Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers

Accumulating evidence suggests that post‐diagnostic insulin levels may influence colorectal cancer (CRC) survival. Yet, no previous study has examined CRC survival in relation to a post‐diagnostic diet rich in foods that increase post‐prandial insulin levels. We hypothesized that glycemic and insulin scores (index or load; derived from food frequency questionnaire data) may be associated with survival from specific CRC subtypes sensitive to the insulin signaling pathway. We prospectively followed 1,160 CRC patients from the Nurses' Health Study (1980–2012) and Health Professionals Follow‐Up Study (1986–2012), resulting in 266 CRC deaths in 10,235 person‐years. CRC subtypes were defined by seven tumor biomarkers (KRAS, BRAF, PIK3CA mutations, and IRS1, IRS2, FASN and CTNNB1 expression) implicated in the insulin signaling pathway. For overall CRC and each subtype, hazard ratio (HR) and 95% confidence interval (95% CI) for an increase of one standard deviation in each of glycemic and insulin scores were estimated using time‐dependent Cox proportional hazards model. We found that insulin scores, but not glycemic scores, were positively associated with CRC mortality (HR = 1.19, 95% CI = 1.02–1.38 for index; HR = 1.23, 95% CI = 1.04–1.47 for load). The significant positive associations appeared more pronounced among PIK3CA wild‐type cases and FASN‐negative cases, with HR ranging from 1.36 to 1.60 across insulin scores. However, we did not observe statistically significant interactions of insulin scores with PIK3CA, FASN, or any other tumor marker (p interaction > 0.12). While additional studies are needed for definitive evidence, a high‐insulinogenic diet after CRC diagnosis may contribute to worse CRC survival.     

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

Although experimental evidence suggests calcium‐sensing receptor (CASR) as a tumor‐suppressor, the prognostic role of tumor CASR expression in colorectal carcinoma remains unclear. We hypothesized that higher tumor CASR expression might be associated with improved survival among colorectal cancer patients. We evaluated tumor expression levels of CASR by immunohistochemistry in 809 incident colorectal cancer patients within the Nurses' Health Study and the Health Professionals Follow‐up Study. We used Cox proportional hazards regression models to estimate multivariable hazard ratio (HR) for the association of tumor CASR expression with colorectal cancer‐specific and all‐cause mortality. We adjusted for potential confounders including tumor biomarkers such as microsatellite instability, CpG island methylator phenotype, LINE‐1 methylation level, expressions of PTGS2, VDR and CTNNB1 and mutations of KRAS, BRAF and PIK3CA. There were 240 colorectal cancer‐specific deaths and 427 all‐cause deaths. The median follow‐up of censored patients was 10.8 years (interquartile range: 7.2, 15.1). Compared with patients with no or weak expression of CASR, the multivariable HRs for colorectal cancer‐specific mortality were 0.80 [95% confidence interval (CI): 0.55–1.16] in patients with moderate CASR expression and 0.50 (95% CI: 0.32–0.79) in patients with intense CASR expression (p‐trend = 0.003). The corresponding HRs for overall mortality were 0.85 (0.64–1.13) and 0.81 (0.58–1.12), respectively. Higher tumor CASR expression was associated with a lower risk of colorectal cancer‐specific mortality. This finding needs further confirmation and if confirmed, may lead to better understanding of the role of CASR in colorectal cancer progression.     

Neoadjuvant chemotherapy and radiation for inoperable carcinoma of the maxillary antrum: a matched-control study

A matched-control study comparing standard radiotherapy versus neoadjuvant chemotherapy and radiation was undertaken to clarify the effects of neoadjuvant systemic chemotherapy for locally advanced squamous cell carcinoma of the maxillary antrum. Thirty-four patients with inoperable maxillary cancer were treated with neoadjuvant chemotherapy and radiotherapy (Group II). Before starting radiotherapy, all patients in Group II received two or three cycles of neoadjuvant chemotherapy consisting of cisplatin and a 5-day continuous infusion of 5-fluorouracil with or without intravenous injection of vinblastine. Radiation doses ranged from 66 Gy to 75 Gy (median, 70 Gy). The response rate, patterns of failure, toxicity, and survival for Group II were compared with those for 34 stage-matched patients treated with radiation alone (Group I). Despite a higher response rate to neoadjuvant chemotherapy, the recurrence rate and patterns of treatment failure were not influenced by the addition of neoadjuvant chemotherapy. In most cases, neoadjuvant chemotherapy did not interfere with subsequent radiotherapy, and radiation-induced late complications occurred equally in both treatment groups. After a median follow-up of 48 months, there was no significant difference in 5-year actuarial survival or disease-free survival between the two treatment groups. Radiation alone for inoperable maxillary cancer was clearly suboptimal for improving local control and survival rate, but neoadjuvant chemotherapy in addition to standard radiotherapy failed to demonstrate any therapeutic advantage over radiation alone.     

Identification of novel 17-estradiol (E2) target genes using cross-experiment gene expression datasets

17β-estradiol (E2) is an environmental estrogen-like chemicals that is known to affect mainly reproductive functions of exposed targets. Although microarray based toxicogenomics approach allows the investigation of the potential risks of E2 in DNA level, the underling mechanisms related to their toxic effect is not fully understood. In this work, we identified genes responding toE2 by analyzing cross-experiment public gene expression datasets that studied on E2 using RankProd algorithm. We have identified 348 DEGs which play important roles in fatty acid metabolism, infection, and DNA repair. This result was also compared with conventional PubMed data mining analysis.     

Inhibition of lung metastasis in mice by oligonol

Oligonol is a polyphenol formulation enriched with catechin‐type oligomers. As an initial approach to assess the chemopreventive potential of Oligonol, the study investigated the effects of Oligonol on the inhibition of lung metastasis induced by B16F‐10 melanoma cells in C57BL/6 mice. Oligonol, which is abundantly found in plants, vegetables and fruits, was found to possess antimetastatic activity against B16F‐10 melanoma cells. Continued consumption of Oligonol, even at high doses, for long periods does not seem to cause any toxic symptoms because excess Oligonol is stored in adipose tissue rather than in the liver. However, the mechanism by which Oligonol exerts its antimetastatic activity remains unclear. Further investigations are required to clarify the exact role of Oligonol in such B16F‐10 melanoma regulation. Copyright © 2009 John Wiley & Sons, Ltd.     

Long-term patterns of fasting blood glucose levels and pancreatic cancer incidence

Background

Whether type 2 diabetes is cause or consequence, or both, of pancreatic cancer (PaC) remains unresolved. Leveraging repeated measurements of fasting blood glucose (FBG), we examined the temporal relationship between hyperglycemia and PaC incidence.

Methods

We conducted a nested case–control study of 278 cases and 826 matched-controls from the Korean National Health Insurance Service-Health Screening Cohort. Over 11 years before index date (date of PaC diagnosis for cases), all participants had at least one FBG measurement in each of the three time windows: ??11 to ??8, ??7 to ??4, and ??3 to 0 years. Using conditional logistic regression, we estimated odds ratios(ORs) of PaC and 95% confidence intervals (CIs) for hyperglycemia in the overall period and at each interval; for major long-term patterns of FBG across the three intervals (recent-onset, medium-term, and long-standing hyperglycemia).

Results

Higher FBG over the past 11 years was associated with an increased odds of PaC (p _trend < .0001), with recent FBG more predictive of PaC than distant FBG. By FBG assessed in the ??3 to 0 interval, OR was 1.97 (95% CI 1.32–2.93) for 110–125 mg/dL and 3.17 (95% CI 2.09–4.80) for ≥?126 mg/dL. By long-term patterns of FBG, compared to consistent normoglycemia, OR was 2.02 (95% CI 1.24–3.31) for long-standing hyperglycemia and 3.38 (95% CI 1.87–6.13) for recent-onset hyperglycemia. These associations were more pronounced among never-smokers than ever-smokers (p _interaction?=?.06).

Conclusion

Recent-onset hyperglycemia may be an early manifestation of undetected PaC, while long-lasting hyperglycemia may serve as a moderate etiologic factor for PaC.

     

Synergistic effect of tetrandrine and ethidium bromide against methicillin-resistant Staphylococcus aureus (MRSA)

Methicillin-resistant Staphylococcus aureus (MRSA) along with other resistant bacteria have become a significant social and clinical problem. Therefore, there is an urgent need to develop bioactive compounds from natural products as alternatives to the very few antibiotics that remain effective. Recently, the efflux mechanism has been identified as the main contributor to antibiotic resistance in bacteria. This study therefore aimed to evaluate tetrandrine (TET), an efflux pump inhibitor (EPI), as a potential antibiotic against MRSA. We investigated the antimicrobial activity of TET against 17 MRSA strains, of which 3 selected strains were studied in further detail using a time-kill assay. When these bacterial strains (1 × 10(6) colony-forming units (cfu)/ml) were incubated with TET in a time-kill assay, log-scale bactericidal activity was observed, which lasted for 24 hr. In addition, TET exhibits a synergistic effect when combined with the multi-drug resistance (MDR)-efflux pump substrate ethidium bromide (EtBr). Structure-function studies of the antibiotic activity of TET in combination with EtBr may lead to the discovery of more effective efflux pump inhibitors.     

Calcium as a chemopreventive agent against colorectal neoplasm: does obesity play a role?

Background

Concerning the chemopreventive potential of calcium against colorectal neoplasms, strong evidence from initial randomized controlled trials (RCTs) of colorectal adenoma has not been confirmed from the most recent large RCT. To explain the conflicting results, a new hypothesis was proposed that the benefit of calcium may be confined to lean individuals.

Methods

To test this hypothesis, we examined heterogeneity of the associations of calcium intake with adenoma and CRC, using data from the most recent meta-analyses of observational studies and conducting subgroup analysis by average body mass index (BMI) of study population.

Results

An inverse association of calcium intake with adenoma and CRC did not vary by population average BMI. By anatomical subsites of CRC, while there was no significant evidence of heterogeneity by population average BMI (P _{heterogeneity} > 0.05), the benefit of calcium was confined to studies with population average BMI of ≥25 kg/m² for both colon cancer and rectal cancer, contradicting the hypothesis.

Conclusions

In our study-level meta-analysis, we found no evidence to support that the chemopreventive potential of calcium, if real, may be stronger in leaner individuals.