Cancer Cachexia: Molecular Targets and Pathways for Diagnosis and Drug Intervention
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Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Skeletal muscle wasting is a prominent feature of the disease and is believed to result from the loss of balance between protein synthesis and degradation. Quality of life and prognosis are severely compromised in patients with cancer cachexia. Despite current knowledge on the mediators involved in cancer cachexia, treatment targeting a single molecule has rendered limited effectiveness. This article aims to review the mediators of cancer cachexia and interventions attempted in the literature and discuss the common pathways leading to protein loss that these mediators modulate during cachexia. We believe that by targeting downstream effectors that are common in these pathways, a better therapeutic approach to reverse muscle wasting and maintain muscle function during cancer cachexia will be achieved. Keywords: Cancer cachexia, mediators, metabolism, muscle wasting, signalling, transcription factors, RORα, Calcineurin, RNA-dependent, Protein, myotubes.Keywords:
Cancer Cachexia
Heart failure is a growing public health concern. Advanced heart failure is frequently associated with severe muscle wasting, termed cardiac cachexia . This process is driven by systemic inflammation and tumor necrosis factor in a manner common to other forms of disease‐related wasting seen with cancer or human immunodeficiency virus. A variable degree of malnutrition is often superimposed from poor nutrient intake. Cardiac cachexia significantly decreases quality of life and survival in patients with heart failure. This review outlines the evaluation of nutrition status in heart failure, explores the pathophysiology of cardiac cachexia, and discusses therapeutic interventions targeting wasting in these patients.
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Cachexia, weight loss, and muscular wasting are characteristics of advanced infection with the human immunodeficiency virus (HIV). Death usually occurs when 20% of total body weight is lost. Usually, when an individual develops this syndrome, commonly known as AIDS wasting, it is a poor prognostic sign for survival. The impact of modern treatments for AIDS infections with antiretroviral drugs and protease inhibitors has had a positive impact to increase long-term survival with the disease. AIDS wasting is now becoming much less common The pathogenesis of AIDS wasting involves poor appetite, inefficient use of caloric intake because of intercurrent diseases, medication-induced gastrointestinal problems (nausea, vomiting, and diarrhea), and the effect of HIV infection itself on muscle and tissue breakdown (1,2).
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Abstract Muscle wasting is common and persistent in severely burned patients, worsened by immobilization during treatment. In this review, we posit two major phenotypes of muscle wasting after severe burn, cachexia and sarcopenia, each with distinguishing characteristics to result in muscle atrophy; these characteristics are also likely present in other critically ill populations. An online search was conducted from the PubMed database and other available online resources and we manually extracted published articles in a systematic mini review. We describe the current definitions and characteristics of cachexia and sarcopenia and relate these to muscle wasting after severe burn. We then discuss these putative mechanisms of muscle atrophy in this condition. Severe burn and immobilization have distinctive patterns in mediating muscle wasting and muscle atrophy. In considering these two pathological phenotypes (cachexia and sarcopenia), we propose two independent principal causes and mechanisms of muscle mass loss after burns: (1) inflammation‐induced cachexia, leading to proteolysis and protein degradation, and (2) sarcopenia/immobility that signals inhibition of expected increases in protein synthesis in response to protein loss. Because both are present following severe burn, these should be considered independently in devising treatments. Discussing cachexia and sarcopenia as independent mechanisms of severe burn–initiated muscle wasting is explored. Recognition of these associated mechanisms will likely improve outcomes.
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Abstract: Cachexia and muscle wasting are frequently observed in heart failure patients. Cachexia is a predictor of reduced survival, independent of important parameters such as age, heart failure functional class, and functional capacity. Muscle and fat wasting can also predict adverse outcome during cardiac failure. Only more recently were these conditions defined in International Consensus. Considering that heart failure is an inflammatory disease, cardiac cachexia has been diagnosed by finding a body weight loss >5%, in the absence of other diseases and independent of other criteria. Muscle wasting has been defined as lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean for healthy individuals between 20 years and 30 years old from the same ethnic group. The etiology of heart failure-associated cachexia and muscle wasting is multifactorial, and the underlying physiopathological mechanisms are not completely understood. The most important factors are reduced food intake, gastrointestinal alterations, immunological activation, neurohormonal abnormalities, and an imbalance between anabolic and catabolic processes. Cachexia and muscle wasting have clinical consequences in several organs and systems including the gastrointestinal and erythropoietic systems, and the heart, previously affected by the primary disease. We hope that a better understanding of the mechanisms involved in their physiopathology will allow the development of pharmacological and nonpharmacological therapies to effectively prevent and treat heart failure-induced cachexia and muscle wasting before significant body weight and muscle wasting occurs. Keywords: heart failure, prognosis, anorexia, inflammatory activation, cardiac wasting
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This article highlights pre-clinical and clinical studies into the field of wasting disorders that were presented at the 8th Cachexia Conference held in Paris, France December 2015. This year some interesting results of clinical trials and different new therapeutic targets were shown. This article presents the biological and clinical significance of different markers and new drugs for the treatment of skeletal muscle wasting. Effective treatments of cachexia and wasting disorders are urgently needed in order to improve the patients' quality of life and their survival.
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Cachexia is a complex metabolic syndrome characterised by severe weight loss due largely to skeletal muscle wasting. It correlates with poor survival times and a decreased quality of life. Although most cancer patients develop cachexia at some point during their illness, the condition is seldom given the recognition it deserves by healthcare staff
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Weight loss is a negative prognostic indicator in patients infected with HIV. Mortality rates rise measurably with as little as 3-5% weight loss over 6 months. The sensitivity of this measure is at least partly due to the correlation between weight loss and a metabolic cachexia that has been observed with other infections, trauma, and some cancers. However, the cachexia in patients with HIV, commonly termed wasting, may also be due to, or exacerbated by, reduced caloric intake, gastrointestinal dysfunction, or metabolic abnormalities independent of abnormal energy expenditure. In patients with HIV wasting, therapies should be directed both at reversing the underlying source of protein energy malnutrition and at other factors that may be contributing to weight loss.
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