Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Acute pulmonary toxicity following occupational exposure to a floor stain protector in the building industry in Switzerland.

BACKGROUND: Waterproofing agents are widely applied to leather and textile garments; they are also used as floor stain protectors by professionals. Acute respiratory injury is described in three cases of young healthy adults following occupational inhalation of a new waterproofing formulation containing an acrylate fluoropolymer. Within 1 or 2 h after exposure they developed a rapidly progressive dyspnoea; two of them had hypoxaemia and flu-like reactions. All patients improved with supportive treatment in a few days. The mechanism of toxicity is still under investigation, but experimental data suggest the role of this new acrylate fluoropolymer. CONCLUSION: Tilers should be warned against spraying floor stain repellents; there is also a need to make consumers aware that the spraying of waterproofing agents in a closed environment and concomitant smoking should be avoided.

The JAK/STAT3 Pathway Is a Common Inducer of Astrocyte Reactivity in Alzheimer's and Huntington's Diseases.

Astrocyte reactivity is a hallmark of neurodegenerative diseases (ND), but its effects on disease outcomes remain highly debated. Elucidation of the signaling cascades inducing reactivity in astrocytes during ND would help characterize the function of these cells and identify novel molecular targets to modulate disease progression. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is associated with reactive astrocytes in models of acute injury, but it is unknown whether this pathway is directly responsible for astrocyte reactivity in progressive pathological conditions such as ND. In this study, we examined whether the JAK/STAT3 pathway promotes astrocyte reactivity in several animal models of ND. The JAK/STAT3 pathway was activated in reactive astrocytes in two transgenic mouse models of Alzheimer's disease and in a mouse and a nonhuman primate lentiviral vector-based model of Huntington's disease (HD). To determine whether this cascade was instrumental for astrocyte reactivity, we used a lentiviral vector that specifically targets astrocytes in vivo to overexpress the endogenous inhibitor of the JAK/STAT3 pathway [suppressor of cytokine signaling 3 (SOCS3)]. SOCS3 significantly inhibited this pathway in astrocytes, prevented astrocyte reactivity, and decreased microglial activation in models of both diseases. Inhibition of the JAK/STAT3 pathway within reactive astrocytes also increased the number of huntingtin aggregates, a neuropathological hallmark of HD, but did not influence neuronal death. Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly conserved between disease states, species, and brain regions. This universal signaling cascade represents a potent target to study the role of reactive astrocytes in ND.

Reinvention of chemotherapy: drug conjugates and nanoparticles.

PURPOSE OF REVIEW: Recent advances in nanotechnology have addressed some of the issues related to lack of selectivity and nonspecific toxicities associated with conventional chemotherapy. Nanoparticles are therapeutic carriers that can be fine tuned for specific application and for passive or active tumor targeting. RECENT FINDINGS: Although the nanoparticle field is rapidly expanding, there are to date only six nanoparticle-based drug delivery platforms and two antibody-drug conjugates that are clinically approved for cancer therapy. Here, we review the clinical data of liposomal anthracyclines, nanoparticle formulations of paclitaxel and trastuzumab emtansine. We then briefly comment on efficacy and safety issues of nanoparticles, as well as on the next-generation nanoparticles for cancer therapy. SUMMARY: The emerging development of cancer nanotechnology offers the opportunity of reinvestigating the potential of cytotoxic agents, improving tumor targeting and drug delivery, leading to better safety profile and antitumor activity. Adding specificity to nanoparticles may allow personalization of cancer therapy using chemotherapy.