Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Clustering and Classification Techniques for Gene Expression Profile Pattern Analysis

The analysis of gene expression profiles from microarray/RNA sequencing (RNA-Seq) experimental samples demands new efficient methods from statistics and computer science. This chapter considers two main types of gene expression data analysis such as gene clustering and experiment classification. It introduces the transcriptome analysis, highlighting the widespread approaches to handle it. The chapter provides an overview of the microarray and RNA-Seq technologies. In addition, the integrated software packages GenePattern, Gene Expression Logic Analyzer (GELA), TM4 software suite, and other common analysis tools are illustrated. For gene expression profile pattern discovery and experiment classification, the software packages are tested on four real case studies: Alzheimer's disease versus healthy mice; multiple sclerosis samples; psoriasis tissues; and breast cancer patients. The performed experiments and the described techniques provide an effective overview to the field of gene expression profile classification and clustering through pattern analysis

Gene expression profiling of hypoxic response in different models of senescent endothelial cells

Endothelial cells senescence is a physiological process affecting vascular integrity. It can contribute to heart and arterial stiffening and remodeling, impaired angiogenesis, defective vascular repair, and with an increasing prevalence of atherosclerosis. Drugs used as antineoplastic therapies, targeting tumor as well as endothelial cells, can also trigger endothelial cells senescence. We demonstrated that a short pulse of axitinib, a specific inhibitor of vascular endothelial growth factor receptors, induces cell senescence of endothelial cells. Here, we performed a high-throughput gene expression analysis to characterize the response of proliferating versus senescent endothelial cells to hypoxia, the main trigger of neo-angiogenetic phenomena in tumors. We compared the response to hypoxia of replicative senescent cells, with that of axitinib or of DNA damage-induced senescence. Overall, we enlightened common and specific responses to different senescence inducers and changes in the Senescent Associated Secretory Phenotype

Comparative metabolic profiling by 1H-NMR spectroscopy analysis reveals the adaptation of S. mansoni from its host to in vitro culture conditions: a pilot study with ex vivo and GSH-supplemented medium-cultured parasites

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms (blood fluke) of the genus Schistosoma. Parasites acquire most nutrients for their development and sustainment within the definitive host either by ingestion into the gut or across the body surface. Over the years, the best conditions for long-term maintenance of parasites in vitro have been thoroughly established. In our hands, H-1-NMR spectroscopy represents a powerful tool to characterize the metabolic changes in S. mansoni in response to culturing condition perturbations. In order to compare the metabolic fingerprint of ex vivo and parasites cultured in vitro with or without the supplement of reduced glutathione, we conducted a pilot study applying the H-1-NMR spectroscopy-based metabolomics. We obtained new insight into specific metabolic pathways modulated under these different experimental conditions

Mitochondrial Genome Profile in Demyelinating Diseases

Multiple sclerosis and neuromyelitis optica are chronic inflammatory diseases of the central nervous system. These pathologies share clinical similarities with Leber hereditary optic neuropathy, which is primarily due to mutations of mitochondrial DNA. Mitochondrial genetic variations may influence susceptibility to develop multiple sclerosis and neuromyelitis optica. In order to explore the possible correlation between mitochondrial DNA specific patterns and demyelinating diseases involving central nervous system, mitochondrial DNA from 13 patients with relapsing-remitting multiple sclerosis, 4 patients with neuromyelitis optica, 1 patient with myelitis, 2 patient with optic neuritis, and 7 healthy controls were analyzed by sequencing the full length 16 Kbs of the mitochondrial DNA genome. Common variants presence in healthy controls and patients showing no clinical impact on diseases development were not further explored. Analyzing 414 patient specific variants, six nonsense mutations, causing early stop-codon formation, and nine previously described variants, associated with demyelinating/degenerative disease of central nervous system were identified. Some of these variants are linked to disease development through known and previously described mechanisms. We report for the first time other truncating mutations leading to incomplete proteins involved in Oxidative Phosporilation complexes and we speculate their role in demyelinating diseases developmen