Coffee drinking and colorectal cancer and its subsites: A pooled analysis of 8 cohort studies in Japan

Coffee is a rich source of bioactive compounds that have potential anticarcinogenic effects. However, it remains unclear whether coffee drinking is associated with colorectal cancer. Also, despite different etiological factors involved in gut physiology, few studies have investigated this association by anatomical site of the lesion. To address these issues, this study examined the association between coffee drinking and colorectal cancer in a pooled analysis from 8 cohort studies conducted in Japan. Among 320,322 participants followed up for 4,503,274 person‐years, 6,711 incident colorectal cancer cases were identified. Study‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using the random effects model. Coffee drinking was not materially associated with colorectal cancer risk in men or women (pooled HR 0.92, 95% CI 0.82–1.03 in men and pooled HR 0.90, 95% CI 0.76–1.07 in women). Analysis by subsite showed a lower risk of colon cancer among female drinkers of ≥3 cups coffee/day (pooled HR 0.80, 95% CI 0.64–0.99). There was no such association in men. Coffee drinking was not associated with risk of rectal cancer in men or women. Results were virtually the same among never smokers except for an increased risk of rectal cancer associated with frequent coffee consumption. Coffee drinking may be associated with lower risk of colon cancer in Japanese women.     

Adjuvant radiotherapy after radical hysterectomy of the cervical cancer

Aim

To investigate prognostic factors and complications after radical hysterectomy followed by postoperative radiotherapy for carcinoma of the uterine cervix.

Patients and Methods

One hundred twenty-eight patients with Tlb-2b carcinoma of the uterine cervix following radical hysterectomy with bilateral pelvic lymphadenectomy and postoperative radiation therapy were reviewed. Pathologic and treatment variables were assessed by multivariate analysis for local recurrence, distant metastases and cause specific survival.

Results

The number of positive nodes (PN) in the pelvis was the strongest predictor of pelvic recurrence and distant metastases. These 2 failure patterns independently affect the cause specific survival. The 5-year cumulative local and distant failure were PN(0): 2% and 12%, PN(1–2): 23% and 25%, PN(2<): 32% and 57%, respectively (p=0.0029 and p=0.0051). The 5-year cause specific survival rates were PN(0): 90%, PN(1–2): 59% and PN(2<): 42% (p=0.0001). The most common complication was lymphedema of the foot experienced by one-half of the patients (5-year: 42%, 10-year: 49%).

Conclusion

These results suggest that patients with pathologic Tlb-T2b cervix cancer with pelvic lymph node metastases are at high risk of recurrence or metastases after radical hysterectomy with pelvic lymphadenectomy and postoperative irradiation.     

UICC International Session: What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC – Asia Regional Office organized an international session as part of the 74th Annual Meeting of the Japanese Cancer Association on the topic “What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?” Universal Health Coverage (UHC) is included in the United Nations’ Sustainable Development Goals and aims to ensure that all people can receive high‐quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The session discussed the growing cost of cancer and the challenges that this poses to the establishment and deployment of UHC in the Asian region, where countries face budgetary and other systemic constraints in tackling and controlling cancer. It was noted how sharing concepts on UHC will assist mutual learning among Asian countries and help in the formation of guidelines that can be adapted to national and regional realities. Presentations included a status report on UHC for cancer control in Thailand, and a report from the WHO Kobe Centre concerning prospects for collaborative research on UHC. Also discussed were the current status of cancer burden and control in China and Korea and Japan's progress in systemizing cost‐effectiveness evaluation. The final presentation highlighted the importance of gathering social and economic data across Asia in order to build a picture of commonalities and differences in the region.     

Regulation of Akt mRNA and protein levels by glycogen synthase kinase-3beta in adrenal chromaffin cells: effects of LiCl and SB216763

In cultured bovine adrenal chromaffin cells, where Akt1 is the predominant isoform over Akt2 and Akt3, chronic (> or =12 h) treatment with 1-20 mM LiCl, an inhibitor of glycogen synthase kinase-3, decreased Akt1 level by approximately 52% (EC50=3.7 mM; t1/2=l2 h); it was associated with LiCl-induced increased levels of Ser9-phosphorylated glycogen synthase kinase-3beta (approximately 37%) and beta-catenin (approximately 59%), two hallmarks of glycogen synthase kinase-3beta inhibition. The same LiCl treatment did not change phosphoinositide 3-kinase, phosphoinositide-dependent kinase 1, and extracellular signal-regulated kinase-1/2 levels. Treatment with SB216763 [3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], a selective inhibitor of glycogen synthase kinase-3, lowered Akt1 level by approximately 67% (EC50=2 microM; t1/2=l2 h), when SB216763 caused concentration- and time-dependent increase of beta-catenin level by approximately 76%. LiCl- or SB216763-induced Akt1 decrease, as well as increases of Ser9-phosphorylated glycogen synthase kinase-3beta and beta-catenin were restored to the control levels of nontreated cells after the washout of LiCl (20 mM for 24 h)- or SB216763 (30 microM for 24 h)-treated cells. LiCl-induced Akt1 reduction was not prevented by beta-lactone, lactacystin (two inhibitors of proteasome), calpastatin (an inhibitor of calpain), or leupeptin (an inhibitor of lysosome). LiCl decreased Akt1 mRNA level by 20% at 6 h, with no effect on Akt1 mRNA stability. These results suggest that glycogen synthase kinase-3beta inhibition caused down-regulation of Akt1 mRNA and Akt1 protein levels; conversely, constitutive activity of glycogen synthase kinase-3beta maintains steady-state level of Akt1 in quiescent adrenal chromaffin cells.     

Identification of putative substrates for cynomolgus monkey cytochrome P450 2C8 by substrate depletion assays with 22 human P450 substrates and inhibitors

Cynomolgus monkeys are widely used in drug developmental stages as non‐human primate models. Previous studies used 89 compounds to investigate species differences associated with cytochrome P450 (P450 or CYP) function that reported monkey specific CYP2C76 cleared 19 chemicals, and homologous CYP2C9 and CYP2C19 metabolized 17 and 30 human CYP2C9 and/or CYP2C19 substrates/inhibitors, respectively. In the present study, 22 compounds selected from viewpoints of global drug interaction guidances and guidelines were further evaluated to seek potential substrates for monkey CYP2C8, which is highly homologous to human CYP2C8 (92%). Amodiaquine, montelukast, quercetin and rosiglitazone, known as substrates or competitive inhibitors of human CYP2C8, were metabolically depleted by recombinant monkey CYP2C8 at relatively high rates. Taken together with our reported findings of the slow eliminations of amodiaquine and montelukast by monkey CYP2C9, CYP2C19 and CYP2C76, the present results suggest that these at least four chemicals may be good marker substrates for monkey CYP2C8. Copyright © 2016 John Wiley & Sons, Ltd.     

Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13

Abstract

1.?The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme.

2.?Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6-dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13.

3.?1-Nitropyrene and 1-acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis.

4.?Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297 and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1.

5.?These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans.     

A novel branching pattern of the superior mesenteric artery found in the bullfrog (Rana catesbeiana) amphibian

The branching and distribution patterns of the superior mesenteric artery were studied in 10 adult bullfrogs ( Rana catesbeiana ) after injection of coloured latex solution into the vasculature. The abdominal digestive organs in the bullfrog were mainly supplied by the coeliac artery and the superior mesenteric artery, both of which arose as a common trunk, the coeliacomesenteric artery, from the abdominal aorta. The coeliac artery supplied the stomach, liver, gallbladder and the pancreas, whereas the first branch of the superior mesenteric artery was the splenic artery with other branches supplying the greater part of intestine. The apex of the intestinal loop was defined as the region supplied by the trunk of the superior mesenteric artery, and its intestinal branches constituted a 'nested formation' which had the following characteristics. (1) The branches of the trunk were distributed to both sides of the apex, and the distribution regions of younger branches were located more distant from the apex than those of older branches. (2) Two branches directed towards both sides of the trunk frequently made a common stem arising from the trunk. The second branch of the superior mesenteric artery constituted a secondary trunk and its distribution region could be defined as a secondary apex, since 1 of its branches also constituted a nested formation which was distributed to both sides of the primary and secondary apices. The intestinal branches of the superior mesenteric artery were divided into 4 types on the basis of their pattern of branching and course. It is suggested that the nested formation of the superior mesenteric artery in the bullfrog is a remnant of the vascular pattern of the tadpole, which possesses a double spiral mode of intestinal convolution, probably supplied by arteries with the nested formation in a latent form.     

Female reproductive factors and risk of lymphoid neoplasm: The Japan Public Health Center‐based Prospective Study

Although a possible role of reproductive factors in lymphomagenesis has been hypothesized, results of epidemiological studies have been inconsistent. Here, we investigated the association between reproductive factors and the risk of lymphoid neoplasm and its subgroups. We used data from a large‐scale, population‐based prospective study in a Japanese cohort with 42 691 eligible women aged 40‐69 years from 1990 to 1994. During a mean follow up of 18.7 years, we identified 176 cases of lymphoid neoplasm and 90 of non‐Hodgkin lymphoma (NHL). A multivariable‐adjusted Cox proportional hazards regression model was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the risk of lymphoid neoplasms and its subgroups according to self‐reported reproductive factors. Parous women had an increased risk of lymphoid neoplasm compared with nulliparous women (HR = 2.51, 95% CI, 1.03‐6.13). An increased risk of lymphoid neoplasms was found in women with later onset of menarche (≤13 years old; reference: 14‐15; HR = 1.75, 95% CI = 1.10‐2.79: ≥16; HR = 1.93, 95% CI = 1.17‐3.19: P‐trend: 0.01) and a shorter menstrual cycle (28‐29 days; reference: ≤27; HR = 1.60, 95% CI = 1.05‐2.43, P‐trend = 0.81). No association was observed between lymphoid neoplasms and other reproductive factors, including age at first birth, breastfeeding, type of menopause, or exogenous hormone use. Our study suggests that ever parity, late age at menarche and a short menstrual cycle length may be associated with the development of lymphoid neoplasms. The inconsistency seen in epidemiological research to date warrants further investigation.