bims-meluca 2018-09-23 papers

Comput Biol Med. 2018 Sep 08. pii: S0010-4825(18)30258-0. [Epub ahead of print]102 1-15

A smart and operator independent system to delineate tumours in Positron Emission Tomography scans.

Albert Comelli, Alessandro Stefano, Giorgio Russo, Maria Gabriella Sabini, Massimo Ippolito, Samuel Bignardi, Giovanni Petrucci, Anthony Yezzi.

Positron Emission Tomography (PET) imaging has an enormous potential to improve radiation therapy treatment planning offering complementary functional information with respect to other anatomical imaging approaches. The aim of this study is to develop an operator independent, reliable, and clinically feasible system for biological tumour volume delineation from PET images. Under this design hypothesis, we combine several known approaches in an original way to deploy a system with a high level of automation. The proposed system automatically identifies the optimal region of interest around the tumour and performs a slice-by-slice marching local active contour segmentation. It automatically stops when a "cancer-free" slice is identified. User intervention is limited at drawing an initial rough contour around the cancer region. By design, the algorithm performs the segmentation minimizing any dependence from the initial input, so that the final result is extremely repeatable. To assess the performances under different conditions, our system is evaluated on a dataset comprising five synthetic experiments and fifty oncological lesions located in different anatomical regions (i.e. lung, head and neck, and brain) using PET studies with 18F-fluoro-2-deoxy-d-glucose and 11C-labeled Methionine radio-tracers. Results on synthetic lesions demonstrate enhanced performances when compared against the most common PET segmentation methods. In clinical cases, the proposed system produces accurate segmentations (average dice similarity coefficient: 85.36 ± 2.94%, 85.98 ± 3.40%, 88.02 ± 2.75% in the lung, head and neck, and brain district, respectively) with high agreement with the gold standard (determination coefficient R2 = 0.98). We believe that the proposed system could be efficiently used in the everyday clinical routine as a medical decision tool, and to provide the clinicians with additional information, derived from PET, which can be of use in radiation therapy, treatment, and planning.

Keywords: 18F-fluoro-2-deoxy-d-glucose and 11C-labeled methionine PET imaging; Active contour algorithm; Biological target volume; Cancer segmentation

DOI: https://doi.org/10.1016/j.compbiomed.2018.09.002

Gene. 2018 Sep 13. pii: S0378-1119(18)30973-9. [Epub ahead of print]679 352-359

Targeting apoptosis by 1,2-diazole through regulation of EGFR, Bcl-2 and CDK-2 mediated signaling pathway in human non-small cell lung carcinoma A549 cells.

Venugopal Vinod Prabhu, Perumal Elangovan, Sivasithambaram Niranjali Devaraj, Kunnathur Murugesan Sakthivel.

Lung cancer is the leading cause of cancer deaths worldwide and non-small cell lung carcinoma (NSCLC), a heterogeneous class of tumors, represents approximately 85% of all new lung cancer diagnosis. Conventional treatment options have limited efficacy because most cases are in the advanced stage at the time of diagnosis. The present study evaluates the anti-cancer activity of 1,2-diazole (pyrazole), a natural compound from mangrove plant Rhizophora apiculata (R.apiculata) on A549 lung carcinoma cells. In the present study the anti-cancer mechanism of pyrazole, was examined by the expression level of proteins Epidermal growth factor receptor (EGFR), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2) and Cyclin-dependent kinase-2 (CDK-2) which are commonly associated with the cell signaling pathways that control cell survival and apoptosis, that could facilitate to develop a novel target and effective treatment approach for patients with NSCLC. Pyrazole significantly induced cell cycle arrest and initiated apoptosis through inhibition of downstream components of EGFR tyrosine kinase pathway. Pyrazole disrupts the mitochondrial membrane potential and modulated the protein levels of Bax and Bcl-2 which could probably lead to caspase-3 activation. Furthermore, Pyrazole suppresses the expression of CDK-2 resulting in cell cycle arrest at G1 phase and in the G1-S phase transition. Taken together, the current study provides new insight in to the precise molecular mechanisms responsible for the anti-cancer activity of pyrazole in NSCLC, A549 cells. The study opens an avenue for development of a natural compound as a potential therapeutic agent which could target cell signaling pathways to combat human NSCLC.

Keywords: 1,2-diazole; Apoptosis; Epidermal growth factor receptor; Lung cancer; Non-small cell lung carcinoma; Pyrazole; Targeted gene therapy

DOI: https://doi.org/10.1016/j.gene.2018.09.014

Hum Pathol. 2018 Sep 12. pii: S0046-8177(18)30352-6. [Epub ahead of print]

Usefulness of complementary next-generation sequencing and quantitative immunohistochemistry panels for predicting brain metastases and selecting a treatment outcomes of non-small cell lung cancer.

Juliana Machado-Rugolo, Alexandre Todorovic Fabro, Daniel Ascheri, Cecília Farhat, Alexandre Muxfeldt Ab'Saber, Vanessa Karen de Sá, Maria Aparecida Nagai, Teresa Takagaki, Ricardo Terra, Edwin Roger Parra, Vera Luiza Capelozzi.

To demonstrate the usefulness of complementary next-generation sequencing (NGS) and immunohistochemistry (IHC) counting, we analyzed 196 patients with non-small cell lung cancer (NSCLC) who underwent surgical resection and adjuvant chemotherapy. Formalin-fixed paraffin-embedded samples of adenocarcinoma (ADC), squamous cell carcinoma (SqCC), and large-cell carcinoma (LCC) were used to prepare tissue microarrays and were examined by protein H-score IHC image analysis and NGS for oncogenes and proto-oncogenes and genes of tumor suppressors, immune checkpoints, epithelial-mesenchymal transition factors, tyrosine kinase receptors, and vascular endothelial growth factors (VEGFs). In patients with brain metastases, primary tumors expressed lower PIK3CA protein levels. Overexpression of TP53 and a higher PD-L1 protein H-score were detected in patients that underwent surgical treatment followed by chemotherapy as compared to those that underwent only surgical treatment The absence of brain metastases was associated with wild-type sequences of genes EGFR, CD267, CTLA-4, and ZEB1. The combination of protein overexpression according to IHC and mutation according to NGS was rare (i.e., represented by a very low percentage of concordant cases), except for TP53 and VEGF. Our data suggest that protein levels detected by IHC may be a useful complementary tool when mutations are not detected by NGS and also support the idea to expand this approach beyond ADC to include SqCC and even LCC, particularly for patients with unusual clinical characteristics. Conversely, well-pronounced immunogenotypic features appeared to predict the clinical outcome after univariate and multivariate analyses. Patients with a solid ADC subtype and mutated genes EGFR, CTLA4, PDCD1LG2, or ZEB1 complemented with PD-L1 or TP53 protein lower expression that only underwent surgical treatment, who develop brain metastases, may have the worst prognosis.

Keywords: Adenocarcinoma, Squamous Cell Carcinoma, Large Cell Carcinoma; Epithelial-Mesenchymal Transition; H-Score; Immunohistochemistry; Next-Generation Sequencing

DOI: https://doi.org/10.1016/j.humpath.2018.08.026

PET Clin. 2018 Oct;pii: S1556-8598(18)30067-1. [Epub ahead of print]13(4): 491-503

Radionuclide Therapy for Bone Metastases: Utility of Scintigraphy and PET Imaging for Treatment Planning.

Hojjat Ahmadzadehfar, Markus Essler, Kambiz Rahbar, Ali Afshar-Oromieh.

The skeleton is a common site for cancer metastases. Bone metastases are a major cause of morbidity and mortality and associated with pain, pathologic fractures, spinal cord compression, and decreased survival. Various radionuclides have been used for pain therapy. Recently, an α-emitter has been shown to improve overall survival of patients with bone metastases from castration-resistant prostate cancer and was approved as a therapeutic agent. The aim of this article is to provide an overview regarding state of the art radionuclide therapy options for bone metastases, with focus on the role of PET imaging in therapy planning.

Keywords: Bone metastases; Breast cancer; Lung cancer; PET; Prostate cancer; Radionuclide therapy; Radium-223

DOI: https://doi.org/10.1016/j.cpet.2018.05.005

Biomed Pharmacother. 2018 Sep 13. pii: S0753-3322(18)33601-1. [Epub ahead of print]108 224-231

Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats.

Mohammad Raish, Ajaz Ahmad, Mushtaq Ahmad Ansari, Abdul Ahad, Fahad I Al-Jenoobi, Abdullah M Al-Mohizea, Altaf Khan, Naushad Ali.

BACKGROUND: Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.
PURPOSE: We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways.
DESIGN/METHODS: Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues.
RESULTS: SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-β expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury.
CONCLUSION: The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-β. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.

Keywords: Extracellular matrix deposition; Inflammation; Lung fibrosis; Sinapic acid

DOI: https://doi.org/10.1016/j.biopha.2018.09.032