| 1. |
- Ajona, Daniel, et al.
(författare)
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Complement C4d-specific antibodies for the diagnosis of lung cancer
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:5, s. 6346-6355
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Tidskriftsartikel (refereegranskat)abstract
- Development of molecular markers that help to identify high-risk individuals or diagnose indeterminate pulmonary nodules could have a major impact on lung cancer clinical management. In this study, we evaluated the diagnostic potential of a newly-developed ELISA that specifically detects complement C4d. We measured this marker in five independent cohorts of plasma and bronchoalveolar lavage samples from lung cancer patients and controls. In case-control studies, the area under the ROC curve for the diagnosis of lung cancer was 0.82 (95%CI = 0.72-0.92) in plasma samples, and 0.80 (95%CI = 0.69 to 0.90) in bronchoalveolar lavage fluids. In a set of plasma samples from the MILD CT-screening trial, the assay was unable to discriminate between asymptomatic high-risk individuals with or without early stage lung cancer. On the contrary, in two independent cohorts of individuals with indeterminate pulmonary nodules, plasma samples from patients with lung cancer nodules presented higher levels of C4d than those from patients with benign nodules. Using a target population of patients with 8 to 30 mm nodules, the test identified likely benign lung nodules with 84% negative predictive value and 54% positive predictive value, at 89% specificity and 44% sensitivity. In conclusion, the specific determination of C4d may serve as an adjunct to current clinical practice in the diagnosis of indeterminate pulmonary nodules.
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| 2. |
- Felberg, Anna, et al.
(författare)
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Elevated expression of complement factor I in lung cancer cells associates with shorter survival–Potentially via non-canonical mechanism
- 2024
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Ingår i: Translational Research. - 1931-5244. ; 269, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis of low vs. high FI content revealed HR 0.55, 95 % CI 0.32-0.95, p=0.031 for PFS, HR 0.51, 95 % CI 0.25-1.02, p=0.055 for OS, and HR 0.32, 95 % CI 0.12-0.84, p=0.021 for DSS. Unfavorable prognosis might stem from the non-canonical role of FI, as the staining pattern did not correlate with C4d - the product of FI-supported degradation of active complement component C4b. To elucidate that, we engineered three human NSCLC cell lines naturally expressing FI with CRISPR/Cas9 technology, and compared the transcriptome of FI-deficient and FI-sufficient clones in each cell line. RNA sequencing revealed differentially expressed genes engaged in intracellular signaling pathways controlling proliferation, apoptosis, and responsiveness to growth factors. Moreover, in vitro colony-formation assays showed that FI-deficient cells formed smaller foci than FI-sufficient NSCLC cells, but their size increased when purified FI protein was added to the medium. We postulate that a non-canonical activity of FI influences cellular physiology and contributes to the poor prognosis of lung cancer patients.
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| 3. |
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| 4. |
- Okroj, Marcin, et al.
(författare)
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Hypoxia increases susceptibility of non-small cell lung cancer cells to complement attack.
- 2009
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Ingår i: Cancer immunology, immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 58, s. 1773-1782
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Tidskriftsartikel (refereegranskat)abstract
- The complement system can be specifically targeted to tumor cells due to molecular changes on their surfaces that are recognized by complement directly or via naturally occurring antibodies. However, tumor cells often overexpress membrane-bound complement inhibitors protecting them from complement attack. We have previously shown that non-small cell lung cancer (NSCLC) cells, additionally to membrane-bound inhibitors, produce substantial amounts of soluble regulators such as factor I (FI) and factor H (FH). Since low oxygen concentration is associated with rapidly growing solid tumors, we studied how NSCLC cells protect themselves from complement attack under hypoxic conditions. Unexpectedly, mRNA levels and secretion of both FI and FH were significantly decreased already after 24 h exposure to hypoxia while cell viability measured by XTT assay and annexin V/7-AAD staining was affected only marginally. Furthermore, we observed decrease of mRNA level and loss of membrane-bound complement inhibitor CD46 and increased deposition of early (C3b) and terminal (C9) complement components on hypoxic NSCLC cells. All three complement pathways (classical, lectin and alternative) were employed to deposit C3b on cell surface. Taken together, our results imply that under hypoxic conditions NSCLC give up some of their available defense mechanisms and become more prone to complement attack.
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| 5. |
- Okroj, Marcin, et al.
(författare)
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Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors
- 2008
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Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 45:1, s. 169-179
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Tidskriftsartikel (refereegranskat)abstract
- The complement system is important for protection from invading pathogens, removal of waste products and guidance of the immune response. Furthermore, complement can be also targeted to cancer cells. However, membrane-bound inhibitors over-expressed by certain types of tumor cells restrict the cytotoxic activity of complement. Herein we report that non-small cell lung cancer (NSCLC) cells produce soluble complement inhibitors factor I (FI) and C4b-binding protein (C4BP). FI is a serine protease capable of degrading the activated complement components C3b and C4b, whilst C4BP acts as its cofactor. Furthermore, NSCLC cells express membrane-bound regulators and shed membrane cofactor protein (MCP), which shares cofactor function with C4BP. Secretion of FI from NSCLC cells was higher than previously reported for any non-hepatic source and FI produced by these cells could efficiently support cleavage of C3b and C4b. In vitro functional assays revealed that additional FI significantly decreased C3 deposition and complement-dependent lysis, particularly when cofactors were added. Our results demonstrate that soluble inhibitors produced by NSCLC cells may provide further protection from complement beyond the level ensured by membrane-bound inhibitors and, as such, contribute to the aggressive phenotype of these lung cancer cells.
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| 6. |
- Perez-Gracia, Jose Luis, et al.
(författare)
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Strategies to design clinical studies to identify predictive biomarkers in cancer research
- 2017
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Ingår i: Cancer Treatment Reviews. - : Elsevier BV. - 0305-7372. ; 53, s. 79-97
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Forskningsöversikt (refereegranskat)abstract
- The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework—the DESIGN guidelines—to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field.
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| 7. |
- Stanaway, Jeffrey D., et al.
(författare)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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