The sirtuin family in health and disease.

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

Alterations in hormonal receptor expression and HER2 status between primary breast tumors and paired nodal metastases: discordance rates and prognosis.

BACKGROUND: We aimed to evaluate the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression discordance in matched pairs of primary breast cancer and lymph node metastasis specimens and determine the effect of discordance on prognosis. MATERIALS AND METHODS: Among all patients diagnosed with lymph node metastases from 2004 to 2007, primary tumors and paired lymph node metastases were resected from 209 patients. The status of ER, PR, and HER2 expression was analyzed immunohistochemically in 200, 194, and 193 patients, respectively. Discordance was correlated with prognosis. RESULTS: Biomarker discordance between primary tumors and paired lymph node metastases was 25.0% (50/200) for ER status, 28.9% (56/194) for PR status, and 14.0% (27/193) for HER2 status. ER positivity was a significant independent predictor of improved survival when analyzed in primary tumors and lymph node metastases. Patients with PR-positive primary tumors and paired lymph node metastases displayed significantly enhanced survival compared to patients with PR-positive primary tumors and PR-negative lymph node metastases. Patients with ER- and PR-positive primary tumors and paired lymph node metastases who received endocrine therapy after surgery displayed significantly better survival than those not receiving endocrine therapy. Similalry treated patients with PR-negative primary tumors and PR-positive paired lymph node metastases also displayed better survival than those not receiving endocrine therapy. CONCLUSIONS: Biomarker discordance was observed in matched pairs of primary tumors and lymph node metastases. Such cases displayed poor survival. Thus, it is important to reassess receptor biomarkers used for lymph node metastases.

Serum soluble ST2 is associated with ER-positive breast cancer.

BACKGROUND: ST2, a member of the interleukin (IL)-1receptor family, regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions. However, the role of ST2 signaling in tumor growth and metastasis of breast cancers has not been investigated. This study investigated the possible role of soluble ST2 (sST2) in breast cancer. METHODS: The serum levels of IL-33, sST2, and vascular endothelial growth factor (VEGF) in 150 breast cancer patients and 90 healthy women were measured by enzyme-linked immunosorbent assay. Estrogen receptor(ER), progesterone receptor, human epithelial receptor (HER)-2, and cell cycle regulated protein Ki-67 were measured. Clinical stage, tumor size, lymph node metastasis, and histological type were also recorded. RESULTS: The serum levels of sST2, IL-33, and VEGF were significantly higher in breast cancer patients than in the control group (P < 0.05, each). Serum sST2 levels in ER-positive breast cancer patients were significantly associated with age, histological type, clinical stage, tumor size, and Ki-67 status (P < 0.05, each). Moreover, the serum levels of IL-33 and sST2 in breast cancers significantly correlated with VEGF levels (IL-33: r = 0.375, P < 0.0001; sST2: r = 0.164, P = 0.045). Serum levels of sST2, IL-33, and VEGF decreased after modified radical mastectomy in ER-positive breast cancers. Serum levels of IL-33, sST2, and VEGF and clinicopathological factors were not significantly correlated with disease-free survival and overall survival of ER-positive breast cancer women during follow-up. CONCLUSION: Serum sST2 levels in ER-positive breast cancer patients are significantly associated with factors that indicate poor prognosis.

[Prognostic value of metastatic lymph node ratio in gastric cancer].

OBJECTIVES: To evaluate the value of the metastatic to examined lymph nodes (rN) ratio in gastric cancer patients who underwent radical resection. METHODS: In this retrospective study, data were collected from the medical records of 710 patients who underwent radical gastrectomy (R0) for gastric cancer from 1980 to 2006 in the Department of Surgical Oncology at the First Affiliated Hospital of China Medical University. The patients were divided into 2 groups according to the number of examined lymph nodes: Group 1 consisted of 327 patients with <15 examined lymph nodes and Group 2 consisted of 383 patients with ≥15 lymph nodes. rN categories staging and pN categories were divided separately according to the metastatic lymph node ratio and the examined lymph nodes. The prognostic factors were analyzed by univariate (Log-rank) and multivariate (Cox model) analysis methods. RESULTS: The median survival time was 74 months (95% CI:55.6-92.4 months) in Group 1 and 96 months (95% CI:77.8-119.2 months) in Group 2, and the difference was not statistically significant (P>0.05). On multivariate analysis, the N ratio remained as an independent prognostic factor in both Group 1 (P<0.01, RR=1.225, 95% CI:1.102-1.362) and Group 2 (P<0.01, RR=1.421, 95% CI:1.269-1.592). However, pN stage was an independent prognostic factor only in Group 1. When the rN ratio classification was applied, there were no significant differences between each categories (P>0.05). However, the overall survival of patients with pN1 disease in Group 1 was significantly shorter than that in Group 2 according to the pN stage classification (P<0.01). CONCLUSIONS: The metastatic lymph node ratio is an independent prognostic factor of the prognosis of gastric cancer. The staging system based on metastatic lymph node ratio (rN) is more reliable than the system based on the number of metastatic lymph nodes in the prediction of the prognosis of gastric cancer.

Log-normal censored regression model detecting prognostic factors in gastric cancer: a study of 3018 cases.

AIM: To investigate the efficiency of Cox proportional hazard model in detecting prognostic factors for gastric cancer. METHODS: We used the log-normal regression model to evaluate prognostic factors in gastric cancer and compared it with the Cox model. Three thousand and eighteen gastric cancer patients who received a gastrectomy between 1980 and 2004 were retrospectively evaluated. Clinic-pathological factors were included in a log-normal model as well as Cox model. The akaike information criterion (AIC) was employed to compare the efficiency of both models. Univariate analysis indicated that age at diagnosis, past history, cancer location, distant metastasis status, surgical curative degree, combined other organ resection, Borrmann type, Lauren's classification, pT stage, total dissected nodes and pN stage were prognostic factors in both log-normal and Cox models. RESULTS: In the final multivariate model, age at diagnosis, past history, surgical curative degree, Borrmann type, Lauren's classification, pT stage, and pN stage were significant prognostic factors in both log-normal and Cox models. However, cancer location, distant metastasis status, and histology types were found to be significant prognostic factors in log-normal results alone. According to AIC, the log-normal model performed better than the Cox proportional hazard model (AIC value: 2534.72 vs 1693.56). CONCLUSION: It is suggested that the log-normal regression model can be a useful statistical model to evaluate prognostic factors instead of the Cox proportional hazard model.

Clinical implications of stem cell gene Oct-4 expression in breast cancer.

PURPOSE: To explore the expression of stem cell genes in breast cancer and the relationship between stem cell gene expression and clinical and pathological characteristics and prognosis of breast cancer. BACKGROUND: By now, stem cell differentiation-related genes and the relationship between the genes and clinic-pathological characteristics and prognosis of breast cancer are still unclear. MATERIALS AND METHODS: CD44+/CD24- tumor cells were selected by Flow cytometry. The differential expression of genes between CD44+/CD24- tumor cells and non-CD44+/CD24- tumor cells were detected by RT(2) Profiler™ PCR Array. The expression of stem cell gene Octamer-4 (Oct-4) was analyzed by immunohistochemistry staining and the relationship between Oct-4 and clinicopathological parameters of breast cancer was determined. RESULTS: Seven different genes including stem cell differentiation-related factors (CD44, Oct-4, and nestin), cell cycle regulators (APC and CDC2), and growth factors (HGF and TGF) were detected as significantly differently expressed between CD44+/CD24- tumor cells and non-CD44+/CD24- tumor cells. Oct-4 protein expressed significantly higher in cancerous tissues than adjacent-tumor tissues (P = 0.001). Moreover, we observed that the expression of Oct-4 protein was related to histological type, lymph node status and molecular type of breast cancer (P = 0.001, 0.006, and 0.001, respectively). After survival analysis, the cases with highly expressed Oct-4 protein attained a significantly poorer postoperative disease-specific survival than those with none/low expressed Oct-4 protein (P = 0.001). In the Cox regression test, tumor size, histological type, disease stage, lymph node metastasis, Her-2 and Oct-4 were detected as the independent prognostic factors (P = 0.031, 0.012, 0.001, 0.002, 0.030, and 0.003, respectively). CONCLUSIONS: Oct-4 was highly expressed in CD44+/CD24- tumor cells, and may be a potential biomarker for the initiation, progression, and differentiation of breast cancer.

Predictive factors for lymph node metastasis in poorly differentiated early gastric cancer and their impact on the surgical strategy.

AIM: To identify the predictive clinicopathological factors for lymph node metastasis (LNM) in poorly differentiated early gastric cancer (EGC) and to further expand the possibility of using endoscopic mucosal resection (EMR) for the treatment of poorly differentiated EGC. METHODS: Data were collected from 85 poorly-differentiated EGC patients who were surgically treated. Association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. RESULTS: Univariate analysis showed that tumor size (OR= 5.814, 95% CI = 1.050 - 32.172, P = 0.044), depth of invasion (OR=10.763, 95% CI=1.259 - 92.026, P = 0.030) and lymphatic vessel involvement (OR= 61.697, 95% CI= 2.144 - 175.485, P = 0.007) were the significant and independent risk factors for LNM. The LNM rate was 5.4%, 42.9% and 50%, respectively, in poorly differentiated EGC patients with one, two and three of the risk factors, respectively. No LNM was found in 25 patients without the three risk factors. Forty-four lymph nodes were found to have metastasis, 29 (65.9%) and 15 (34.1%) of the lymph nodes involved were within N1 and beyond N1, respectively, in 12 patients with LNM. CONCLUSION: Endoscopic mucosal resection alone may be sufficient to treat poorly differentiated intramucosal EGC (< or = 2.0 cm in diameter) with no histologically-confirmed lymphatic vessel involvement. When lymphatic vessels are involved, lymph node dissection beyond limited (D1) dissection or D1+ lymph node dissection should be performed depending on the tumor location.

[Rational approach to the management of IV stage gastric carcinoma with hepatic metastasis].

OBJECTIVE: To investigate the benefit of surgical resection on the prognosis of patients with advanced gastric carcinoma and liver metastasis. METHODS: Data of 102 cases of advanced gastric carcinoma with liver metastases from 1993 to 2004 were studied retrospectively. RESULTS: The half-, one- and two-year postoperative survival rates of gastric carcinoma patients with H(1) metastasis undergone palliative resections were 69%, 44% and 6% respectively, which were significantly better than those of patients not undergone resection(accepted by-pass procedure or exploratory laparotomy) (P=0.009). The half-, one- and two-year postoperative survival rates of gastric carcinoma patients with H(2) metastasis undergone palliative resections were 56%,13% and 6% respectively, which were not significantly different compared with those of patients not undergone resection(P=0.068). The half-, one- and two-year postoperative survival rates of gastric carcinoma patients with H(3) metastasis undergone palliative resections were 25%, 13% and 0, which were not significantly different compared with those of cases not undergone resection (P=0.157). Regardless of peritoneal metastases, there were no significant differences between the survival rate of resection group and that of non-resection group. CONCLUSIONS: Gastric carcinoma patients with H(1) metastasis would benefit from palliative resection regardless of peritoneal metastasis. Gastric carcinoma patients with H(2) or H(3) metastasis are not benefit from surgical resection.

Distribution of solitary lymph nodes in primary gastric cancer: a retrospective study and clinical implications.

AIM: To investigate the distribution pathway of metastatic lymph nodes in gastric carcinoma as a foundation for rational lymphadenectomy. METHODS: We investigated 173 cases with solitary or single station metastatic lymph nodes (LN) from among 2476 gastric carcinoma patients. The location of metastatic LN, histological type and growth patterns were analyzed retrospectively. RESULTS: Of 88 solitary node metastases cases, 65 were limited to perigastric nodes (N(1)), while 23 showed skipping metastasis. Among 8 tumors in the upper third stomach, 3 involved right paracardial LN (station number: No.1), and one in the greater curvature was found in No.1. In the 28 middle third stomach tumors, 10 were found in LN of the lesser curvature (No.3) and 6 in LN of the left gastric artery (No.7); 5 of the 20 cases on the lesser curvature spread to No.7, while 2 of the 8 on the greater curvature metastasized to LN of the spleen hilum (No.10). Of 52 lower third stomach tumors, 13 involved in No.3 and 19 were detected in inferior pyloric LN (No.6); 9 of the 29 cases along the lesser curvature were involved in No.6. CONCLUSION: Transversal and skipping metastases of sentinel lymph nodes (SLN) are notable, and rational lymphadenectomy should, therefore, be performed.