Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Positive acceleration adaptive training attenuates gastric ischemia-reperfusion injury through COX-2 and PGE2 expression.

The mechanism involved in the effects of positive acceleration adaptive training (PAAT) on gastric ischemia-reperfusion injury (GI-RI) has not been fully characterized. The aim of the present study was to investigate the effects of PAAT in attenuating GI-RI in a rat model. The inflammatory factor and caspase-3 levels were measured using ELISA kits. A western blot assay was used to analyze tumor necrosis factor-α (TNF)-α, tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor-related apoptosis inducing ligand (TRAIL), death receptor (DR) 4, DR5, cyclooxygenase (COX)-2, COX-1 and prostaglandin E2 (PGE2) protein expression levels. It was revealed that PAAT could alleviate GI-RI and inflammatory factor levels in a rat model. PAAT suppressed TNF-α and TNFR1 protein expression levels, inhibited TRAIL, DR4, DR5, COX-2 and PGE2 protein expression levels; however, it did not have an effect on COX-1 protein expression in the model of GI-RI. The data indicated that the effects of PAAT attenuated GI-RI through the downregulation of COX-2 and PGE2 expression.

Genetic predisposition of stroke: understanding the evolving landscape through meta-analysis.

Stroke, either ischemic or hemorrhagic, is the leading cause of death and morbidity worldwide. Identifying the risk factors is a prerequisite step for stroke prevention and treatment. It is believed that a major portion of the currently unidentified risk factors is of genetic origin. Consistent with this idea, numerous potential risk alleles for stroke have been reported, however, the genetic evidence so far is not conclusive. The major goal of this review is to update the current knowledge about the genetic predisposition to the common multifactorial stroke, and to provide a bird's-eye view of this fast moving field. We selectively review and meta-analyze the related English literatures in public domain (PubMed) from 2000 onward, including the original reports and meta-analyses, to evaluate the genetic risk factors of common multifactorial stroke. The results indicated that we reviewed and meta-analyzed original reports and existing meta-analyses that studied the genetic predisposition to the common multifactorial stroke. Some original reports and meta-analyses were specific for ischemic stroke and others were for hemorrhagic stroke only. We also evaluated the major evolving issues in this field and discussed the future directions. In conclusion, strong evidences suggest that genetic risk factors contribute to common multifactorial stroke, and many genetic risk genes have been implicated in the literatures. However, not a single risk allele has been conclusively approved.

[Effects of glutathione on plasma heat shock protein 70 of acute gastric mucosal injury in rats exposed to positive acceleration].

OBJECTIVE: To explore the change of plasma heat shock protein 70 (HSP70) in rats exposed to acute gastric mucosal injury under the condition of positive acceleration (+Gz) and elucidate the effects of glutathione (GSH) and the corresponding protective mechanisms. METHODS: A total of 40 male SD rats were randomly by computer randomization into 4 groups of ethanol control, +5 Gz value exposure, +10 Gz value exposure and GSH protection (n = 10 each). GSH protection group received adaptive feeding for 7 days and then an intraperitoneal injection of GSH for 3 consecutive days. All 4 groups fasted for 24 hours within 10 days, water deprivation for 12 hours and a gastric lavage of anhydrous ethanol (0.4 ml/100 g) for 1 hour, ethanol control group had no acceleration,+5 Gz value exposure group at + 5 Gz and the latter two groups respectively at +10 Gz for around 3 min.Each group underwent anesthesia of pentobarbital after centrifuge immediately. Abdominal aortic blood samples were collected and gastric tissues harvested for observation of mucosal injury. Mucosal damage index was calculated by the GUTH method. And the plasma content of HSP70 was measured by radioimmunoassay. RESULTS: (1) Gastric mucosa of each groups rats were injured. Damage was significantly reduced by GSH pretreatment, ethanol control group had less injury, the injury of +5 Gz value exposure group was aggravated compared with the control group (gastric mucosal injury index: 25.4 (14.0-30.0) vs 10.0 (9.2-13.9), P = 0.001); +10 Gz value exposure group mucosal injury was heaviest (47.2 (41.5-60.1)) . There were diffuse hyperemia, edema and erosion with a large area of bleeding spots and flat mucosal folds.It had statistically significant differences with the first two groups (all P < 0.01); GSH protection group was lightest at 9.5 (7.5-14.1). Compared with the +10 Gz value exposure group, mucosal damage was milder (P < 0.01).(2) The plasma levels of HSP70 of +5 Gz value exposure had no significant differences with the control and ethanol groups ((6.5 ± 0.5) ng/ml, P = 0.897); HSP70 plasma level ((5.9 ± 0.5) ng/ml) of +10 Gz value exposure was significantly lower than those of the first two groups (P = 0.018,0.014); GSH protection group ((7.0 ± 0.5) ng/ml) was significantly higher than the level of +10 Gz value exposure group (P < 0.01). CONCLUSIONS: +Gz exposure may cause the altered levels of plasma HSP70.High +Gz value exposure reduces its content and aggravates gastric mucosal injury. And glutathione reduces the injury of gastric mucosa through elevated plasma HSP70.

[Effects of acute hypobaric hypoxia on gastric emptying and intestinal propulsion: experiment with rats].

OBJECTIVE: To investigate the impact of acute hypobaric hypoxia on the gastrointestinal motility. METHODS: Eighty Wistar rats were randomly divided into 4 equal groups to be fed with (99)Tc(m)-labeled test food: ground level control group, put in the hypobaric chamber for 30 minutes; 3000 m simulated altitude group, exposed to the environment of simulated altitude of 3000 m for 30 minutes; 5000 m simulated altitude group, exposed to the environment of simulated altitude of 5000 m for 30 minutes; and mosapride + 5000 m simulated altitude group, fed with mosapride 2 mg/kg by perfusing stomach and fed with isotope-labeled test food 30 minutes later, and then exposed to 5000 m simulated altitude for 30 minutes. By the end of experiment the rats were killed, their stomachs were taken out to calculate the gastric emptying rate. Their intestine from pylorus to ileocecum was taken out to measure the intestinal propulsion function by using charcoal particle method. At the beginning and at the end of experiment abdominal arterial blood samples were collected to detect the plasma motilin and nitric oxide (NO) concentrations. RESULTS: The gastric emptying rate of the 5000 m simulated altitude group was 41% +/- 10%, significantly lower than that of the ground level group (62% +/- 12%, P < 0.01), and the charcoal transit rate of the 5000 m simulated altitude group was 37% +/- 8%, significantly lower than that of the ground level group (61% +/- 13%, P < 0.01). The gastric emptying rate and intestine propulsion rate of the 3000 m simulated altitude group were not significantly different from those of the ground level group. The gastric emptying rate of the mosapride + 5000 m simulated altitude group was 55% +/- 12%, significantly higher than that of the 5000 m simulated altitude group (P < 0.05), however, the intestine propulsion rate of the mosapride + 5000 m simulated altitude group was not significantly different from that of the 5000 m simulated altitude group (P > 0.05). The plasma motilin level of the 5000 m simulated altitude group was 88 pg/ml +/- 19 pg/ml, significantly lower than that of the ground level group (123 pg/ml +/- 28 pg/ml, P < 0.01), in contrast, the plasma NO level of the 5000 m simulated altitude group was 106 micromol/L +/- 24 micromol/L, significantly higher than that of the ground level group (80 micromol/L +/- 18 micromol/L, P < 0.01). CONCLUSION: Acute exposure to hypobaric hypoxia at the height of 5000 m inhibits the gastric emptying and intestinal propulsion. Mosapride may alleviate the inhibitory effect of hypobaric hypoxia on gastric emptying. Decrease of plasma motilin and elevation of NO level may be the main mechanism of inhibition of gastrointestinal motility by hypobaric hypoxia.