12 research outputs found
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Predicting Response to Immunotherapy in Non-Small Cell Lung Cancer — From Bench to Bedside
Immune checkpoint inhibitor (ICI) therapy has emerged as the standard of care for patients with advanced non-small cell lung cancer (aNSCLC). Immuno-monotherapy (ImT) offers a better side effect profile than combination ICIs, but treatment response rates remain less than 25%. Predicting response to ImT could spare potential responders from adverse events and direct non-responders toward alternative treatments. Radiomics, a datamining technique that extracts patterns from medical imaging, has been incorporated into predictive models for many cancers. We hypothesized that a model combining pre-ImT radiomics, clinical, and laboratory data can predict patient response and guide clinical decision-making.
A murine model was designed to search for texture features and blood biomarkers predictive of ImT response. Nineteen C57BL/6 mice had Lewis Lung Carcinoma tumors injected into bilateral flanks. Pre-ImT CTs and bloodwork were obtained on day 7 post-implant. On day 8, 15 mice underwent radiotherapy (RT) to the right flank tumor (24 Gy in 3 daily fractions), followed by daily anti-PDL-1 ImT. Tumors on both flanks were assessed for treatment response. Bilateral response was seen in 4 mice. Pre-ImT CTs were mined for texture features correlating with systemic response. Next, 117 consecutive aNSCLC patients treated with nivolumab monotherapy were identified in an IRB-approved database. Baseline clinical features were assessed, including laboratory data and RT history. For all patients, the primary tumor in the last pre-ImT CT was segmented per RTOG guidelines. These volumes were analyzed for texture features associated with overall survival (OS). Univariate and multivariate cox regression were used to identify pre-ImT imaging, clinical, and laboratory parameters associated with OS. Areas under the receiver operating characteristic curve (AUC) were estimated to assess accuracy to predict greater than median OS.
Identical texture features (surface-to-mass ratio, average Gray, and 2D kurtosis) and neutrophil-to-lymphocyte (NLR) correlated with OS in humans (P = 0.041, < 0.001) and systemic response in mice (P < 0.001, = 0.01). A murine model using NLR and radiomics predicted systemic response with AUC of 1. A human model incorporating baseline ECOG, sex, pre-ImT NLR and radiomics had an AUC for predicting greater than median OS (308 days) of 0.808. Half of patients had a history of RT, but location, dose, fractionation, and timing were heterogeneous and RT was not significant.
For patients with aNSCLC treated with ImT, a combined model of pre-ImT radiomics, NLR, ECOG, and sex is predictive of OS. Texture features and NLR correlated with treatment response in both human and murine cohorts, suggesting generalizability. RT history was too heterogeneous to factor significantly as a predictor of OS. Future directions include identification of genomic biomarkers and model validation on an external patient cohort
Incorporating Perceptual Task Effort into the Recognition of Intention in Information Graphics
The rapidly increasing availability of electronic publications containing information graphics poses some interesting challenges in terms of information access. For example, visually impaired individuals should ideally be provided with access to the knowledge that would be gleaned from viewing the information graphic. Similarly, digital libraries must take into account the content of information graphics when constructing indices. This paper outlines our approach to recognizing the intended message of an information graphic, focusing on the concept of perceptual task effort, its role in the inference process, our rules for estimating effort, and the results of an eye tracking experiment conducted in order to evaluate and modify those rules
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Role of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in Renal Toxicity
Cisplatin-induced kidney damage, compounded by radiation therapy, leads to acute kidney injury (AKI) and chronic kidney disease (CKD), necessitating renal replacement therapies. We hypothesize that chemoradiotherapy-induced ABCA1 deficiency may disturb cholesterol metabolism, making podocytes susceptible and cancer cells resistant to treatment-induced injury.
To assess podocyte response to radiation, cultured podocytes were exposed to varying doses of radiation, and their cell index was monitored using a real-time cell index assay (RTCA). Cisplatin-induced podocytopathy was evaluated by treating an androgen-sensitive human prostate adenocarcinoma cell line (LNCaP) and human kidney cells (podocytes) with Cisplatin (10µM) ± ABCA1 inducer (GW3965; Sigma; 10µM) in an e-plate reader for 24 hours.,. Nuclear membrane fluidity was measured using an Abcam Membrane Fluidity Kit (ab189819) on nuclei isolated from ABCA1scrabmle (SC) and siABCA1 cell lines with PDA and pluronic F-127. Mice received bilateral kidney X-irradiation (4Gy, 14Gy, or fractionated 6x5Gy), and changes in ABCA1 expression and podocyte count were quantified using IHC.
The podocyte index was significantly decreased post 4 Gy (5.1±0.4 vs. 4.8± 0.2, p<0.0492) and further reduced at 8Gy (4.8±0.2 vs. 3.8± 0.25, p<0.0098), indicating a dose-dependent decrease in podocyte survival after RT. Cisplatin treatment alone reduces LNCaP (2.06±0.6 vs. 1.1± 0.1, p<0.0001) and podocyte differentiation (4.3±0.2 vs. 0.5± 0.1, p<0.0001). However, LXR agonist treatment enhances Cisplatin efficacy against LNCaP (2.06±0.2 vs. 0.53± 0.2, p<0.0001) and increases podocyte growth (6.06±0.3 vs. 2.1± 0.3, p<0.0001). Nuclear membrane fluidity assay indicates a significant reduction in podocyte nuclear membrane fluidity in siABCA1 podocytes compared to ABCA1 scramble podocytes (0.53±0.1 vs. 0.3± 0.08, p<0.0113) [3]. In vivo, studies show a decrease in ABCA1 expression in tubular and glomerular cells, including podocytes, after 4 Gy (21.69±4.8 vs. 11.47± 3.1, p<0.0001), which was further reduced after 14 Gy but not significantly (11.47±3.1 vs. 10.2± 3.8, p<0.8326). Fractionated 6x5Gy also resulted in a significant reduction in ABCA1 expression (21.69±4.7 vs. 12.73± 3.8, p<0.0001), with a lesser reduction compared to single dose 14Gy, though insignificant (10.2±3.9 vs. 12.73± 3.8, p< 0.3360).
Our findings indicate that ABCA1 deficiency makes podocytes susceptible and cancer cells resistant to radiation injury. Targeting pathways associated with ABCA1-mediated cholesterol metabolism might offer a promising approach to alleviate kidney injury while improving the effectiveness of cancer treatment
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Dose Escalation to 60 Gy in 3 Fractions with Stereotactic Body Radiation Therapy (SBRT) for Poor Surgical Candidates with Localized Renal Cell Carcinoma: Expansion of a Phase I Study
Resource Advantage Theory and Fair Trade Social Enterprises
This paper will investigate the competitive position of both fair trade (FT) social enterprises Divine Chocolate Ltd (Divine) and Cafédirect in their respective UK markets, namely chocolate confectionery and hot beverages. Using Eisenhardt’s (1989, 1991, and 2007) approach to building theory from multiple case studies, this four-year PhD study aims to identify the resources that enable FT social enterprises to compete. This research draws on recent developments in competition theory such as resource advantage theory (R-A theory), termed a general theory of competition. The paper will critically analyse if the social and ethical elements of these firm’s product offerings really constitute meaningful differentiators (i.e. comparative advantage) as required by R-A theory (Hunt and Morgan 1995, Hunt 2001). Hunt and Derozier (2004) argue that R-A theory can ground theories of business and marketing strategy and therefore identifying the competitive resources of FT social enterprises will have important strategic implications. The research findings show that both Divine and Cafédirect have established a mainstream competitive position in specific product segments and distribution channels. Thus illustrating intra-industry demand to be heterogeneous. In addition, both companies have been a catalyst for change by influencing the strategies and policies of both branded manufactures and retailers such as Cooperative Food (CF). The key theoretical contribution validates ‘social resources’ and its three inter-related components: ethical and social commitments, connections with partners and consistency of behaviour as a resource to extend R-A theory. These ‘social resources’ in combination with both relational resources and threshold capabilities (e.g. product quality) result in a competitive position for both case organisations. The ethical and social commitments of ‘social resources’ also appears to provide an example of an ethical underpinning to Relationship Marketing. The identification of ‘social resources’ has important wider implications for both other social enterprises and those companies who are aiming to achieve a competitive position based on social commitments