Large-scale network dysfunction in youths with Internet gaming disorder: a meta-analysis of resting-state functional connectivity studies.

Internet gaming disorder (IGD) has been defined as a specific behavioral disorder, associated with abnormal interactions among large-scale brain networks. Researchers have sought to identify the network dysfunction in IGD using resting-state functional connectivity (rsFC). However, results across studies have not reached an agreement yet and the mechanism remains unclear. The present research aimed to investigate network dysfunction in IGD through a meta-analysis of rsFC studies. Twenty-two seed-based voxel-wise rsFC studies from 25 publications (594 individuals with IGD and 496 healthy controls) were included. By categorizing seeds into seed-networks based on their location within a prior functional network parcellations, we performed a Multilevel kernel density analysis (MKDA) within each seed-network to identify which brain systems showed abnormal interaction with particular seed-network in individuals with IGD. Compared to healthy control groups, individuals with IGD exhibited significant hypoconnectivity within the default mode network, and enhanced connectivity between the default mode network and insula within the ventral attention network. IGD was also associated with increased connectivity between the ventral attention network and somatomotor regions. Furthermore, the IGD groups showed hyperconnectivity between the limbic network and regions of the frontoparietal network. The results suggest that individuals with IGD show large-scale functional network alteration which underpins their core symptoms including poor emotional competence, cue-reactivity and craving, habitual addictive behaviors and impaired executive control. Whether the compensation mechanism exists in IGD is discussed, and further research is needed. The findings provide a neurocognitive network model of IGD, which may serve as functional biomarkers for IGD and have potentials for development of effective diagnosis and therapeutic interventions.

Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.

Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability of bufalin to reverse both inherent and acquired resistance to sorafenib. Bufalin synergized with sorafenib to inhibit tumor cell proliferation and induce apoptosis. This effect was at least partially due to the ability of bufalin to inhibit Akt activation by sorafenib. Moreover, the ability of bufalin to inactivate Akt depended on endoplasmic reticulum (ER) stress mediated by inositol-requiring enzyme 1 (IRE1). Silencing IRE1 with siRNA blocked the bufalin-induced Akt inactivation, but silencing eukaryotic initiation factor 2 (eIF2) or C/EBP-homologous protein (CHOP) did not have the same effect. Additionally, silencing Akt did not influence IRE1, CHOP or phosphorylated eIF2α expression. Two sorafenib-resistant HCC cell lines, which were established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to bufalin. Thus, Bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the IRE1 pathway. These findings warrant further studies to examine the utility of bufalin alone or in combination with sorafenib as a first- or second-line treatment after sorafenib failure for advanced HCC.