Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma, unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We found similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increased cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects.

Background: Gram-negative late-onset neonatal sepsis has high mortality, but initial antibiotic regimens may not cover these most virulent pathogens. While heart rate characteristics (HRC) monitoring can lead to early sepsis diagnosis, other non-infective conditions elevate the HRC index, or HeRO score. Since a recent randomized trial showed reduced mortality with HeRO monitoring, we expect its use to increase. Cytokine levels rise in response to systemic inflammation and sepsis, and patterns of expression might differ depending on the infective organism.

Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drug drains via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used chemotherapeutic, to directly induce systemic VEGFR3-dependent lymphangiogenesis. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We saw similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment results in lymphatic hyperplasia and secretion of prochemotactic factors in lymph nodes. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increases cancer metastasis. These findings have broad-reaching implications for cancer patients receiving platinums and support the inclusion of anti-VEGFR3 therapy into treatment regimens.Summary Platinum chemotherapy induces lymphangiogenesis priming tissues for metastasis of breast cancer. Inhibition of VEGFR3 via antibody blockade can reverse these effects.

Mitochondrial dysfunction plays an important role in many diseases, but there is no satisfactory method to assess mitochondrial quantity and quality in vivo. Here we engineered a novel pMito‐Timer reporter gene from the existing pTimer‐1 reporter gene. pMito‐Timer encodes a mitochondria‐targeted green fluorescent protein (GFP) when newly synthesized, which shifts irreversibly to red fluorescence (DsRed) when oxidized. Confocal microscopy confirmed that Mito‐Timer targets to mitochondria in cultured mouse myoblasts, Drosophila heart and indirect flight muscles, and adult mouse skeletal muscle. Ratiometric algorithm showed that conditions that cause mitochondrial stress lead to a significant fluorescence shift toward DsRed with a significant increase of DsRed puncta. Somatic gene transfer in adult skeletal muscle in mice showed that high‐fat diet induces the same changes, which could be completely ameliorated by exercise training. Exercise training also results in increases in mitochondrial volume that could be quantified. Therefore, pMito‐Timer can be used to report mitochondrial health under both normal and pathological conditions and will provide a valuable tool to multiple disciplines investigating the role of the mitochondria in disease.

The spatiotemporal fidelity of signal transduction is maintained in large part by scaffolding proteins. In particular, A‐Kinase Anchoring Proteins (AKAPs) accelerate and amplify the phosphorylation of substrate proteins by anchored kinases. However, the mechanisms underlying these phenomena remain unclear. Our present study endeavors to clarify this mechanism utilizing a combination of mathematical modeling, biochemistry, and FRET microscopy. We propose a model wherein enzymes on a scaffold undergo a “conformational switch” into an active intermediate. This model predicts anchored enzymatic reactions to be accelerated, amplified, and insulated from inhibition in comparison to those occuring in solution. We are exploring a novel interaction between AKAP7α and Protein Kinase C (PKC) as a model system to validate these predictions. Our preliminary data comparing the FRET responses of a genetically encoded PKC activity reporter (CKAR) to an AKAP7α‐CKAR fusion protein reveal that both the speed and strength of the CKAR substrate phosphorylation is enhanced when it is tethered to AKAP7α. Additionally, PKC bound to AKAP7α appears to be less susceptible to several classes of PKC inhibitors, including the ATP competitive inhibitor Gö6976 and the substrate inhibitor PKC 20–28. Collectively, our findings provide strong theoretical and molecular evidence that more narrowly defines the anchoring hypothesis.