br Sickle Cell Disease SCD is

Sickle Cell Disease (SCD) is one of the most common severe inherited disorders. Approximately 300,000 SCD babies are born yearly, mostly in Africa, the USA and the Caribbean, but also in Northern Europe (). In the UK, SCD patients number around 12–15,000 individuals () making it dhfr inhibitors a disease of considerable significance. There is no specific treatment. Nor is it understood why some patients have a more severe course of the disease, whereas others are mildly or even subclinically affected. Without this prognostic knowledge, it is not possible to instigate more aggressive therapies for children who will be most compromised later in life. For example, hydroxyurea therapy for these individuals may lessen later complications such as renal pathology and stroke.
Lung cancer and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer by 4–5 folds, even when the smoking history is controlled for (). Lung cancer may consist of small cell carcinoma and non-small cell carcinomas encompassing squamous cell carcinoma, adenocarcinoma and large cell carcinoma. In a recent very comprehensive study by Huang and colleagues published in , provided compelling evidence suggesting strong association between smoking, COPD and small cell lung cancer (SCLC) (). This publication is a very timely reminder highlighting the importance of this lethal association between COPD/lung cancer and warrants further experimental studies exploring this link not only in SCLC but lung cancer in general. Unfortunately, the research effort directed into this has been disproportionately weak compared to its clinical and scientific importance, and indeed COPD itself is the least researched of all common chronic conditions compared to its social importance. Lung cancer and COPD share a common etiology i.e. mainly tobacco smoking. This implies that mechanisms specific to COPD may be involved in the development of lung cancer (). Potential shared biological mechanisms in COPD and lung cancer include: chronic inflammation, matrix degradation, cell proliferation and anti-apoptosis, abnormal wound repair and angiogenesis, but perhaps especially the process of epithelial mesenchymal transition (EMT), a highly plastic process in which epithelial cells change into a mesenchymal phenotype (). There is much support for a major role for EMT in the pathogenesis of epithelial cancers (). It is clear that several of the key pathways driving EMT, which is designed teleologically for the highly controlled process of embryogenesis, are also aberrantly activated in cancer (). EMT is a vital process during embryogenesis (Type I EMT), but can also be induced as a result of persistent damage and inflammation. There are then two subsequent outcome possibilities with active EMT: severe and even complete organ fibrosis and secondarily association with malignancy; both of these processes may be relevant to COPD pathology and natural history. Lung cancer evolves as a result of a series of mutational events in epithelial cells that have been studied in detail by numerous investigators. However, it is not only epithelial malignant transformation that matters, but also the environment in which these cells develop i.e. the tumor microenvironment. We suggest that EMT-Type-3 provides a pro-cancer stroma that both stimulates epithelial cancer cell transformation, in addition to the genetic changes induced by cigarette smoke, but then allows these cells to thrive, invade and metastasise (). In a separate twist to this complex story, the epithelial cancer itself also directly uses EMT mechanisms to spread and metastasise. It is of interest and relevance in this context that over 90% of human cancer arises in epithelia (e.g., breast, colon, stomach, liver, prostate, ovary/fallopian tube and bladder), and the involvement of EMT in all of these may be a central paradigm (). It is pertinent that up to 70% of lung cancer occurs in the context of mild-to-moderate (not severe) COPD (), and COPD-related cancer may well be just another example of this core principle of unstable epithelium in the context of tissue inflammation and/or chronic stimulation.