic surgery) tend to be customized for individual hospitals. Procedural standardization is required to improve surgical tasks and patient outcomes. This study aimed to evaluate the effects of an initiative to standardize surgical tasks for efficient and safe performance.MethodsHospitals associated with the Division of Chest Surgery of the Kyoto Prefectural University of Medicine held joint meetings involving their thoracic surgeons and operating room nurses between February 2011 and November 2012 to standardize surgical tasks. Operation times and blood loss were compared before and after standardization.ResultsThe implementation rate of standardized surgical tasks was 97%. The pre-operative (from entry to the operating room until commencement of surgery) and post-operative (from conclusion of surgery until departure from the operating room) times were significantly decreased after the standardization. When compared according to operative group (all thoracic surgery, lung lobectomy, and partial lung resection), operation times were shorter for all three groups; in addition, the amount of blood loss was lower in all three groups after standardization. A post-standardization survey showed improved morale among the meeting participants.ConclusionsInterdisciplinary standardization of surgical tasks across institutions improved thoracic surgery tasks and surgical outcomes.

Extrapericardial Pulmonary Vein Clamp Technique for Pulmonary Arteriovenous Fistula: Report of a Case

The major concern when operating on a patient with a neurologically symptomatic pulmonary arteriovenous fistula (PAVF) is how to prevent a thromboembolic event during surgery. We describe a new technique whereby the extrapericardial pulmonary vein is clamped before transecting the afferent and efferent vessels of the fistula. The potentially pooled clots that can form while manipulating lung are stopped by the clamp. Before the extrapericardial pulmonary vein is declamped, one of the drainage veins is incised halfway and the pooled blood containing the potential clots is completely washed out. We successfully performed segmentectomy using this technique in a 66-year-old man with chronic left hemianopia and a large PAVF in the left anteromedial and lateral basal segments, and no thromboembolic events occurred.