We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.

Oncogenic tyrosine kinases have proven to be promising targets for the development of highly effective anticancer drugs. However HER family tyrosine kinase inhibitors (TKIs) show only limited activity against HER2-driven cancers despite effective inhibition of EGFR and HER2 in vivo 1–8. The reasons for this are unclear. Signaling in trans is a key feature of this multimember family and the critically important PI3K/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 9,10. We report that HER3 and consequently PI3K/Akt signaling evade inhibition by current HER family TKIs in vitro and in tumors in vivo. This is due to a compensatory shift in HER3 phosphorylation-dephosphorylation equilibrium driven by increased membrane HER3 expression driving the phosphorylation reaction and reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt mediated negative feedback signaling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abbrogation of HER3 resistance by siRNA knockdown restores potent pro-apoptotic effects to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumors and the therapeutic promise of this oncoprotein target. However, since HER3 signaling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to effectively silence oncogenic HER2 signaling. The biologic marker to guide HER TKIs should be the transphosphorylation of HER3.

TiO(2) bilayer films with a normal surface (Ns-TiO(2)), surface defects (Sd-TiO(2)), and interface defects (Id-TiO(2)) were successfully prepared by a combination of cold plasma treatment (CPT) and sol-gel dip-coating technology. The photodegradation of rhodamine B (RhB) over these as-prepared TiO(2) films was investigated via UV-vis irradiation. Results indicate that the three kinds of films exhibit very different photodegradation processes for RhB. A mainly N-deethylation reaction over the Ns-TiO(2) films, whereas an efficient degradation (cycloreversion) of RhB occurs over the Sd-TiO(2) films. In the RhB/Id-TiO(2) system, however, efficient N-deethylation concomitant with the highly efficient cycloreversion of RhB is observed. The efficiency of the complete mineralization of RhB dye follows the order of Id-TiO(2) > Sd-TiO(2) > Ns-TiO(2). It is proposed that the defect sites at the surface or the interface of TiO(2) films promote the separation of photogenerated electron-holes, leading to a higher photoactivity of defective TiO(2) films. Moreover, the higher stability over Id-TiO(2) as compared to Sd-TiO(2) indicates that the interface defect sites in TiO(2) could be applied in environmental photocatalysis.

About 25% of breast cancers harbor the amplified oncogene HER2 and are dependent on HER2 kinase function, identifying HER2 as a vulnerable target for therapy. However,. HER2-HER3 activation is buffered so that it is protected against a nearly two log inhibition of HER2 catalytic activity; this buffering is driven by the negative regulation of HER3 by Akt. We have now further characterized HER2-HER3 signaling activity and shown that the compensatory buffering prevents apoptotic tumor cell death from occurring as a result of the combined loss of MAPK and Akt signaling. To overcome the cancer cells' compensatory mechanisms, we co-administered a PI3K/ mTor inhibitor and a HER2 tyrosinc kinase inhibitor. This treatment strategy proved suboptimal because it induced both tyrosine kinase inhibitor sensitizing and desensitizing effects and robust cross-compensation of MAPK and Akt signaling pathways. Noting that HER2-HER3 activity was completely inhibited by higher, fully inactivating doses of TKI, we then attempted to overcome the cells compensatory buffering with this higher dose. This treatment crippled all downstream signaling and induced tumor apoptosis. Although such high doses of TKI are toxic in vivo when given continuously, we found that intermittent doses of TKI administered to mice produced sequential cycles of tumor apoptosis and ultimately complete tumor regression in mouse models, with much less toxicity. This strategy for inactivation of HER2-HER3 tumorigenic activity is proposed for clinical testing.