Life in aerobic environments requires organisms to maintain strict control over their internal redox status. At the cellular level, aerobic respiration poses a particularly unique challenge for living systems, as the energy-releasing reduction of oxygen to water generates partially reduced reactive oxygen species (ROS) intermediates that can exert widely divergent physiological and/or pathological effects. 1 Unregulated production of ROS results in oxidative stress, and subsequent buildup of free radical damage to proteins, lipids, and nucleic acids is connected to serious human diseases where age is a risk factor. 2,3 However, emerging evidence suggests that controlled production of one ROS in particular, hydrogen peroxide, can mediate cellular signal transduction through reversible oxidation and reduction of cysteine thiols and other redox-active groups. 4-8The complex, reversible oxidation biology of the cell and its broad implications in human health and disease provide motivation for developing new ways to study dynamic redox chemistry in living systems. In this regard, fluorescence imaging with redox-responsive chemosensors is a potentially powerful approach to probe various stages of oxidative signaling, stress, or repair in real time in living cells. Traditional fluorescent probes for redox activity, including dichlorodihydrofluorescein or dihydrorhodamine 123, are useful for cellular studies but can only respond irreversibly to a single initial oxidation event. 9-11 In contrast, fluorophores that can respond reversibly to changes in oxidation or reduction events would be much more valuable for visualizing cycles of redox signaling, stress, or repair and their dynamic interconversion. A few redox-sensitive fluorescent reporters based on protein 12,13 or peptide 14,15 scaffolds have been described, but no small molecules have been reported to date for imaging reversible oxidation and reduction events in living biological systems. We now present the synthesis, properties, and live-cell imaging applications of Redoxfluor-1 (RF1), a new type of fluorescent sensor for detecting reversible redox cycles in aqueous solution and in living cells. RF1 features a dual colorimetric/fluorimetric readout for oxidation-reduction events, a >50-fold fluorescence dynamic range, and visible wavelength excitation and emission profiles to minimize cellular damage and autofluorescence. In addition, RF1 can be loaded into living cells and image multiple, reversible cycles of oxidative stress and reductive repair.Our design strategy for fluorescence detection of reversible oxidation-reduction events is inspired by the extensive use of disulfides as redox resevoirs in biology. We anticipated that integrating this unit into a fluorescein scaffold would provide a small-molecule redox reporter with desirable optical properties and biological compatibility. Along these lines, the synthesis of RF1 proceeds in three steps as shown in Scheme 1. Lithiation of naphthalene in the presence of TMEDA and quenching with sulfur affords disulfid...

Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate.

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OBJECTIVE Tumor and edema volume changes of brain metastases after stereotactic radiosurgery (SRS) and ipilimumab are not well described, and there is concern regarding the safety of combination treatment. The authors evaluated tumor, edema, and adverse radiation-induced changes after SRS with and without ipilimumab and identified associated risk factors. METHODS This single-institution retrospective study included 72 patients with melanoma brain metastases treated consecutively with upfront SRS from 2006 to 2015. Concurrent ipilimumab was defined as ipilimumab treatment within 4 weeks of SRS. At baseline and during each follow-up, tumor and edema were measured in 3 orthogonal planes. The (length × width × height/2) formula was used to estimate tumor and edema volumes and was validated in the present study for estimation of edema volume. Tumor and edema volume changes from baseline were compared using the Kruskal-Wallis test. Local failure, lesion hemorrhage, and treatment-related imaging changes (TRICs) were analyzed with the Cox proportional hazards model. RESULTS Of 310 analyzed lesions, 91 were not treated with ipilimumab, 59 were treated with concurrent ipilimumab, and 160 were treated with nonconcurrent ipilimumab. Of 106 randomly selected lesions with measurable peritumoral edema, the mean edema volume by manual contouring was 7.45 cm and the mean volume by (length × width × height)/2 formula estimation was 7.79 cm with R = 0.99 and slope of 1.08 on line of best fit. At 6 months after SRS, the ipilimumab groups had greater tumor (p = 0.001) and edema (p = 0.005) volume reduction than the control group. The concurrent ipilimumab group had the highest rate of lesion response and lowest rate of lesion progression (p = 0.002). Within the concurrent ipilimumab group, SRS dose ≥ 20 Gy was associated with significantly greater median tumor volume reduction at 3 months (p = 0.01) and 6 months (p = 0.02). The concurrent ipilimumab group also had the highest rate of lesion hemorrhage (p = 0.01). Any ipilimumab was associated with higher incidence of symptomatic TRICs (p = 0.005). The overall incidence of pathologically confirmed radiation necrosis (RN) was 2%. In multivariate analysis, tumor and edema response at 3 months were the strongest predictors of local failure (HR 0.131 and HR 0.125) and lesion hemorrhage (HR 0.225 and HR 0.262). Tumor and edema response at 1.5 months were the strongest predictors of TRICs (HR 0.144 and HR 0.297). CONCLUSIONS The addition of ipilimumab improved tumor and edema volume reduction but was associated with a higher incidence of lesion hemorrhage and symptomatic TRICs. There may be a radiation dose-response relationship between SRS and ipilimumab when administered concurrently. Early tumor and edema response were excellent predictors of subsequent local failure, lesion hemorrhage, and TRICs. The incidence of pathologically proven RN was low, supporting the relative safety of ipilimumab in radiosurgery treatment.

Treatment of disseminated PA is frequently multi-modal, including surgical resection, chemotherapy, and radiation therapy. On the basis of early clinical data, extended-field radiation therapy is a viable option for treating disseminated PA.