No abstract

Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.

BACKGROUND The risk for cardiovascular events increases within hours of near-roadway exposures. We aimed to determine the traffic-related air pollution (TRAP) and biological mechanisms involved and if reducing particulate matter <2.5 µm (PM2.5) inhalation is protective. METHODS Fifty healthy-adults underwent multiple 2-hour near-roadway exposures (Tuesdays to Fridays) in Ann Arbor during 2 separate weeks (randomized to wear an N95 respirator during 1 week). Monday both weeks, participants rested 2 hours in an exam room (once wearing an N95 respirator). Brachial blood pressure, aortic hemodynamics, and heart rate variability were repeatedly measured during exposures. Endothelial function (reactive hyperemia index [RHI]) was measured post-exposures (Thursdays). Black carbon (BC), total particle count (PC), PM2.5, noise and temperature were measured throughout exposures. RESULTS PM2.5 (9.3 ± 7.7 µg/m3), BC (1.3 ± 0.6 µg/m3), PC (8,375 ± 4,930 particles/cm3) and noise (69.2 ± 4.2 dB) were higher (P values <0.01) and aortic hemodynamic parameters trended worse while near-roadway (P values<0.15 vs. exam room). Other outcomes were unchanged. Aortic hemodynamics trended towards improvements with N95 respirator usage while near-roadway (P values<0.15 vs. no-use), whereas other outcomes remained unaffected. Higher near-roadway PC and BC exposures were associated with increases in aortic augmentation pressures (P values<0.05) and trends toward lower RHI (P values <0.2). N95 respirator usage did not mitigate these adverse responses (nonsignificant pollutant–respirator interactions). Near-roadway outdoor-temperature and noise were also associated with cardiovascular changes. CONCLUSIONS Exposure to real-world combustion-derived particulates in TRAP, even at relatively low concentrations, acutely worsened aortic hemodynamics. Our mixed findings regarding the health benefits of wearing N95 respirators support that further studies are needed to validate if they adequately protect against TRAP given their growing worldwide usage.

Histologic changes in dermal inflammation, elastin organization, and vascularity do not appear to correspond with the gradual improvement of hyperpigmentation, resulting from postmastectomy radiation. These histologic changes persist beyond the 12 month observation period and will require clinical correlation to determine the potential impact on postoperative outcomes.

Background Toxicity can lead to nonpersistence with adjuvant endocrine therapy (ET). We hypothesized that ET-induced change in grip strength would predict for early discontinuation of therapy because of musculoskeletal toxicity, and would be associated with BMI. Patients and Methods Postmenopausal women with breast cancer starting a new adjuvant ET were enrolled. Patients were monitored for 12 months to assess symptoms and ET adherence as well as change in grip strength and body mass index (BMI). The association between the change in grip strength and time to discontinuation was assessed using a joint longitudinal and survival model. Results 40.9% of 93 AI-treated and 9% of 22 tamoxifen-treated patients discontinued ET within 12 months because of toxicity (p=0.019). There was a trend towards a greater decrease in grip strength in AI-treated patients over time (p=0.055), which was not significantly associated with time to discontinuation (p=0.96). Receipt of an AI (HR 5.49, p= 0.019) and baseline pain (HR 1.19, p=0.004) significantly decreased the time to discontinuation. Conclusion In contrast with prior reports, change in grip strength was not associated with time to discontinuation of AI therapy. Future research should focus on proactive management of patients at increased risk of AI intolerance, such as those with high levels of pre-existing pain.