Correction: Early assessment of tumor response to photodynamic therapy using combined diffuse optical and diffuse correlation spectroscopy to predict treatment outcome.

[This corrects the article DOI: 10.18632/oncotarget.15720.].

Early assessment of tumor response to photodynamic therapy using combined diffuse optical and diffuse correlation spectroscopy to predict treatment outcome.

Photodynamic therapy (PDT) of cancer involves the use of a photosensitizer that can be light-activated to eradicate tumors via direct cytotoxicity, damage to tumor vasculature and stimulating the body's immune system. Treatment outcome may vary between individuals even under the same regime; therefore a non-invasive tumor response monitoring system will be useful for personalization of the treatment protocol. We present the combined use of diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) to provide early assessment of tumor response. The relative tissue oxygen saturation (rStO2) and relative blood flow (rBF) in tumors were measured using DOS and DCS respectively before and after PDT with reference to baseline values in a mouse model. In complete responders, PDT-induced decreases in both rStO2 and rBF levels were observed at 3 h post-PDT and the rBF remained low until 48 h post-PDT. Recovery of these parameters to baseline values was observed around 2 weeks after PDT. In partial responders, the rStO2 and rBF levels also decreased at 3 h post PDT, however the rBF values returned toward baseline values earlier at 24 h post-PDT. In contrast, the rStO2 and rBF readings in control tumors showed fluctuations above the baseline values within the first 48 h. Therefore tumor response can be predicted at 3 to 48 h post-PDT. Recovery or sustained decreases in the rBF at 48 h post-PDT corresponded to long-term tumor control. Diffuse optical measurements can thus facilitate early assessment of tumor response. This approach can enable physicians to personalize PDT treatment regimens for best outcomes.

Attenuation of Histone Methyltransferase KRYPTONITE-mediated transcriptional gene silencing by Geminivirus.

Although histone H3K9 methylation has been intensively studied in animals and a model plant Arabidopsis thaliana, little is known about the evolution of the histone methyltransferase and its roles in plant biotic stress response. Here we identified a Nicotiana benthamiana homolog of H3K9 histone methyltransferase KRYPTONITE (NbKYP) and demonstrated its fundamental roles on methylation of plant and virus, beside of leading to the suppression of endogenous gene expression and virus replication. NbKYP and another gene encoding DNA methyltransferase CHROMOMETHYLTRANSFERASE 3 (NbCMT3-1) were further identified as the key components of maintenance of transcriptional gene silencing, a DNA methylation involved anti-virus machinery. All three types of DNA methylations (asymmetric CHH and symmetric CHG/CG) were severely affected in NbKYP-silenced plants, but only severe reduction of CHG methylation found in NbCMT3-1-silenced plants. Attesting to the importance of plant histone H3K9 methylation immunity to virus, the virulence of geminiviruses requires virus-encoded trans-activator AC2 which inhibits the expression of KYP via activation of an EAR-motif-containing transcription repressor RAV2 (RELATED TO ABI3 and VP1). The reduction of KYP was correlated with virulence of various similar geminiviruses. These findings provide a novel mechanism of how virus trans-activates a plant endogenous anti-silencing machinery to gain high virulence.

A terpenoid phytoalexin plays a role in basal defense of Nicotiana benthamiana against Potato virus X.

Terpenoid phytoalexins function as defense compound against a broad spectrum of pathogens and pests in the plant kingdom. However, the role of phytoalexin in antiviral defense is still elusive. In this study, we identified the biosynthesis pathway of a sesquiterpenoid phytoalexin, capsidiol 3-acetate as an antiviral response against RNA virus Potato Virus X (PVX) in Nicotiana benthamiana. NbTPS1 and NbEAH genes were found strongly induced by PVX-infection. Enzymatic activity and genetic evidence indicated that both genes were involved in the PVX-induced biosynthesis of capsidiol 3-acetate. NbTPS1- or NbEAH-silenced plant was more susceptible to PVX. The accumulation of capsidiol 3-acetate in PVX-infected plant was partially regulated by jasmonic acid signaling receptor COI1. These findings provide an insight into a novel mechanism of how plant uses the basal arsenal machinery to mount a fight against virus attack even in susceptible species.

Hemodynamic monitoring of Chlorin e6-mediated photodynamic therapy using diffuse optical measurements.

Tumor response during photodynamic therapy (PDT) is heavily dependent on treatment parameters such as light dose, photosensitizer concentration, and tissue oxygenation. Therefore, it is desirable to have a real-time hemodynamic monitoring device in order to fine-tune the parameters and improve PDT efficacy. In this paper, such a tumor response monitoring system was built incorporating both frequency domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS), which enables concurrent monitoring of tissue oxygenation (StO2), total hemoglobin concentration (THC) and relative blood flow (rBF). The tumor metabolic rate of oxygen (TMRO2) was calculated by using the hemodynamic parameters. Mouse models bearing xenograft tumors were subjected to chlorin e6 (Ce6)-mediated PDT, and the four parameters were monitored with varying treatment conditions. The results show (1) At 3 h post-PDT, rStO2, rBF and rTMRO2 exhibited sharp PDT-induced decreases in responders (>40% reduction in tumor volume). Statistically significant difference between responders and non-responders were observed in rStO2 and rBF, but not in rTMRO2. (2) Non-responders show gradual recovery of rStO2, rBF and rTMRO2 from ∼24 h post-PDT, while responder group did not show recovery up until 48 h post-PDT. Long-term study results up to 2 weeks are also shown. It suggests the hybrid diffuse optical system is not only capable of real-time treatment monitoring, but also able to extract tumor metabolic rate of oxygen to provide more insights about therapy mechanism. Translation of this technique to the clinic will make a quick prognosis feasible and help with treatment optimization.