Hypersomnolence and Reduced Activity in Pan-Leptin Receptor Knockout Mice

Excessive obesity correlates with hypersomnolence and impaired cognitive function, presumably induced by metabolic factors and cytokines. Production of the adipokine leptin correlates with the amount of adiposity, and leptin has been shown to promote sleep. To determine whether leptin plays a major role in the hypersomnolence of obesity, we measured sleep architecture in pan-leptin receptor knockout (POKO) mice that do not respond to leptin because of the production of a mutant, non-signaling receptor. The obese POKO mice had more non-rapid eye movement (NREM) sleep and less waking time than their littermate controls. This was mainly seen during the light span, although increased bouts of rapid eye movement sleep were also seen in the dark span. The increase of NREM sleep correlated with the extent of obesity. The POKO mice also had decreased locomotor activity and more immobility in the open field test, but there was no increase of forced immobility nor reduction of sucrose intake as would be seen in depression. The increased NREM sleep and reduced locomotor activity in the POKO mice suggest that it was obesity, rather than leptin signaling, that played a predominant role in altering sleep architecture and activity.     

The Expression Changes of Cystathionine-β-synthase in Brain Cortex After Traumatic Brain Injury

Cystathionine-β-synthase (CBS) catalyzes the condensation of serine with homocysteine to form cystathionine and occupies a crucial regulatory position between the methionine cycle and the biosynthesis of cysteine by transsulfuration. It was reported that CBS was a novel marker of both differentiation and proliferation for certain cell types, suggesting that CBS represents a survival-promoting protein. However, its expression and function in the central nervous system lesion are not well understood. To investigate changes of CBS after traumatic brain injury (TBI) and its possible role, mice TBI model was established by controlled cortical impact system, and the expression and cellular localization of CBS after TBI was investigated in the present study. Western blot analysis revealed that CBS was present in normal mice brain cortex. It gradually decreased, reached a valley at the third day after TBI, and then restored to basal level. Importantly, more CBS was colocalized with neuron. In addition, Western blot detection showed that the third day postinjury was also the apoptosis peak indicated by the elevated expression of caspase-3. Importantly, immunohistochemistry analysis revealed that injury-induced expression of CBS was colabeled by Bcl-2 and had no co-localization with caspase-3. These data suggested that CBS may be implicated in the apoptosis of neuron and involved in the pathophysiology of brain after TBI.     

Extensive removal of thallium by graphene oxide functionalized with aza-crown ether

Thallium (Tl) is a highly toxic heavy metal, and its pollution and remediation in aquatic environments has attracted considerable attention. To reduce or remove Tl pollution in the environment, various strategies have been applied. Graphene oxide (GO) has abundant oxygen-containing functional groups, indicating its high application potential for pollution remediation via methods involving binding to metal ions or positively charged organic molecules or electrostatic interaction and coordination. However, the adsorption of Tl to GO occurs via physical adsorption, for which the adsorption efficiency is low. Therefore, herein, we report a new method to effectively remove Tl pollution in water. We combined GO with aza-crown ether, which enhanced the electronegativity and ability to bind metal ions. The functionalized graphene oxide (FGO) demonstrated high efficiency through a wide pH gradient of 5–10, with a dominant Tl(i) adsorption capacity (112.21 mg g⁻¹) based on the Langmuir model (pH 9.0, adsorbent concentration of 0.8 g L⁻¹). The adsorption of Tl(i) during removal fit a pseudo-second-order kinetic model well. The mechanisms of Tl removal involve physical and chemical adsorption. In summary, our study provides a new method for the detection and treatment of Tl-containing wastewater by using FGO.

Thallium (Tl) is a highly toxic heavy metal, and its pollution and remediation in aquatic environments has attracted considerable attention.     

A novel semi-mechanistic tumor growth fraction model for translation of preclinical efficacy of anti-glypican 3 antibody drug conjugate to human

The growing fraction (GF) of tumor has been reported as one of the predictive markers of the efficacy of chemotherapeutics. Therefore, a semi-mechanistic model has been developed that describes tumor growth on the basis of cell cycle, allowing the incorporation of the GF of a tumor in pharmacokinetic/pharmacodynamic (PK/PD) modeling. Efficacy data of anti-glypican 3 (GPC3) antibody drug conjugate (ADC) in a hepatocellular carcinoma (HCC) patient derived xenograft (PDX) model was used for evaluation of this proposed model. Our model was able to describe the kinetics of growth inhibition of HCC PDX models following treatment with anti-GPC3 ADC remarkably well. The estimated tumurostatic concentrations were used in tandem with human PKs translated from cynomolgus monkey for prediction of the efficacious dose. The projected efficacious human dose of anti-GPC3 ADC was in the range 0.20–0.63 mg/kg for the Q3W dosing regimen, with a median dose of 0.50 mg/kg. This publication is the first step in evaluating the applicability of GF in PK/PD modeling of ADCs. The authors are hopeful that incorporation of GF will result in an improved translation of the preclinical efficacy of ADCs to clinical settings and thereby better prediction of the efficacious human dose.     

Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling

Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells (MSCs) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on MSC senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging MSCs and the downregulation of autophagy can delay MSC senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and MSC senescence and explore the effects and mechanisms of premodulated autophagy on MSC senescence, we induced the up- or down-regulation of autophagy by using rapamycin (Rapa) or 3-methyladenine, respectively, before MSC senescence induced by D-galactose (D-gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated MSC aging induced by D-gal and inhibited ROS generation. p-Jun N-terminal kinases (JNK) and p-38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on MSC senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H₂O₂ on MSC senescence. In summary, the present study indicates that autophagy plays a protective role in MSC senescence induced by D-gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagy-delaying MSC senescence.     

超声引导下经皮微波消融与冷冻消融治疗高风险部位肝癌的对照研究

目的：比较超声引导下经皮微波消融与冷冻消融治疗高风险部位肝癌的临床结局及术后并发症,并分析影响预后和术后复发的因素。 方法：选取2014年4月至2018年3月广州复大肿瘤医院收治的120例高风险部位肝癌患者,其中64例接受微波消融治疗（微波组）,56例接受冷冻消融治疗（冷冻组）。比较两组的治疗结局,主要包括生存、复发及术后并发症。用Cox回归模型分析预后和术后复发的影响因素。 结果：微波消融组1、3、5年总生存率分别为85.8%、63.5%、63.5%,冷冻消融组为92.0%、87.4%、74.9%,两组差异无统计学意义（P=0.141）。微波消融组1、3、5年无复发生存率分别为77.8%、49.0%、49.0%,冷冻消融组分别为81.4%、58.5%、46.8%,两组差异无统计学意义（P=0.469）。微波消融组的3、6、9、12个月的局部进展率分别为3.1%、6.3%、9.4%、15.9%,高于冷冻消融组（分别为0%、0%、3.7%、19.0%）,差异有统计学意义（P=0.003）。微波组的主要和次要并发症发生率（分别为6.3%、82.8%）均高于冷冻组（分别为0%、32.1%）,差异有统计学意义。年龄≥65岁,直径3~5 cm及Child-Pugh分级B级是肝癌术后预后较差的危险因素;直径3~5 cm、多个肿瘤以及多次消融是消融术后复发的危险因素。 结论：冷冻消融治疗高风险部位的肝癌具有与微波消融接近的生存结局,但具有更好的局部肿瘤控制率及更少的并发症,适合在临床中推广应用。