bims-meluca 2021-10-24 papers

Free Radic Biol Med. 2021 Oct 18. pii: S0891-5849(21)00771-1. [Epub ahead of print]

Thioredoxin reductase-1 levels are associated with NRF2 pathway activation and tumor recurrence in non-small cell lung cancer.

Marina Delgobo, Rosângela Mayer Gonçalves, Marco Antônio Delazeri, Marcelo Falchetti, Alessandro Zandoná, Raquel Nascimento das Neves, Karoline Almeida, Adriane Cristina Fagundes, Daniel Pens Gelain, João Isidro Fracasso, Guilherme Baroni de Macêdo, Leonardo Priori, Nicklas Bassani, Alexander James Roy Bishop, Cassiano Mateus Forcelini, José Cláudio Fonseca Moreira, Alfeu Zanotto-Filho.

Activating mutations in the KEAP1/NRF2 pathway characterize a subset of non-small cell lung cancer (NSCLC) associated with chemoresistance and poor prognosis. We herein evaluated the relationship between 64 oxidative stress-related genes and overall survival data from 35 lung cancer datasets. Thioredoxin reductase-1 (TXNRD1) stood out as the most significant predictor of poor outcome. In a cohort of NSCLC patients, high TXNRD1 protein levels correlated with shorter disease-free survival and distal metastasis-free survival post-surgery, including a subset of individuals treated with platinum-based adjuvant chemotherapy. Bioinformatics analysis revealed that NSCLC tumors harboring genetic alterations in the NRF2 pathway (KEAP1, NFE2L2 and CUL3 mutations, and NFE2L2 amplification) overexpress TXNRD1, while no association with EGFR, KRAS, TP53 and PIK3CA mutations was found. In addition, nuclear accumulation of NRF2 overlapped with upregulated TXNRD1 protein in NSCLC tumors. Functional cell assays and gene dependency analysis revealed that NRF2, but not TXNRD1, has a pivotal role in KEAP1 mutant cells' survival. KEAP1 mutants overexpress TXNRD1 and are less susceptible to the cytotoxic effects of the TXNRD1 inhibitor auranofin when compared to wild-type cell lines. Inhibition of NRF2 with siRNA or ML-385, and glutathione depletion with buthionine-sulfoximine, sensitized KEAP1 mutant A549 cells to auranofin. NRF2 knockdown and GSH depletion also augmented cisplatin cytotoxicity in A549 cells, whereas auranofin had no effect. In summary, these findings suggest that TXNRD1 is not a key determinant of malignant phenotypes in KEAP1 mutant cells, although this protein can be a surrogate marker of NRF2 pathway activation, predicting tumor recurrence and possibly other aggressive phenotypes associated with NRF2 hyperactivation in NSCLC.

Keywords: Disease-free survival; Lung cancer; NRF2; Recurrence; Thioredoxin reductase

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.10.020

Nutrients. 2021 Sep 23. pii: 3332. [Epub ahead of print]13(10):

Relationship between Nutritional Status and Clinical Outcome in Patients Treated for Lung Cancer.

Jacek Polański, Mariusz Chabowski, Natalia Świątoniowska-Lonc, Krzysztof Dudek, Beata Jankowska-Polańska, Jan Zabierowski, Grzegorz Mazur.

BACKGROUND: Between 34.5% and 69% of the patients with lung cancer are at risk of malnutrition. Quality of life (QoL) and physical status assessment provides valuable prognostic data on lung cancer patients. Malnutrition is a prognostic parameter for clinical outcome. Therefore, the identification of significant factors affecting the clinical outcome and QoL is important. The purpose of this study was to evaluate the relationship between nutritional status and outcome, i.e., overall survival, time to tumor progression, and QoL, in lung cancer patients.
MATERIALS AND METHODS: We performed a systematic search of the Pubmed/MEDLINE databases per the Cochrane guidelines to conduct a meta-analysis consistent with the PRISMA statement, using the following keywords: "lung cancer," "malnutrition," "nutrition," "quality of life," "well-being," "health-related quality of life," and "outcome." Out of the 96 papers identified, 12 were included in our meta-analysis.
RESULTS: Our meta-analysis shows that patients with a good nutritional status have a better QoL than malnourished patients in the following functioning domains: physical (g = 1.22, 95% CI = 1.19 to 1.46, p < 0.001), role (g = 1.45, 95% CI = 1.31 to 1.59, p < 0.001), emotional (g = 1.10, 95% CI = 0.97 to 1.24, p < 0.001), cognitive (g = 0.91, 95% CI = 0.76 to 1.06, p < 0.001), and social (g = 1.41, 95% CI = 1.27 to 1.56, p < 0.001). The risk of death was significantly higher in malnourished than in well-nourished patients (HR = 1.53, 95% CI = 1.25 to 1.86, p < 0.001). Nutritional status was significantly associated with survival, indicating that patients with a poorer nutritional status are at more risk of relapse.
CONCLUSIONS: Nutritional status is a significant clinical and prognostic parameter in the assessment of lung cancer treatment. Malnutrition is associated with poorer outcome in terms of overall survival, time to tumor progression, and QoL in patients treated for lung cancer.

Keywords: clinical outcome; lung cancer; nutrition; quality of life; survival

DOI: https://doi.org/10.3390/nu13103332

Future Oncol. 2021 Oct 22.

Detection and verification of coexisting diagnostic markers in plasma and serum of patients with non-small-cell lung cancer.

Mengjie Yu, Runbin Sun, Yuqing Zhao, Feng Shao, Wei Zhu, Jiye Aa.

Aim: To screen and identify the potential biomarkers co-existing in plasma and serum of patients with non-small-cell lung cancer (NSCLC), and establish appropriate diagnostic models. Methods: A cohort of 195 plasma samples and 180 serum samples were obtained from healthy controls (HC), adenocarcinoma (AdC) and squamous cell carcinoma (SqCC) patients enrolled from the First Affiliated Hospital of Nanjing Medical University. Metabolites in plasma and serum were analyzed by GC-MS. Results: Hypoxanthine was found to have good performance in the differential diagnosis of NSCLC (including AdC and SqCC) and HC (area under the receiver operating characteristic [AUROC] ≥0.85). Combinations of metabolites could be used for differential diagnosis of NSCLC and HC (AUROC >0.93), AdC and HC (AUROC >0.91), SqCC and HC (AUROC >0.95), AdC and SqCC (AUROC >0.72). Conclusions: Metabolomics based on GC-MS can screen and identify the differential metabolites coexisting in plasma and serum of patients with NSCLC, and prediction models established by this method can be used for the differential diagnosis of patients with NSCLC.

Keywords: diagnosis; non-small-cell lung cancer; plasma; serum

DOI: https://doi.org/10.2217/fon-2021-0025

Immunotherapy. 2021 Oct 21.

Body composition and inflammation impact in non-small cell lung cancer patients treated by first-line immunotherapy.

Cinzia Baldessari, Annarita Pecchi, Raffaella Marcheselli, Giorgia Guaitoli, Riccardo Bonacini, Filippo Valoriani, Pietro Torricelli, Linda Reverberi, Renata Menozzi, Giuseppe Pugliese, Maria Giuseppa Vitale, Roberto Sabbatini, Federica Bertolini, Fausto Barbieri, Massimo Dominici.

Background: Immunotherapy changed the landscape of non-small cell lung cancer (NSCLC). Efforts were made to implement its action. This study aims to describe body composition, nutritional and inflammatory status in NSCLC patients treated by first-line immunotherapy, their correlation, variation and impact. Patients and methods: We retrospectively analyzed 44 consecutive patients who received pembrolizumab treatment. Results: During the therapy, inflammation and visceral fat increased, whereas muscle and subcutaneous fat decreased. Parameters related to inflammation had an interesting prognostic impact. High numbers of white blood cells remained significantly correlated with a high risk of death in multivariate model. Conclusion: For the best treatment choice, a combination of clinical and biological factors will be most likely be necessary. Prospective and larger studies with a multidimensional approach are needed.

Keywords: body composition; immunotherapy; inflammatory status; non-small cell lung cancer; nutritional status

DOI: https://doi.org/10.2217/imt-2021-0038

PLoS One. 2021 ;16(10): e0258616

Prospective observational study of nutritional/immunologic indices as predictive biomarkers for the response to anti-PD-1 drugs in non-small cell lung cancer (ICI-PREDICT study).

Shinkichi Takamori, Taro Ohba, Mototsugu Shimokawa, Taichi Matsubara, Naoki Haratake, Naoko Miura, Ryo Toyozawa, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient's nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025.

DOI: https://doi.org/10.1371/journal.pone.0258616

J Appl Physiol (1985). 2021 Oct 21.

REDD1 deletion attenuates cancer cachexia in mice.

Brian A Hain, Haifang Xu, Ashley M VanCleave, Bradley S Gordon, Scot R Kimball, David L Waning.

Cancer cachexia is a wasting disorder associated with advanced cancer that contributes to mortality. Cachexia is characterized by involuntary loss of body weight and muscle weakness that affects physical function. Regulated in DNA damage and development 1 (REDD1) is a stress-response protein that is transcriptionally upregulated in muscle during wasting conditions and inhibits mechanistic target of rapamycin complex 1 (mTORC1). C2C12 myotubes treated with Lewis lung carcinoma (LLC)-conditioned media increased REDD1 mRNA expression and decreased myotube diameter. To investigate the role of REDD1 in cancer cachexia, we inoculated 12-week old male wild-type or global REDD1 knockout (REDD1 KO) mice with LLC cells and euthanized 28-days later. Wild-type mice had increased skeletal muscle REDD1 expression, and REDD1 deletion prevented loss of body weight and lean tissue mass, but not fat mass. We found that REDD1 deletion attenuated loss of individual muscle weights and loss of myofiber cross sectional area. We measured markers of the Akt/mTORC1 pathway and found that, unlike wild-type mice, phosphorylation of both Akt and 4E-BP1 was maintained in the muscle of REDD1 KO mice after LLC inoculation, suggesting that loss of REDD1 is beneficial in maintaining mTORC1 activity in mice with cancer cachexia. We measured Foxo3a phosphorylation as a marker of the ubiquitin proteasome pathway and autophagy and found that REDD1 deletion prevented dephosphorylation of Foxo3a in muscles from cachectic mice. Our data provides evidence that REDD1 plays an important role in cancer cachexia through the regulation of both protein synthesis and protein degradation pathways.

Keywords: REDD1; cachexia; muscle

DOI: https://doi.org/10.1152/japplphysiol.00536.2021