Telomerase activation without shortening of telomeric 3'-overhang is a poor prognostic factor in human colorectal cancer

Our previous report demonstrated a good correlation between high telomerase activity of cancer tissues and a poor prognosis of patients with colorectal cancers, except for several cases. To elucidate the additional factors that contribute to patient prognosis, the correlation among the expression levels of telomere binding proteins (TBP), the lengths of telomeres, the lengths of telomere 3'-overhang (3'-OH) and telomerase activity in 106 paired colorectal cancer and corresponding noncancerous mucosa (NCM) specimens were examined. The expression levels of eight TBP genes (TRF1, TRF2, TIN2, TANK1, TANK2, POT1, RAP1 and TPP1) were analyzed. Among the 106 cases, 35 cases had shortened telomeres (<7 kb), 15 had shortened 3'-OH (3'-OH length ratio of cancer/NCM <0.5) and 88 were classified as telomerase-activated cancers (activity ratio of cancer/NCM >2). Comparison between NCM and cancer in each case showed that all TBP except for POT1 were downregulated in cancers. A survival analysis using a Cox proportional hazard model showed that the survival rate of the telomerase-activated cases with shortened 3'-OH and that of telomerase-inactivated cases were significantly better than that of telomerase-activated cases without 3'-OH shortening, that is, restored or maintained 3'-OH (P = 0.018). In the telomerase-activated cancers, the length of 3'-OH was significantly correlated with the expression levels of POT1. Elongation of telomeric overhang by telomerase, which might be regulated by POT1, may contribute to the increase of malignant potential in colorectal cancers.     

Effect of mustard gas exposure on incidence of lung cancer: a longitudinal study

Sulfur mustard, an agent used in chemical warfare, is an alkylating substance with carcinogenic potential. However, the precise long-term carcinogenic effects of mustard gas are unclear. Since 1952, the authors have conducted health surveys of former workers who were employed from 1929 to 1945 in a poisonous gas factory in Okuno-jima, Hiroshima, Japan. This prospective study was undertaken from 1952 to 2005 to examine the incidence of lung cancer among the workers who were exposed to mustard gas (n=480), lewisite (n=55), and/or diphenylcyanarsine (n=178), as well as the incidence among unexposed workers (n=969). The stochastic relation between exposure and lung cancer was explored on the basis of multistage carcinogenesis by using an accelerated hazard model with a transformed age scale. Mustard gas exposure was found to transform the age scale for developing lung cancer. One year of exposure in subjects ≤18 or >18 years old at first exposure shifted the age scale down by 4.9 years and 3.3 years, respectively. On the basis of the long-term follow-up of former workers in the poisonous gas factory, the authors concluded that sulfur mustard decreased the age at which people were at risk of developing lung cancer and that the effect declined with aging.     

Global longitudinal strain by two-dimensional speckle tracking imaging predicts exercise capacity in patients with chronic heart failure

Background

Left ventricular ejection fraction (LVEF) predicts mortality in patients with chronic heart failure (CHF). However, a weak correlation was found between LVEF and peak oxygen uptake ( $ \dot{V}{\text{O}}_{2} $ ) in CHF patients. Global longitudinal strain measured by two-dimensional (2D) strain is regarded as a more useful predictor of cardiac events than LVEF. We investigated whether 2D strain obtained at rest could predict peak $ \dot{V}{\text{O}}_{2} $ in patients with CHF.

Methods

Fifty-one patients (mean age of 54.0 ± 12.0 years, 14 females, LVEF 46.0 ± 15.0%) with stable CHF underwent resting echocardiography and cardiopulmonary exercise testing. Leg muscle strength was measured for the evaluation of peripheral factors. Global longitudinal strain (GLS) in the apical 4-, 3-, and 2-chamber views and global circumferential strain (GCS) in the parasternal mid short-axis view were measured.

Results

In all patients, peak $ \dot{V}{\text{O}}_{2} $ correlated with leg muscle strength (r = 0.55, p < 0.0001), LVEF (r = 0.46, p < 0.001), GLS (r = ?0.45, p < 0.001), and GCS (r = ?0.41, p = 0.005), respectively. No significant correlation was found between the ratio of early transmitral velocity to peak early diastolic mitral annulus velocity (E/E′) and peak $ \dot{V}{\text{O}}_{2} $ . In the patients with heart failure and reduced LVEF, a multiple stepwise linear regression analysis based on leg muscle strength, LVEF, E/E′, GLS, and GCS was performed to identify independent predictors of peak $ \dot{V}{\text{O}}_{2} $ , resulting in leg muscle strength and GLS (R ² = 0.888) as independent predictors of peak $ \dot{V}{\text{O}}_{2} $ .

Conclusion

Global longitudinal strain at rest could possibly predict exercise capacity, which appeared to be more useful than LVEF, E/E′, and GCS in CHF patients with reduced LVEF.     

Oestrogen-dependent stimulation of luteinising hormone release by galanin-like peptide in female rats

Galanin-like peptide (GALP), a ligand for three types of galanin receptor, is reported to have a role in regulating luteinising hormone (LH) release in male rodents and primates, but its role in LH release in female rodents remains controversial. The present study was conducted to test whether GALP has a stimulatory role in regulating LH secretion in female rats. The effect of i.c.v. infusion of GALP (5 nmol) on pulsatile LH release was investigated in Wistar-Imamichi strain female rats, or lean and obese Zucker rats. In oestradiol-17β (oestradiol)-primed ovariectomised (OVX) Wistar-Imamichi female rats, i.c.v. infusion of GALP caused a gradual increase in LH release for the first 1.5 h after the infusion followed by an increased LH pulse frequency during the next 1.5 h, resulting in a significant increase in the mean LH concentrations and baseline levels of LH pulses throughout the sampling period and in the frequency of LH pulses at the last half of the period compared to vehicle-treated controls. The stimulatory effect of GALP was oestrogen-dependent because the same GALP treatment did not affect LH release in OVX rats in the absence of oestradiol. In lean Zucker rats, LH pulses were found in oestradiol-primed OVX individuals and central GALP infusion increased mean LH concentrations in the last half of the period. By contrast, few LH pulses were found in oestradiol-primed OVX obese Zucker rats reportedly with lower hypothalamic GALP expression. Central GALP infusion caused an apparent but transient increase in LH release, resulting in the significant increase in all pulse parameters of LH pulses compared to vehicle-treated controls in the first half of the sampling period. These results suggest that hypothalamic GALP is likely involved in stimulating GnRH/LH release, and that the stimulatory effect of GALP on LH release is oestrogen-dependent in female rats.     

Carrier-mediated processes in blood–brain barrier penetration and neural uptake of paraquat

Due to the structural similarity to N-methyl-4-phenyl pyridinium (MPP⁺), paraquat might induce dopaminergic toxicity in the brain. However, its blood–brain barrier (BBB) penetration has not been well documented. We studied the manner of BBB penetration and neural cell uptake of paraquat using a brain microdialysis technique with HPLC/UV detection in rats. After subcutaneous administration, paraquat appeared dose-dependently in the dialysate. In contrast, MPP⁺ could not penetrate the BBB in either control or paraquat pre-treated rats. These data indicated that the penetration of paraquat into the brain would be mediated by a specific carrier process, not resulting from the destruction of BBB function by paraquat itself or a paraquat radical. To examine whether paraquat was carried across the BBB by a certain amino acid transporter, -valine or -lysine was pre-administered as a co-substrate. The pre-treatment of -valine, which is a high affinity substrate for the neutral amino acid transporter, markedly reduced the BBB penetration of paraquat. When paraquat was administered to the striatum through a microdialysis probe, a significant amount of paraquat was detected in the striatal cells after a sequential 180-min washout with Ringer’s solution. This uptake was significantly inhibited by a low Na⁺ condition, but not by treatment with putrescine, a potent uptake inhibitor of paraquat into lung tissue. These findings indicated that paraquat is possibly taken up into the brain by the neutral amino acid transport system, then transported into striatal, possibly neuronal, cells in a Na⁺-dependent manner.