ABSTRACT
Background: Chronic breathlessness is a prevalent disabling syndrome affecting many people for years. Identifying the impact of chronic breathlessness on people's activities in the general population is pivotal for designing symptom management strategies. Objective: This study aimed to evaluate the association between chronic breathlessness and activities respondents identify can no longer be undertaken ("activities forgone"). Design: This population-based cross-sectional online survey used a market research company's database of 30,000 registrants for each sex, generating the planned sample size-3000 adults reflecting Australia's 2016 Census by sex, age group, state of residence, and rurality. Setting/Subjects: The population of focus (n = 583) reported a modified Medical Research Council (mMRC) breathlessness scale ≥1 and experienced this breathlessness for ≥3 months. Measurements: Activities forgone were categorized by mMRC using coding derived from the Dyspnea Management Questionnaire domains. Activities were classified as "higher/lower intensity" using Human Energy Expenditure scale. Results: Respondents were male 50.3%; median age 50.0 (IQR 29.0); with 66% living in metropolitan areas; reporting 1749 activities forgone. For people with mMRC 1 (n = 533), 35% had not given up any activity, decreasing to 9% for mMRC 2 (n = 38) and 3% for mMRC 3-4 (n = 12). Intense sport (e.g., jogging and bike riding) was the top activity forgone: 42% (mMRC 1), 32% (mMRC 2), and 36% (mMRC 3-4). For respondents with mMRC 3-4, the next most prevalent activities forgone were "sexual activities" (14%), "lower intensity sports" (11%), and "other activities" (11%). Conclusions: People progressively reduce a wide range of activities because of their chronic breathlessness.
ABSTRACT
Cancer is a major public health issue and, despite recent advances, effective clinical management remains elusive due to intra-tumoural heterogeneity and therapeutic resistance. Iron is a trace element integral to a multitude of metabolic processes, including DNA synthesis and energy transduction. Due to their generally heightened proliferative potential, cancer cells have a greater metabolic demand for iron than normal cells. As such, iron metabolism represents an important "Achilles' heel" for cancer that can be targeted by ligands that bind and sequester intracellular iron. Indeed, novel thiosemicarbazone chelators that act by a "double punch" mechanism to both bind intracellular iron and promote redox cycling reactions demonstrate marked potency and selectivity in vitro and in vivo against a range of tumours. The general mechanisms by which iron chelators selectively target tumour cells through the sequestration of intracellular iron fall into the following categories: (1) inhibition of cellular iron uptake/promotion of iron mobilisation; (2) inhibition of ribonucleotide reductase, the rate-limiting, iron-containing enzyme for DNA synthesis; (3) induction of cell cycle arrest; (4) promotion of localised and cytotoxic reactive oxygen species production by copper and iron complexes of thiosemicarbazones (e.g., Triapine(®) and Dp44mT); and (5) induction of metastasis and tumour suppressors (e.g., NDRG1 and p53, respectively). Emerging evidence indicates that chelators can further undermine the cancer phenotype via inhibiting the epithelial-mesenchymal transition that is critical for metastasis and by modulating ER stress. This review explores the "expanding horizons" for iron chelators in selectively targeting cancer cells.
