Guo-Qing Tao

Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor‐κB as well as activation of c‐Jun N‐terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl‐2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects.

Trinucleotide repeat containing 9 (TNRC9) is a gene located at chromosome 16q12. Although of an uncertain function, it is a newly described risk factor for breast cancer. It contains a putative high-mobility group box motif, suggesting its possible role as transcription factor; it has been implicated in breast cancer metastasis. Published studies on the association between TNRC9 polymorphisms and breast cancer risk remain inconclusive, and a meta-analysis is required to verify the association. This pioneering research performed a meta-analysis of eight studies comprising a total of 25,828 cases and 36,177 controls. Significantly elevated breast cancer risk was associated with TNRC9 rs3803662 polymorphism when all studies were pooled in the meta-analysis (T vs. C allele contrast model: OR 1.18, 95% CI 1.09–1.28; TT vs. CC homozygote codominant model: OR 1.26, 95% CI 1.02–1.55; TT vs. CC+CT recessive model: OR 1.23, 95% CI 1.06–1.42). For TNRC9 rs12443621 polymorphism, no significant association was detected in all genetic models. For TNRC9 rs12443621 polymorphism, meanwhile, no significant association was observed in all comparison models. Conclusively, this meta-analysis suggests that TNRC9 rs3803662 polymorphism was significantly correlated with breast cancer risk and the variant T allele of TNRC9 rs3803662 polymorphism is a low-penetrant risk factor for developing breast cancer. There is no significant association between TNRC9 rs12443621 and rs8051542 polymorphisms and risk of breast cancer in current literature.

Association between mitogen-activated protein kinase kinase kinase 1 rs889312 polymorphism and breast cancer risk: evidence from 59,977 subjects

Published data on the association between mitogen-activated protein kinase kinase kinase 1 (MAP3K1) gene rs889312 polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of seven eligible articles including 26,015 cases and 33,962 controls based on the search criteria were involved in this meta-analysis. We observed that the MAP3K1 rs889312 polymorphism was significantly correlated with breast cancer risk from the fixed effects model when all studies were pooled into the meta-analysis (the allele contrast model: OR 1.09, 95% CI 1.07–1.12; the homozygote codominant: OR 1.22, 95% CI 1.15–1.29; the heterozygote codominant: OR 1.07, 95% CI 1.04–1.11; the dominant model: OR 1.10, 95% CI 1.06–1.13; the recessive model: OR 1.18, 95% CI 1.12–1.25). No significant association was found in the BRCA1 mutation carriers in all genetic models. When stratified by BRCA2 mutation carriers status, statistically significantly elevated risk was found in this meta-analysis (C vs. A: OR 1.12, 95% CI 1.01–1.23; CC vs. AA: OR 1.35, 95% CI 1.06–1.71; the recessive model: OR 1.31, 95% CI 1.05–1.65). There was no evidence for significant association between MAP3K1 rs889312 polymorphism and breast cancer risk in BRCA1 and BRCA2 positive cohort for all comparison models. In conclusion, this meta-analysis suggests that the MAP3K1 rs889312 C allele is a low-penetrant risk factor for developing breast cancer, and there is limited evidence to indicate that MAP3K1 rs889312 polymorphism is associated with increased risk of breast cancer in BRCA1 mutation carriers.

SRPK2 promotes the growth and migration of the colon cancer cells.

Colon cancer is one of the major causes of cancer-related death in the world. Understanding the molecular mechanism underlying this malignancy will facilitate the diagnosis and treatment. Serine-arginine protein kinase 2 (SRPK2) has been reported to be upregulated in several cancer types. However, its expression and functions in colon cancer remains unknown. In this study, it was found that the expression of SRPK2 was up-regulated in the clinical colon cancer samples. Overexpression of SRPK2 promoted the growth and migration of colon cancer cells, while knocking down the expression of SRPK2 inhibited the growth, migration and tumorigenecity of colon cancer cells. Molecular mechanism studies revealed that SRPK2 activated ERK signaling in colon cancer cells. Taken together, our study demonstrated the tumor promoting roles of SRPK2 in colon cancer cells and SRPK2 might be a promising therapeutic target for colon cancer.

Same data sources, different pooled analysis result: the ongoing uncertainty in the subgroup analysis of RAD51 135G/C polymorphism and breast cancer risk

We read with great interest the recent meta-analysis by Sun et al. [1], which had reached an important conclusion that the RAD51 135G/C polymorphism was a low-penetrant risk factor for developing breast cancer. Nevertheless, this meta-analysis based on currently available evidence was similar to the researches by Zhou et al. [2] and Gao et al. [3] and was aimed to derive a more precise assessment of the relationship, but these independent articles brought a new conflicting result in the subgroup analysis by Asian populations. Sun et al. [1] demonstrated that statistically significantly decreased risk was found in Asians (additive model: OR 0.977, 95% CI 0.954–1.000; dominant model: OR 0.981, 95% CI 0.963–1.000). Zhou et al. [2] found that there was no significant association in Asian populations (additive model: OR 1.37, 95% CI 0.75–2.52; dominant model: OR 1.02, 95% CI 0.84–1.25; recessive model: OR 1.41, 95% CI 0.77–2.59). And Gao et al. [3] also demonstrated that no significantly elevated risk was observed in Asian populations (additive model: OR 1.37, 95% CI 0.75–2.52; CC vs. CG: OR 1.59, 95% CI 0.84–3.01, dominant model: OR 1.02, 95% CI 0.84–1.25; recessive model: OR 1.41, 95% CI 0.77–2.59). As the searched publications were the same [4–6], the different meta-analysis result needed to be interpreted with caution. First, the Asian populations were relatively small, these meta-analyses were not having enough statistical power to explore the real association in the subgroup analyses according to specific ethnicity of RAD51 135G/C polymorphism and breast cancer risk. Second, additive model suggested CC versus GG in Zhou and Gao’s articles [2, 3], but it represented GG versus CC in Sun’s article [1]. The dominant model and the recessive model were in the same situation. Thus, that was not the cause for different meta-analysis result. The 95% confidence interval range was 0.954–1.000 in the additive model and 0.963–1.000 in the dominant model in Sun’s article [1]. Authors should explain the critical value of 1.000 in the additive and dominant models with caution. Obviously, there was no evidence to indicate that the RAD51 135G/C polymorphism was associated with breast cancer risk in Asian populations under the present conditions. Despite the above, the results reported by Sun et al. [1] confirm the main results compared with other meta-analyses [2, 3, 7, 8]. And further studies on Asian populations are needed so as to validate the present results in larger sets of case–control studies.

No significant association results obtained from significant association evidence: the ongoing uncertainty of TP53 codon 72 polymorphism and breast cancer risk

1.063, 95% CI 0.967–1.169; Arg/Arg vs. Pro/Pro: OR 1.245, 95% CI 0.997–1.554; dominant model: OR 1.146, 95% CI 0.979–1.340; recessive model: OR 1.179, 95% CI 1.020–1.362). Actually, the odds ratio of 1.179 and 95% confidence interval for odds ratio of 1.020–1.362 in recessive model demonstrated some evidence of association between TP53 codon 72 polymorphism and breast cancer risk. Similarly, Ma et al. [1] demonstrated that no significant association was observed for any of the genetic models in the stratified analysis by source of controls (Pro/Arg vs. Pro/Pro: OR 1.075, 95% CI 0.974–1.187; Arg/Arg vs. Pro/ Pro: OR 1.283, 95% CI 1.036–1.588; dominant model: OR 1.158, 95% CI 1.007–1.333; recessive model: OR 1.229, 95% CI 1.054–1.433). Obviously, significant associations were observed in the Arg/Arg vs. Pro/Pro, the dominant and the recessive models. Thus, the ongoing uncertainty still existed and the conclusion by Ma et al. [1] was not entirely credible. Importantly, several sizeable eligible studies (7,601 cases and 11,549 controls) have not been included in this meta-analysis [2–16], even though they satisfied the search criteria. Of note, there were 5 studies of Asians [2–6], 8 studies of Caucasians [7–14], and 2 studies of mixed

New conflicting results obtained in the subgroup analysis of RAD51 135G>C polymorphism and breast cancer risk

We read with great interest the article ‘‘RAD51 135G[C polymorphism and breast cancer risk: a metaanalysis’’ published online in the July 2010 issue of ‘‘Breast Cancer Research And Treatment’’. Zhou et al. [1] have reached an important conclusion that RAD51 variant 135C homozygote is associated with elevated breast cancer risk among BRCA2 mutation carriers, but not in subgroup analysis according to specific ethnicity. Nevertheless, close inspection of the studies analyzed by the authors revealed some methodological issues that are worth mentioning and clarifying. After we adopt the same search strategy and end-of-search date as Zhou et al. [1], six relevant case–control studies in pubmed with a total number of 1,228 breast cancer cases and 1,127 controls [2–7] was not included in this meta-analysis. Of note, except for one study of mixed ethnicities [2], other five case–control studies were performed on Caucasian populations. Sub-analysis on Caucasian and Mixed subjects demonstrated no significant association between RAD51 135G[C polymorphism and breast cancer susceptibility by Zhou et al. [1]. This may imply that the original odds ratio for the eligible studies [2–7] not included in the sub-analysis on Caucasian and Mixed subjects may significantly differ from that calculated by Zhou et al. [1]. As a result, the conclusion by Zhou et al. [1] was not entirely credible. Meanwhile, meta-analysis based on currently available evidence, was to derive a more precise assessment of the relationship, but this research brought a new conflicting result in the subgroup analysis. Zhou et al. [1] demonstrated a significant association was found among BRCA2 mutation carriers in additive (OR = 4.92; 95% CI = 1.11–21.83) and the recessive models (OR = 4.88; 95% CI = 1.10–21.67), but not in BRCA1 mutation carriers in all genetic models. It was different from the meta-analysis result published in the July 17, 2010 issue of ‘‘Breast Cancer Research And Treatment’’ [8]. Jakubowska et al. [3] observed a significantly reduced risk of breast cancer among Polish female carriers of RAD51 135C allele and BRCA1 founder mutations. Gao et al. [8] demonstrated that no significant association was found in stratified analyses according to the BRCA1 or BRCA2 mutation status in the dominant comparison model tested. It can be secondarily noted that this significant association among BRCA2 mutation carriers by Zhou et al. [1] was just based on one study by Antoniou et al. [9]. We also found one relevant case–control study in pubmed, which have not been included in this meta-analysis [2]. The number of studies involved in the meta-analysis for RAD51 135G[C polymorphism among BRCA2 mutation carriers was relatively small, thus performing the subgroup analysis was met with difficulty. The study not included was P.-H. Lu (&) W. Shen M.-Y. Wu G.-Q. Tao (&) Department of General Surgery, Wuxi People’s Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi 214023, Jiangsu, China e-mail: lphty1_1@yahoo.com.cn

Unincluded subjects need to be included for concerning the real association between TNFa-308 G/A polymorphism and cancer susceptibility

ratio = 0.86–1.19, P = 0.000], in the AA versus GG codominant (OR = 1.00; 95% CI = 0.71–1.40; P = 0.072), in the AA versus GA codominant (OR = 1.06; 95% CI = 0.89–1.26; P = 0.330), the dominant (OR = 0.98; 95% CI = 0.82–1.18; P = 0.000), and the recessive (OR = 0.99; 95% CI = 0.84–1.17; P = 0.126) models. However, the OR of 1.10 and the 95% CI of 1.04–1.07 in the recessive model, and the OR of 1.08 and 95% CI of 1.02–1.14 in the A versus G allele contrast model suggest the association between TNFa-308 G/A polymorphism and breast cancer risk as described by Fang et al. [1]. The meta-analysis was based on currently available evidence and was meant to accurately assess the relationship, but these findings brought a new conflicting result in the pooled analysis. In the stratified analysis by ethnicity, no significantly increased risk was found among Asians for all genetic

Is preoperative serum albumin enough to ensure nutritional status in the development of surgical site infection following gastrointestinal surgery

To the Editor: W e have read with great interest the article “Preoperative hypoalbuminemia is an independent risk factor for the development of surgical site infection following gastrointestinal surgery: A multi-institutional study” published in the August 2010 issue of “Annals of Surgery.”1 To date, relatively few studies examining the influence of the nutritional status of patients on the development of surgical site infection (SSI) exist. From our perspective, the manuscript can be merited with further underlining the relevance of preoperative serum albumin on the development of SSI. We are grateful to the authors for their effort. However, deeper analysis of the study brings to light questions that need clarifications to better determine this relationship. Hypoalbuminemia is associated with poor tissue healing, decreased collagen synthesis, and granuloma formation in surgical wounds.2-4 This medical condition increases wound dead space and creates an environment that predisposes a person to infection. Furthermore, low serum albumin causes tissue edema and leak of interstitial fluid into the wound, which provides a medium for bacterial propagation as discussed in the study by Hennessey et al.1 Wound healing is a gradual process based on postoperative persistent nutritional status. Serum albumin value is different from other risk factors previously