Ching Tzao

Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression

CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resistant to radiotherapy. Herein, we demonstrated that glioblastoma-derived CD133-positive cells (GBM-CD133(+)) are capable of self-renewal and express high levels of embryonic stem cell genes and SirT1 compared to GBM-CD133(-) cells. To evaluate the role of SirT1 in GBM-CD133(+), we used a lentiviral vector expressing shRNA to knock-down SirT1 expression (sh-SirT1) in GBM-CD133(+). Silencing of SirT1 significantly enhanced the sensitivity of GBM-CD133(+) to radiation and increased the level of radiation-mediated apoptosis. Importantly, knock-down of SirT1 increased the effectiveness of radiotherapy in the inhibition of tumor growth in nude mice transplanted with GBM-CD133(+). Kaplan-Meier survival analysis indicated that the mean survival rate of GBM-CD133(+) mice treated with radiotherapy was significantly improved by Sh-SirT1 as well. In sum, these results suggest that SirT1 is a potential target for increasing the sensitivity of GBM and glioblastoma-associated cancer stem cells to radiotherapy.

Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer.

Purpose: Lung cancer cells frequently exhibit marked chromosome instability. We postulated that alterations of the double-strand break repair genes (BRCA1, BRCA2, and XRCC5) might be involved in lung cancer. Patients and Methods: We examined the loss of protein and mRNA expression and the 5′CpG hypermethylation and allelic imbalance of the BRCA1, BRCA2, and XRCC5 genes in 98 non–small cell lung cancer (NSCLC) samples. Anchorage-dependent growth after reexpression of these genes was examined in a lung cancer cell line that originally lacked BRCA1 and BRCA2 expression. Results: The data indicated that low protein expression of BRCA1 and BRCA2 was frequent in lung adenocarcinomas (42-44%), whereas low XRCC5 protein expression was more prevalent among squamous cell carcinoma (32%). In addition, low BRCA1 expression was significantly associated with low RB expression, especially in lung adenocarcinoma. Concurrent alterations in XRCC5 and p53 were the most frequent profiles in smoking patients. Importantly, low mRNA and protein expressions of BRCA1, BRCA2, and XRCC5 were significantly associated with their promoter hypermethylation. 5-Aza-2′-deoxycytidine treatment of NSCLC cells showed demethylation and reexpression of the BRCA1 and BRCA2 genes and reduced anchorage-independent growth. Conclusions: Our retrospective study provides compelling evidence that low mRNA and protein expression in the BRCA1/BRCA2 and XRCC5 genes occur in lung adenocarcinoma and squamous cell carcinoma, respectively, and that promoter hypermethylation is the predominant mechanism in deregulation of these genes. Alteration of the double-strand break repair pathway, perhaps by interacting with p53 and RB deregulation, is important in the pathogenesis of a subset of NSCLC.

Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus

Patterns of global histone modifications have been recently suggested as outcome predictors in cancer patients. To date, there has been no report on the prognostic significance of global histone modifications in esophageal squamous cell carcinoma. We investigated the role of global histone modification as outcome predictor in patients undergoing esophagectomy for esophageal squamous cell carcinoma. A retrospective clinicopathologic analysis was undertaken of 97 patients with esophageal squamous cell carcinoma who recovered from esophagectomy. Immunohistochemical expression of five histone modification markers, acetylated histone 3 lysine 18 (H3K18Ac), acetylated histone 4 lysine 12 (H4K12Ac), dimethylated histone 4 arginine 3 (H4R3diMe), dimethylated histone 3 lysine 4 (H3 K4diMe), and trimethylated histone 3 lysine 27 (H3K27triMe) was assessed in paraffin-embedded tumor samples. Results were analyzed in relation to patients’ clinicopathologic parameters. There was a positive relationship between tumor differentiation and H3K18Ac (P<0.001), H4R3diMe (P=0.003), and H3K27triMe (P<0.001). Expression of H3K27triMe correlated positively with nodal (N) status (P=0.012) and stage (P=0.025). Univariate analysis showed that better survival in patients with low expression of H3K18Ac (P=0.038) and H3K27triMe (P=0.003). Multivariate analysis showed that nodal status, metastasis status (M), and expression of H3K27triMe predicted survival independently (P<0.001, P=0.016, and 0.048, respectively). Low expression of H3K18Ac and H3K27triMe correlated with better prognosis of patients with esophageal squamous cell carcinoma, especially for those of early stages. We hypothesize that expression of H3K27triMe may be considered as a significant survival predictor for patients with esophageal squamous cell carcinoma.

Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer‐derived CD133‐positive cells

Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin‐1 (CD133)‐positive lung cancer cells.

Induction Chemoradiation Is Not Superior to Induction Chemotherapy Alone in Stage IIIA Lung Cancer

BACKGROUND The optimal treatment strategy for patients with operable stage IIIA (N2) non-small cell lung cancer is uncertain. We performed a systematic review and meta-analysis to test the hypothesis that the addition of radiotherapy to induction chemotherapy prior to surgical resection does not improve survival compared with induction chemotherapy alone. METHODS A comprehensive search of PubMed for relevant studies comparing patients with stage IIIA (N2) non-small cell lung cancer undergoing resection after treatment with induction chemotherapy alone or induction chemoradiotherapy was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. Hazard ratios were extracted from these studies to give pooled estimates of the effect of induction therapy on overall survival. RESULTS There were 7 studies that met criteria for analysis, including 1 randomized control trial, 1 phase II study, 3 retrospective reviews, and 2 published abstracts of randomized controlled trials. None of the studies demonstrated a survival benefit to adding induction radiation to induction chemotherapy versus induction chemotherapy alone. The meta-analysis performed on randomized studies (n=156 patients) demonstrated no benefit in survival from adding radiation (hazard ratio 0.93, 95% confidence interval 0.54 to 1.62, p=0.81), nor did the meta-analysis performed on retrospective studies (n=183 patients, hazard ratio 0.77, 95% confidence interval 0.50 to 1.19, p=0.24). CONCLUSIONS Published evidence is sparse but does not support the use of radiation therapy in induction regimens for stage IIIA (N2). Given the potential disadvantages of adding radiation preoperatively, clinicians should consider using this treatment strategy only in the context of a clinical trial to allow better assessment of its effectiveness.

Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs

The nitric oxide (NO)‐guanosine 3′,5′‐cyclic monophosphate (cGMP) signaling pathway plays an important role in the pulmonary vascular transition at birth. We studied pulmonary arteries and veins isolated from normal late‐gestation fetal lambs and from fetal lambs with persistent pulmonary hypertension (PPHN) following prenatal ligation of the ductus arteriosus. We additionally used double immunolabeling and immunoblot analysis to determine relative vascular contents of endothelial nitric oxide synthase (NOS‐III) and soluble guanylate cyclase (sGC).

The impact of smoking in primary spontaneous pneumothorax.

BACKGROUND The crucial role of cigarette smoking in the development of pneumothorax is unclear because nonsmokers can also develop primary spontaneous pneumothorax. The purpose of this study was to clarify the pathophysiologic effects of cigarette smoking and its clinical correlations in primary spontaneous pneumothorax. METHODS Included were 115 specimens of lung tissue from patients with primary spontaneous pneumothorax who underwent video-assisted thoracoscopic surgery from January 2001 to December 2002. We reviewed the clinical features of 56 smokers and 59 nonsmokers with an average follow-up of 67 months. The pathologic findings of resected lung specimens were analyzed retrospectively. RESULTS There were no statistical differences in sex, age, body height, body weight, body mass index, or the presence of blebs/bullae on computed tomography scans of the lung or under thoracoscopy between the 2 groups. In the smoking group, patients had more extensive respiratory bronchiolitis (P < .001), a high prevalence of tobacco pigmentation (P < .001), and a higher recurrence rate without or after surgery than the nonsmoking group (57% vs 22%, P = .001 and 8.9% vs 1.7%, P = .02, respectively). Patients with extensive respiratory bronchiolitis had significantly higher nonoperative and postoperative recurrences than patients with nonextensive respiratory bronchiolitis (P = .004 and P < .001, respectively). CONCLUSION Cigarette smoking is associated with the pathophysiologic consequences of extensive respiratory bronchiolitis, which had a significant impact on the recurrence rates of primary spontaneous pneumothorax.

Gastrointestinal stromal tumor (GIST) of the esophagus detected by positron emission tomography/computed tomography

Although rare elsewhere in the gastrointestinal tract, leiomyoma (LM) is the most common esophageal mesenchymal neoplasm. As a comparison, gastrointestinal stromal tumor (GIST) predominates in the stomach and intestines, but esophageal GIST has been reported less frequently. In contrast to other esophageal mesenchymal tumors, GIST is typically immunoreactive for KIT protein (CD117) in more than 95% of cases and is frequently coexpressed with CD34 (60 to 70%) (1, 2). Mutation of the c-kit proto-oncogene is associated with increasing risk for malignant transformation (3). Positron emission tomography (PET) has recently been employed to monitor progression of GIST from gastrointestinal tracts other than the esophagus (4–6) but its role in the diagnosis of GIST remains unclear. Herein we present a case of GIST of the esophagus confirmed by immunohistochemical stain. Conventional radiological studies including barium meal and computed tomography (CT) were unable to differentiate reliably LM or leiomyosarama (LMS) from GIST of the esophagus. Fused PET/CT was performed in this patient and provided additional information preoperatively in terms of its metabolic activity and the likelihood of a submucosal tumor other than LM.

Cortactin, fascin, and survivin expression associated with clinicopathological parameters in esophageal squamous cell carcinoma

Cortactin, fascin, and survivin have been documented in several human cancers and play important roles in tumor progression. We collected 57 surgical specimens, including esophageal squamous cell carcinomas (SqCC; 7 well-differentiated, 15 moderately differentiated, and 24 poorly differentiated), 3 dysplasias, and 8 normal esophageal tissues. Tissue microarrays were constructed and the immunostaining scores for cortactin, fascin, and survivin were assessed. In 46 SqCC specimens, we examined the relationship between the expression of three biomarkers and tumor differentiation or clinical parameters. Higher immunostaining scores for cortactin, fascin, and survivin correlated positively with tumor differentiation of esophageal SqCC. Univariate survival analysis showed significantly worse prognosis in patients with high scores of cortactin (>or=290), fascin (>or=245), and survivin (score >or= 175), poor differentiation, T4 stage, positive for lymph node metastasis, and positive for distant metastasis. In multivariate survival analysis, high scores of survivin (>or=175) and poor differentiation were independent risk factors for worse prognosis. Our results demonstrated that higher expression of survivin may be related to tumor progression and it is an independent risk factor for poor survival time of esophageal SqCC. Survivin may be a good biomarker to be applied in clinic to predict the prognosis of esophageal SqCC.

Simultaneous bilateral primary spontaneous pneumothorax

Objective:  While primary spontaneous pneumothorax (PSP) is common in adolescents and young adults, simultaneous bilateral PSP (SBPSP) is rare and can be life‐threatening if it progresses to tension pneumothorax. This study reviewed cases of PSP to identify the clinical features of SBPSP.