Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.

Ferromagnetic materials are important for modern technology; their applications range from distribution of power to high-speed computers and electronic devices of all kinds. Considerable attention has been paid in recent years to the development of ferromagnetic nanocomposites, such as ferromagnetic metals confined within nanostructures, for their potential use in spintronics, for example magnetoresistive random access memory, anisotropic magnetic response, lowthreshold-voltage electron emitters, and magnetic recording media with high storage densities.[1±5] In particular, extensive investigations [6±14] have been carried out to fill carbon nanotubes (CNTs) with metallic elements or compounds. Here we report an investigation of the possible use of a CNT/Fe nanocomposite as a high-loss material, for example as an electromagnetic shielding material or a high-performance radar-absorbent material (RAM). We will show that Fe can be filled into CNTs by a simple catalytic pyrolysis routine, and that both the shape and phase of the filler Fe, which has a profound effect on the microwave absorption properties and the complex permittivity and permeability of the CNT/Fe nanocomposite, can be controlled. Our CNT samples were prepared by the chemical vapor deposition (CVD) method [15] (see also the Experimental section). The samples used for electromagnetic measurements were prepared by dispersing the CNT/Fe nanocomposite into epoxy resin with a weight ratio of 1:5. In order to measure the reflection loss of the sample, a portion of the sample was coated onto an aluminum substrate (180 mm 180 mm) with a thickness of 1.2 mm. The remaining sample was molded into the hollow pipe of a rectangular waveguide cavity for complex permittivity and permeability measurements; the cavity has a dimension of 10.2 mm 2.9 mm 1.2 mm. For comparison we also prepared a flat sheet of soft Fe 1.2 mm thick (sample F). The complex relative permittivity e r = e¢ ± je² r , permeability lr = l¢ ± jl² r , and reflection loss were measured using a HP8510C vector network analyzer working at the 2±18 GHz band.Comprehensive structural characterizations of the samples were carried out.[15] Three transmission electron microscope (TEM) images of samples A±C are shown in Figures 1a±c, respectively, and Figure 1d shows a high-resolution TEM (HRTEM) image of sample E. These TEM images and the corresponding electron diffraction (ED) patterns (Figs. 1g,h) and element maps (Figs. 1e,f) show that sample A is composed of mainly multiwalled CNTs (MWCNTs; Fig. 1a), sample B is composed of mainly particle-like Fe encapsulated within carbon nanocages (Fig. 1b), and sample C is composed of mainly Fe nanowires encapsulated within MWCNTs (Fig. 1c). Detailed electron energy loss spectroscopy (EELS) and elemental mapping studies showed that the filler Fe is pure Fe rather than its oxide (see Fig. 1c and especially the iron and oxygen maps, Figs.

SUMMARY Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. Breast and lung cancer cells express protocadherin 7 (PCDH7) to favor the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells employ these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines IFNα and TNFα. As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, which support tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle for the applicability of this therapeutic strategy to treat established brain metastasis.

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The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose-and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.