Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice

17beta-estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.     

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose‐limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin‐induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin‐induced neuropathy via the PKC/extracellular signal‐regulated kinase (ERK)/c‐Fos pathway in lumbar spinal cords (lumbar segments 4–6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells‐implanted mice. Moreover, mitogen‐activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin‐induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin‐induced neuropathy is associated with PKC/ERK/c‐Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin‐induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin‐induced neuropathy and could aid in combination antitumor pharmacotherapy.     

Oxidation and hydrogenation of Pd: suppression of oxidation by prolonged H2 exposure

We investigate the phase transition of a Pd surface in both oxidizing and reducing environments by environmental transmission electron microscopy (ETEM). ETEM allows us to study sequential exposure of Pd to O₂ and H₂ in the same TEM conditions. First, under ETEM observation, oxidation occurs at step edges but it can also occur at terraces. Second, as the most important result, we observed a novel process where previous exposure to H₂ suppresses new oxidation of the Pd surface. Third, we show by electron energy loss spectroscopy (EELS) that this process, suppression of oxidation by previous exposure to H₂, is not due to the formation of bulk β-phase Pd hydride. We also demonstrate that this process is not present in Pt. Finally, we discuss the hypothesis to explain this phenomenon: formation of surface–Pd–hydride suppresses the new oxidation. This observation, suppression of oxidation by H₂ exposure, may eventually lead to new breakthroughs.

Oxidation of the Pd surface exhibits dependence on the history of pre-exposure to H₂.     

Distribution of 60Co in steel samples from Hiroshima

This paper describes ultra low-level gamma-ray spectrometry measurements of the (60)Co activity distribution inside one 52 mm and one 41 mm thick steel sample. The samples had been exposed to the Hiroshima atomic bomb and were from the Aioi bridge and the Yokogawa bridge. Both samples were measured in a recent study aiming to back up model calculation of Hiroshima dosimetry. The (60)Co activity distributions found in this study support the assumptions made in the previous study.     

Salvage Hepatectomy for Local Recurrent Hepatocellular Carcinoma After Ablation Therapy

Background

The results of salvage hepatectomy for local recurrent hepatocellular carcinoma after incomplete percutaneous ablation therapy are still unclear.

Methods

We conducted a retrospective analysis of 197 consecutive patients with hepatocellular carcinoma who underwent either salvage hepatectomy after prior incomplete percutaneous ablation therapy (salvage group; n?=?23) or primary hepatectomy as the initial treatment (primary group; n?=?174). The two groups were compared with respect to intraoperative data, operative mortality and morbidity, and long-term survival.

Results

The salvage group showed a significantly longer operation time (385 vs. 300?min; P?=?0.006) and a significantly greater intraoperative blood loss volume (402 vs. 265?ml; P?=?0.024). The postoperative mortality rate was zero in both groups, and the morbidity rates were similar. Although the 1-, 3-, and 5-year disease-free survival rates after hepatectomy were significantly worse in the salvage group than in the primary group (65%, 41%, and 33% vs. 81%, 51%, and 45%, respectively; P?=?0.031), the overall survival rates after hepatectomy did not differ significantly (91%, 91%, and 67% vs. 96%, 79%, and 65%, respectively; P?=?0.790). The 1-, 3-, and 5-year overall survival and disease-free survival rates after percutaneous ablation therapy were also not different from those in the primary group (100, 96, and 83%, P?=?0.115; and 96, 60, and 45%, P?=?0.524, respectively).

Conclusions

The short-term and long-term results of salvage hepatectomy after incomplete percutaneous ablation therapy are equivalent to those of primary hepatectomy. Salvage hepatectomy is an acceptable treatment for patients with local recurrence of hepatocellular carcinoma after ablation therapy.