Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.

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The EA in combination with PI could improve the cognitive function of IA patients, and its mechanism might be related to the speedup of cerebral discrimination on external stimulus and the enhancement of effective resource mobilization during information processing of the brain.

Internet addiction (IA) has become a global mental and social problem, which may lead to a series of psychiatric symptoms including uncontrolled use of internet, and lack of concentration. However, the exact pathophysiology of IA remains unclear. Most of functional connectivity studies were based on pre-selected regions of interest (ROI), which could not provide a comprehensive picture of the communication abnormalities in IA, and might lead to limited or bias observations. Using local functional connectivity density (lFCD), this study aimed to explore the whole-brain abnormalities of functional connectivity in IA. We evaluated the whole-brain lFCD resulting from resting-state fMRI data in 28 IA individuals and 30 demographically matched healthy control subjects (HCs). The correlations between clinical characteristics and aberrant lFCD were also assessed. Compared with HCs, subjects with IA exhibited heightened lFCD values in the right dorsolateral prefrontal cortex (DLPFC), left parahippocampal gyrus (PHG), and cerebellum, and the bilateral middle cingulate cortex (MCC) and superior temporal pole (STP), as well as decreased lFCD values in the right inferior parietal lobe (IPL), and bilateral calcarine and lingual gyrus. Voxel-based correlation analysis revealed the significant correlations between the Young's Internet Addiction Test (IAT) score and altered lFCD values in the left PHG and bilateral STP. These findings revealed the hyper-connectivity in cognitive control network and default mode network as well as the hypo-connectivity in visual attention network, verifying the common mechanism in IA and substance addiction, and the underlying association between IA, and attention deficit/hyperactivity disorder in terms of neurobiology.

Phosphoinositide 3-kinase (PI3K) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. Wortmannin and its analogues are potent PI3K inhibitors whose therapeutic use has been impeded by inherent defects such as instability and toxicity. Pegylation of wortmannin and 17-hydroxywortmannin gives rise to conjugates with improved properties, including a higher therapeutic index. Pegylated 17-hydroxywortmannin (8, PWT-458) has been selected for further development.