No predictive biomarkers can robustly identify patients with non-small cell lung cancer (NSCLC) who will benefit from immune checkpoint inhibitor (ICI) therapies. Here, in a machine learning setting, we compared changes ("delta") in the radiomic texture (DelRADx) of CT patterns both within and outside tumor nodules before and after two to three cycles of ICI therapy. We found that DelRADx patterns could predict response to ICI therapy and overall survival (OS) for patients with NSCLC. We retrospectively analyzed data acquired from 139 patients with NSCLC at two institutions, who were divided into a discovery set (D 1 ¼ 50) and two independent validation sets (D 2 ¼ 62, D 3 ¼ 27). Intranodular and perinodular texture descriptors were extracted, and the relative differences were computed. A linear discriminant analysis (LDA) classifier was trained with 8 Del-RADx features to predict RECIST-derived response. Association of delta-radiomic risk score (DRS) with OS was determined. The association of DelRADx features with tumor-infiltrating lymphocyte (TIL) density on the diagnostic biopsies (n ¼ 36) was also evaluated. The LDA classifier yielded an AUC of 0.88 AE 0.08 in distinguishing responders from nonresponders in D 1 , and 0.85 and 0.81 in D 2 and D 3. DRS was associated with OS [HR: 1.64; 95% confidence interval (CI), 1.22-2.21; P ¼ 0.0011; C-index ¼ 0.72). Peritumoral Gabor features were associated with the density of TILs on diagnostic biopsy samples. Our results show that DelRADx could be used to identify early functional responses in patients with NSCLC.

No abstract

Inhalation of nanoparticles has been implicated in respiratory morbidity and mortality. In particular, carbon black nanoparticles are found in many different environmental exposures. Macrophages take up inhaled nanoparticles and respond via release of inflammatory mediators and in some cases cell death. Based on new data, we propose that exposure of macrophages (both a macrophage cell line and primary human alveolar macrophages) to carbon black nanoparticles induces pyroptosis, an inflammasome-dependent form of cell death. Exposure of macrophages to carbon black nanoparticles resulted in inflammasome activation as defined by cleavage of caspase 1 to its active form and downstream IL-1␤ release. The cell death that occurred with carbon black nanoparticle exposure was identified as pyroptosis by the protective effect of a caspase 1 inhibitor and a pyroptosis inhibitor. These data demonstrate that carbon black nanoparticle exposure activates caspase 1, increases IL-1␤ release after LPS priming, and induces the proinflammatory cell death, pyroptosis. The identification of pyroptosis as a cellular response to carbon nanoparticle exposure is novel and relates to environmental and health impacts of carbon-based particulates.Macrophages are critical regulators of local immune homeostasis. They are highly adaptive components of the innate immune system and respond in diverse ways to pathogens and other potential danger signals (1-3). In the lung, the alveolar macrophage is the first line of defense against environmental exposures. Alveolar macrophages phagocytose particulate matter, release inflammatory cytokines, and interact with other cells and molecules through the expression of surface receptors. One way in which an immune response is generated in alveolar macrophages is through the phagocytosis of deposited particles within the respiratory tract (4).The nanoparticle industry has expanded substantially in recent years. A variety of engineered carbon nanoparticles is used in consumer products such as car tires, rubber, and printer toner cartridges (5). Nanoparticles are also being used as novel means of drug delivery. Additionally, carbonaceous nanoparticles are present as an environmental contaminant. Combustion processes are a significant source of carbon nanoparticles. Elemental carbon-based nanoparticles with a diameter of less than 100 nm are a major part of diesel exhaust and ambient pollution (6).Particulate ambient pollution is known to cause adverse health effects in susceptible individuals and aggravates existing respiratory conditions such as asthma and chronic obstructive pulmonary disease (7). Even moderate levels of ambient air particulates are known to induce acute adverse health effects such as mortality in heart and lung diseases and chronic lung morbidity (8). Ultrafine particles are unique in their ability to bypass mucociliary clearance mechanisms and penetrate into deeper regions of the respiratory tract (9 -12). Although bulk elemental carbon is considered chemically inert (as in diamond and gra...

While several recent reports have described the toxicity of water-soluble C60 fullerene nanoparticles, none have reported the toxicity resulting from the inhalation exposures to C60 fullerene nanoparticles or microparticles. To address this knowledge gap, we exposed male rats to C60 fullerene nanoparticles (2.22 mg/m3, 55 nm diameter) and microparticles (2.35 mg/m3, 0.93 microm diameter) for 3 h a day, for 10 consecutive days using a nose-only exposure system. Nanoparticles were created utilizing an aerosol vaporization and condensation process. Nanoparticles and microparticles were subjected to high-pressure liquid chromatography (HPLC), XRD, and scanning laser Raman spectroscopy, which cumulatively indicated no chemical modification of the C60 fullerenes occurred during the aerosol generation. At necropsy, no gross or microscopic lesions were observed in either group of C60 fullerene exposures rats. Hematology and serum chemistry results found statistically significant differences, although small in magnitude, in both exposure groups. Comparisons of bronchoalveolar (BAL) lavage fluid parameters identified a significant increase in protein concentration in rats exposed to C60 fullerene nanoparticles. BAL fluid macrophages from both exposure groups contained brown pigments, consistent with C60 fullerenes. C60 lung particle burdens were greater in nanoparticle-exposed rats than in microparticle-exposed rats. The calculated lung deposition rate and deposition fraction were 41 and 50% greater, respectively, in C60 fullerene nanoparticle-exposed group than the C60 fullerene microparticle-exposed group. Lung half-lives for C60 fullerene nanoparticles and microparticles were 26 and 29 days, respectively. In summary, this first in vivo assessment of the toxicity resulting from inhalation exposures to C60 fullerene nanoparticles and microparticles found minimal changes in the toxicological endpoints examined. Additional toxicological assessments involving longer duration inhalation exposures are needed to develop a better and more conclusive understanding of the potential toxicity of inhaled C60 fullerenes whether in nanoparticle or microparticle form.