Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

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Endogenous TNF␣ prevents the attainment of maximum achievable peak bone mass in vivo. In vitro, TNF␣ suppresses BMP-2-and TGF␤-mediated Smad activation through induction of NF-B. Consistently, pharmacological suppression of NF-B augments osteoblast differentiation and mineralization in vitro.Introduction: Osteoporosis is a major health threat. Traditional therapeutic strategies have centered on anti-catabolic drugs that block bone resorption. Recently focus has shifted to anabolic agents that actively rebuild lost bone mass. Future strategies may involve elevating peak bone mass to delay osteoporosis development. Recent in vitro studies show that TNF␣ represses osteoblast differentiation and mineralization; however, the mechanisms are poorly understood and the impact of basal TNF␣ concentrations on the acquisition of peak bone mass in vivo is unknown. Materials and Methods: We examined peak BMD, bone volume, and bone turnover makers in mice deficient in TNF␣ or its receptors. We further examined the effect of TNF␣ on Smad-induced signaling by TGF␤ and BMP-2 in vitro using a Smad responsive reporter. The effect of TNF␣-induced NF-B signaling on Smad signaling and on in vitro osteoblast mineralization was examined using specific NF-B inhibitors and activators, and effects of TNF␣-induced NF-B signaling on BMP-2-induced Runx2 mRNA were examined using RT-PCR. Results: Mice null for TNF␣ or its p55 receptor had significantly increased peak bone mass, resulting exclusively from elevated bone formation. In vitro, TNF␣ potently suppressed Smad signaling induced by TGF␤ and BMP-2, downregulated BMP-2-mediated Runx2 expression, and inhibited mineralization of osteoblasts. These effects were mimicked by overexpression of NF-B and prevented by pharmacological NF-B suppression. Conclusions: Our data suggest that TNF␣ and NF-B antagonists may represent novel anabolic agents for the maximization of peak basal bone mass and/or the amelioration of pathological bone loss.

Changes in PCC functional connectivity comprised bidirectional alterations in the resting networks in AD-affected brains, and the impaired resting functional connectivity seemed to change with AD progression. Therefore, alterations in functional connectivity in the default mode network might play a role in the progression of AD.

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