bims-mesote 2023-05-28 papers

Issue of 2023–05–28
seven papers selected by
Laura Mannarino, Humanitas Research

Mol Med Rep. 2023 Jul;pii: 132. [Epub ahead of print]28(1):

Immunohistochemical expression of cAMP in fluoroedenite‑induced malignant pleural mesothelioma: Preliminary results.

Giuseppe Broggi, Veronica Filetti, Gaetano Magro, Brunella Morante, Rossella Garro, Caterina Ledda, Venerando Rapisarda, Claudia Lombardo, Carla Loreto, Rosario Caltabiano.

Despite advances in understanding of the biology of malignant pleural mesothelioma (MPM), the prognosis of this malignancy remains poor. Although asbestos still remains the main pathogenic agent of MPM, other asbestos‑like fibers such as fluoro‑edenite (FE) fibers, induce MPM. Notable incidence and mortality rates of MPM have been found in Biancavilla, Italy, where FE fibers have been extracted from building materials for >50 years. Cyclic adenosine monophosphate (cAMP) is a secondary messenger that plays a key role in several physiological and pathological mechanisms regulating protein kinase A (PKA) and the CREB pathway. Hyperactivation of the cAMP/PKA/CREB pathway is involved in many neoplastic processes, including tumor cell proliferation, invasion and metastatic spread. The present study investigated immunohistochemical expression of cAMP in patients with FE‑induced MPM, which included six males and four females with an age range of 50‑93 years. There was high immunoexpression of cAMP in 5 out of 10 tumors while the remaining 5 cases showed low immunoexpression. In addition, there was a correlation between cAMP overexpression and decreased survival times (mean overall survival times, 7.5 months in high expression group vs. 18 months in low expression group).

Keywords: cAMP; fluoro‑edenite; immunohistochemistry; malignant pleural mesothelioma; prognosis

DOI: https://doi.org/10.3892/mmr.2023.13019

Nat Commun. 2023 May 20. 14(1): 2897

Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma.

Danielle S Potter, Ruochen Du, Stephan R Bohl, Kin-Hoe Chow, Keith L Ligon, Raphael Bueno, Anthony Letai.

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.

DOI: https://doi.org/10.1038/s41467-023-38552-z

Appl Radiat Isot. 2023 May 17. pii: S0969-8043(23)00210-5. [Epub ahead of print]198 110857

Influence of lung physical density on dose calculation in boron neutron capture therapy for malignant pleural mesothelioma.

Hiroyuki Sato, Takushi Takata, Minoru Suzuki, Yoshinori Sakurai.

The boron neutron capture therapy treatment planning systems such as SERA and TSUKUBA Plan, which are mainly based on the Monte Carlo method, require the lung physical density and composition of the tissue for the dose calculation. However, the physical density and composition of lungs may change because of diseases such as pneumonia and emphysema. We investigated the effect of the lung physical density on the neutron flux distribution and dose for the lung and tumor.

Keywords: Atomic number densities; Boron neutron capture therapy; Dose calculation; Lung physical density; Malignant pleural mesothelioma

DOI: https://doi.org/10.1016/j.apradiso.2023.110857

PeerJ. 2023 ;11 e15302

GC-MS-based untargeted metabolic profiling of malignant mesothelioma plasma.

Ding Wang, Jing Zhu, Na Li, Hongyang Lu, Yun Gao, Lei Zhuang, Zhongjian Chen, Weimin Mao.

Background: Malignant mesothelioma (MM) is a cancer caused mainly by asbestos exposure, and is aggressive and incurable. This study aimed to identify differential metabolites and metabolic pathways involved in the pathogenesis and diagnosis of malignant mesothelioma.
Methods: By using gas chromatography-mass spectrometry (GC-MS), this study examined the plasma metabolic profile of human malignant mesothelioma. We performed univariate and multivariate analyses and pathway analyses to identify differential metabolites, enriched metabolism pathways, and potential metabolic targets. The area under the receiver-operating curve (AUC) criterion was used to identify possible plasma biomarkers.
Results: Using samples from MM (n = 19) and healthy control (n = 22) participants, 20 metabolites were annotated. Seven metabolic pathways were disrupted, involving alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; butanoate and histidine metabolism; beta-alanine metabolism; and pentose phosphate metabolic pathway. The AUC was used to identify potential plasma biomarkers. Using a threshold of AUC = 0.9, five metabolites were identified, including xanthurenic acid, (s)-3,4-hydroxybutyric acid, D-arabinose, gluconic acid, and beta-d-glucopyranuronic acid.
Conclusions: To the best of our knowledge, this is the first report of a plasma metabolomics analysis using GC-MS analyses of Asian MM patients. Our identification of these metabolic abnormalities is critical for identifying plasma biomarkers in patients with MM. However, additional research using a larger population is needed to validate our findings.

Keywords: Biomarker; GC-MS; Malignant mesothelioma; Metabolomics

DOI: https://doi.org/10.7717/peerj.15302

Cancer Med. 2023 May 24.

Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321.

Takashi Kasai, Kiyoshi Mori, Yoichi Nakamura, Nobuhiko Seki, Yasuko Ichikawa, Haruhiro Saito, Tetsuro Kondo, Kazuo Nishikawa, Satoshi Otsu, Akihiro Bessho, Hiroshi Tanaka, Hiroyuki Yamaguchi, Takayuki Kaburagi, Hisao Imai, Keita Mori, Junya Ohtake, Hiroaki Okamoto.

INTRODUCTION: Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non-squamous, non-small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient.
METHODS: Eligibility criteria included: no prior chemotherapy; advanced, non-squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation-negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four-week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression-free survival (PFS) after induction chemotherapy. Myeloid-derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed.
RESULTS: Thirty-five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34-0.93], log-rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log-rank p = 0.077). Pretreatment monocytic (M)-MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724).
CONCLUSIONS: Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non-squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M-MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.

Keywords: advanced, non-squamous, non-small cell lung cancer; bevacizumab maintenance therapy; cisplatin; pemetrexed; randomized, Phase II study

DOI: https://doi.org/10.1002/cam4.6135