Akt isoforms differentially protect against stroke-induced neuronal injury by regulating mTOR activities

Protein kinases Akt1 and Akt3 are considered to be more crucial to brain function than Akt2. We investigated the roles of Akt1 and Akt3 in stroke-induced brain injury and examined their interactions with the Akt/mTOR pathways. Focal ischemia was induced in rats. Lentiviral vectors expressing constitutively active Akt1 and Akt3 (cAkt1 and cAkt3) were injected into the ischemic cortex. Infarct sizes and gene and protein expressions in the Akt/mTOR pathways were evaluated. The results show that Akt1 and Akt3 proteins were degraded as early as 1 hour after stroke, whereas Akt2 proteins remained unchanged until 24 hours after stroke. Lentiviral-mediated overexpression of cAkt1 or cAkt3 reduced neuronal death after in vitro and in vivo ischemia. Interestingly, cAkt3 overexpression resulted in stronger protection than cAkt1 overexpression. Western blot analyses further showed that cAkt3 promoted significantly higher levels of phosphorylated Akt and phosphorylated mTOR than cAkt1. The mTOR inhibitor rapamycin blocked the protective effects of both cAkt1 and cAkt3. In conclusion, Akt isoforms are differentially regulated after stroke and Akt3 offers stronger protection than cAkt1 by maintaining Akt levels and promoting mTOR activity.     

Hypoxic Preconditioning Alleviates Ethanol Neurotoxicity: The Involvement of Autophagy

Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. A sublethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system neurodegenerative diseases. We have recently demonstrated that autophagy is a protective response to alleviate ethanol toxicity. A modest hypoxic preconditioning (1 % oxygen) did not cause neurotoxicity but induced autophagy (Tzeng et al. Free Radic Biol Med 49: 839–846, 2010). We, therefore, hypothesize that the modest hypoxic preconditioning may offer a protection against ethanol-induced neurotoxicity. We showed here that the modest hypoxic preconditioning (1 % oxygen) for 8 h significantly alleviated ethanol-induced death of SH-SY5Y neuroblastoma cells. Under the normoxia condition, cell viability in ethanol-exposed cultures (316 mg/dl for 48 h) was 49 ± 6 % of untreated controls; however, with hypoxic preconditioning, cell viability in the ethanol-exposed group increased to 78 ± 7 % of the controls (p < 0.05; n = 3). Bafilomycin A1, an inhibitor of autophagosome and lysosome fusion, blocked hypoxic preconditioning-mediated protection. Similarly, inhibition of autophagic initiation by wortmannin also eliminated hypoxic preconditioning-mediated protection. In contrast, activation of autophagy by rapamycin further enhanced neuroprotection caused by hypoxic preconditioning. Taken together, the results confirm that autophagy is a protective response against ethanol neurotoxicity and the modest hypoxic preconditioning can offer neuroprotection by activating autophagic pathways.     

Autologous fat as a rectal–prostate spacer for prostate brachytherapy: Results at 6 months

PurposeImplanted rectal spacers (IRS) have been developed to increase the distance between the prostate and the rectum, thus optimizing dose escalation. Cost is a disadvantage and there are still uncertainties as to their durability. We have developed an autologous fat transfer (AFT) technique to use as an IRS. We aim to present the feasibility and durability at 6 months of AFT placed immediately after the implant of the seeds in low-dose-rate brachytherapy (BT).Methods and MaterialsThirty-five patients underwent AFT (12 were treated with primary BT, 7 with a combined primary treatment of external beam radiotherapy + BT, 16 with salvage BT). The isodose used for primary BT was 14400 cGy, 11,000 cGy after 4600 cGy of external beam radiotherapy in the combined group, and 14400 cGy for the salvage group. Patients underwent a CT scan at 1, 3, and 6 months to measure the distance between the rectum and the prostate.ResultsAn average of 32.7 cc (20–40) of fat was transferred successfully in 100% of cases. The mean distance to the rectum at the level of the base, middle, and apex at 1 and 6 months were 11.2, 9.7, and 7.6 mm; 8.3, 8.1, and 5.9 mm, respectively. No rectal toxicity or major complications were reported.ConclusionsThe use of fat as an IRS seems to be a valid alternative to reduce rectal toxicity after BT, achieving equivalent distances to synthetic IRS. It is feasible, safe, and the loss of distance at 6 months is small. Cost is lower than other alternatives.     

DWI及DCE-MRI评价新辅助化疗对不同分子分型乳腺癌的疗效

目的探讨MRI功能成像评价乳腺癌新辅助化疗疗效的价值。方法回顾性分析本院38例经手术病理证实为浸润性乳腺癌行术前新辅助化疗的患者资料。依据化疗前后组织病理学改变进行疗效评价,将病例资料分为病理完全缓解组(pCR)和病理非完全缓解组(NpCR);对比分析两组免疫组化差异及化疗前后MRI检查指标数值变化的差异,以病理反应性标准分组为金标准,对其中有统计学意义的参数进行ROC曲线分析,并计算曲线下面积(AUC),评价其对NAC疗效的预测效能;最后应用相关分析结果建立乳腺癌新辅助化疗疗效预测模型logistP。结果38例中pCR13例,NpCR25例。两组免疫组化参数(ER/PR、HER-2、ki-67)及分子分型、ΔADC%差异均无统计学意义,化疗前后两组ΔD%、ΔV%、ΔS%、ΔSmax%、ΔTIC差异有统计学意义(P<0.05);ΔD%、ΔV%、ΔS%、ΔSmax%、ΔTIC的AUC分别为0.748、0.822、0.708、0.828、0.700,灵敏度/特异度分别为0.769/0.68、0.846/0.72、0.538/0.84、0.769/0.80、0.692/0.64,其logistP与病理组织学疗效的AUC为0.846(95%CI0.708~0.984)。结论乳腺癌新辅助化疗早期动态增强MRI参数变化能预测NAC疗效。     

Achievement of safer palladium nanocrystals by enlargement of {100} crystallographic facets

Developing catalytic and safe nanomaterials is very necessary for the reduction of potential risk to human health; however, this strategy has been found extremely challenging because the enhancement in catalytic activity of nanomaterials is inevitably accompanied with more potent cell injury. The relationship of physicochemical properties and biological responses in catalytic nanomaterials needs to be clarified at the nano–bio interface for achieving the safe application. Herein, high-energy crystallographic facets of palladium (Pd) nanocrystals that have been known to significantly contribute to the catalytic activity were introduced to attenuate the toxicity, and the underlying mechanism was unraveled. Polyhedral Pd nanocrystals with morphology evolution from truncated octahedron to cuboctahedron and cube were prepared for elaborately tuning the extents of high-energy {100} facets, and hierarchical in vitro and in vivo biological evaluation were performed to clarify that Pd nanocrystals exposed with the more {100} facets could show the less toxicity to cells and animals. Density functional theory (DFT) calculation revealed {100} facet exposure was endowed with a strong oxygen adsorption, which weakens the breakage of the water molecule and suppresses the hazardous water dissociation and hydroxyl radical generation, which was supported by electron spin resonance (ESR)–based radical evaluation and X-ray photoelectron spectroscopy (XPS)-based oxygen identification. This means high-energy facet-based catalytic Pd nanocrystals can deliver low toxicity due to their unique surface properties.