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Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia. Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia. Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss. Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.
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The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.
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Some chemotherapeutic agents have been shown to lead to the severe wasting syndrome known as cachexia resulting in dramatic losses of both skeletal muscle and adipose tissue. Previous studies have shown that chemotherapy-induced cachexia is characterized by unique metabolic alterations. Recent results from our laboratory and others have shown that the use of ACVR2B/Fc, a soluble form of the activin receptor 2B (ACVR2B), can mitigate muscle wasting induced by chemotherapy, although the underlying mechanisms responsible for such protective effects are unclear. In order to understand the biochemical mechanisms through which ACVR2B/Fc functions, we employed a comprehensive, multi-platform metabolomics approach. Using both nuclear magnetic resonance (NMR) and mass-spectrometry (MS), we profiled the metabolome of both serum and muscle tissue from four groups of mice including (1) vehicle, (2) the chemotherapeutic agent, Folfiri, (3) ACVR2B/Fc alone, and (4) combined treatment with both Folfiri and ACVR2B/Fc. The metabolic profiles demonstrated large effects with Folfiri treatment and much weaker effects with ACVR2B/Fc treatment. Interestingly, a number of significant effects were observed in the co-treatment group, with the addition of ACVR2B/Fc providing some level of rescue to the perturbations induced by Folfiri alone. The most prominent of these were a normalization of systemic glucose and lipid metabolism. Identification of these pathways provides important insights into the mechanism by which ACVR2B/Fc protects against chemotherapy-induced cachexia.
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. METHODS: Isoform-specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed-forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. RESULTS: Murine PDAC tumour-derived cell lines expressed activin-ßA but not activin-ßB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin-low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin-high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin-ßA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. CONCLUSIONS: Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ-specific and gene-specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle-specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene-specific and organ-specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.
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Activinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Activinas Tipo II/metabolismo , Activinas/sangre , Animales , Biomarcadores , Pesos y Medidas Corporales , Caquexia/etiología , Caquexia/metabolismo , Caquexia/mortalidad , Caquexia/terapia , Carcinoma Ductal Pancreático/complicaciones , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/mortalidad , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
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Caquexia/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/patología , Neoplasias/complicaciones , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/fisiología , Animales , Caquexia/etiología , Línea Celular , Masculino , Ratones , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/metabolismo , Músculo Esquelético/enzimología , Atrofia Muscular/enzimología , Oxidación-ReducciónRESUMEN
BACKGROUND: Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer-induced and chemotherapy-induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. METHODS: The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer-induced cachexia. In vivo administration of Folfiri (5-fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy-induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance-based and mass spectrometry-based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. RESULTS: The study involved four groups of CD2F1 male mice (n = 4-5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (-3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (-38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (-47% in CC vs. V; P < 0.001) and depletion of liver glucose (-51% in CC vs. V; P < 0.001) and glycogen (-74% in CC vs. V; P < 0.001). The cancer-induced and chemotherapy-induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and ß-oxidation pathways. Cancer-induced cachexia was uniquely characterized by a dramatic elevation in low-density lipoprotein particles (+6.9-fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001). CONCLUSIONS: The results of this study demonstrated for the first time that cancer-induced and chemotherapy-induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer-induced and chemotherapy-induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.
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Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Caquexia/metabolismo , Camptotecina/análogos & derivados , Metabolismo Energético , Neoplasias/metabolismo , Animales , Caquexia/inducido químicamente , Caquexia/patología , Camptotecina/efectos adversos , Línea Celular Tumoral , Fluorouracilo/efectos adversos , Glucosa/metabolismo , Leucovorina/efectos adversos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Metabolómica , Ratones , Fuerza Muscular , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neoplasias/inducido químicamente , Neoplasias/patología , Especies Reactivas de Oxígeno/metabolismo , Receptores de LDL/metabolismoAsunto(s)
Histoplasmosis/diagnóstico , Histoplasmosis/tratamiento farmacológico , Enfermedades Faríngeas/diagnóstico , Enfermedades Faríngeas/tratamiento farmacológico , Adulto , Antifúngicos/uso terapéutico , Seronegatividad para VIH , Histoplasmosis/complicaciones , Humanos , Itraconazol/uso terapéutico , Masculino , Enfermedades Faríngeas/microbiologíaRESUMEN
PURPOSE OF REVIEW: Cancer patients undergoing chemotherapy often experience very debilitating side effects, including unintentional weight loss, nausea, and vomiting. Changes in body composition, specifically lean body mass (LBM), are known to have important implications for anticancer drug toxicity and cancer prognosis. Currently, chemotherapy dosing is based on calculation of body surface area, although this approximation does not take into consideration the variability in lean and adipose tissue mass. RECENT FINDINGS: Patients with depletion of muscle mass present higher chemotherapy-related toxicity, whereas patients with larger amounts of LBM show fewer toxicities and better outcomes. Commonly used chemotherapy regimens promote changes in body composition, primarily by affecting skeletal muscle, as well as fat and bone mass. Experimental evidence has shown that pro-atrophy mechanisms, abnormal mitochondrial metabolism, and reduced protein anabolism are primarily implicated in muscle depletion. Muscle-targeted pro-anabolic strategies have proven successful in preserving lean tissue in the occurrence of cancer or following chemotherapy. SUMMARY: Muscle wasting often occurs as a consequence of anticancer treatments and is indicative of worse outcomes and poor quality of life in cancer patients. Accurate assessment of body composition and preservation of muscle mass may reduce chemotherapy toxicity and improve the overall survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Composición Corporal/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Relación Dosis-Respuesta a Droga , Ghrelina/uso terapéutico , Humanos , Atrofia Muscular/tratamiento farmacológico , Enfermedades Musculoesqueléticas/inducido químicamente , Enfermedades Musculoesqueléticas/fisiopatología , Evaluación Nutricional , Calidad de Vida , Receptores de Ghrelina/agonistasRESUMEN
BACKGROUND: Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. METHODS: Nod SCID gamma mice (n = 6-10) were injected intraperitoneally with 1 × 107 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. RESULTS: In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (-12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour-bearing mice (approximately -35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (-34%, P < 0.01) and muscle weakness (-50%, P < 0.001). Body composition assessment by dual-energy X-ray absorptiometry revealed decreased bone mineral density (-8%, P < 0.01) and bone mineral content (-19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho-AKT (-44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (-16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. CONCLUSIONS: Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.
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Huesos/patología , Caquexia/diagnóstico , Caquexia/etiología , Atrofia Muscular/patología , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/patología , Animales , Biomarcadores , Composición Corporal , Densidad Ósea , Huesos/diagnóstico por imagen , Línea Celular Tumoral , Modelos Animales de Enfermedad , Metabolismo Energético , Femenino , Xenoinjertos , Humanos , Ratones , Mitocondrias/metabolismo , Fuerza Muscular , Atrofia Muscular/diagnóstico por imagen , Atrofia Muscular/metabolismo , Tamaño de los Órganos , Neoplasias Ováricas/metabolismo , Transducción de Señal , Microtomografía por Rayos XRESUMEN
A compounding feature of greater than 50% of all cancers is the high incidence of the cachexia syndrome, a complex metabolic disorder characterized by extreme weight loss due mainly to the gross depletion of skeletal muscle tissue. Although studies into the cause of cancer cachexia has spanned over multiple decades, little is known about the effects of various cancer treatments themselves on cachexia. For example, chemotherapy agents induce side effects such as nausea and anorexia, but these symptoms do not fully account for the changes seen with cancer cachexia. In this study we examine the effects of chemotherapeutic compounds, specifically, cisplatin in the colon-26 adenocarcinoma model of cancer cachexia. We find that although cisplatin is able to reduce tumor burden as expected, muscle wasting in mice nevertheless persists. Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system. Finally, we show that cisplatin is able to induce NF-κB activity in both mouse muscles and myotube cultures, suggesting that an additional side effect of cancer treatment is the regulation of muscle wasting that may be mediated through activation of the NF-κB signaling pathway.
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BACKGROUND: By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. METHODS: We performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. RESULTS: Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. CONCLUSIONS: Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.
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Tejido Adiposo/patología , Caquexia/diagnóstico , Caquexia/etiología , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/mortalidad , Fenotipo , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Composición Corporal , Pesos y Medidas Corporales , Carcinoma Ductal Pancreático/complicaciones , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/mortalidad , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/efectos adversos , Oxaliplatino/uso terapéutico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.
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Receptores de Activinas Tipo II/fisiología , Densidad Ósea/efectos de los fármacos , Distrofias Musculares/patología , Receptores de Activinas Tipo II/metabolismo , Animales , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Huesos , Caquexia/tratamiento farmacológico , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Quimioterapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/fisiopatología , Femenino , Fémur/efectos de los fármacos , Fluorouracilo/efectos adversos , Quimioterapia de Inducción/métodos , Leucovorina/efectos adversos , Masculino , Ratones , Ratones Endogámicos , Músculo Esquelético/patologíaRESUMEN
Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Up to 80% of cancer patients experience cachexia, with 20-30% of cancer-related deaths directly linked to cachexia. Despite efforts to identify early cachexia and cancer relapse, clinically useful markers are lacking. Recently, we identified the role of muscle-specific ubiquitin ligases Atrogin-1 (MAFbx, FBXO32) and Muscle Ring Finger-1 in the pathogenesis of cardiac atrophy and hypertrophy. We hypothesized that during cachexia, the Atrogin-1 and MuRF1 ubiquitin ligases are released from muscle and migrate to the circulation where they could be detected and serve as a cachexia biomarker. To test this, we induced cachexia in mice using the C26 adenocarcinoma cells or vehicle (control). Body weight, tumor volume, and food consumption were measured from inoculation until ~day 14 to document cachexia. Western blot analysis of serum identified the presence of Atrogin-1 and MuRF1 with unique post-translational modifications consistent with mono- and poly- ubiquitination of Atrogin-1 and MuRF1 found only in cachectic serum. These findings suggest that both increased Atrogin-1 and the presence of unique post-translational modifications may serve as a surrogate marker specific for cachexia.
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BACKGROUND: An increasing number of women are pursuing a career in surgery. Concurrently, the percentage of surgeons in dual-profession partnerships is increasing. We sought to evaluate the gender differences in professional advancement, work-life balance, and satisfaction at a large academic center. MATERIALS AND METHODS: All surgical trainees and faculty at a single academic medical center were surveyed. Collected variables included gender, academic rank, marital status, family size, division of household responsibilities, and career satisfaction. Student t-test, Fisher's exact test, and chi-square test were used to compare results. RESULTS: There were 127 faculty and 116 trainee respondents (>80% response rate). Respondents were mostly male (77% of faculty, 58% of trainees). Women were more likely than men to be married to a professional (90% versus 37%, for faculty; 82% versus 41% for trainees, P < 0.001 for both) who was working full time (P < 0.001) and were less likely to be on tenure track (P = 0.002). Women faculty were more likely to be primarily responsible for childcare planning (P < 0.001), meal planning (P < 0.001), grocery shopping (P < 0.001), and vacation planning (P = 0.003). Gender-neutral responsibilities included financial planning (P = 0.04) and monthly bill payment (P = 0.03). Gender differences in division of household responsibilities were similar in surgical trainees except for childcare planning, which was a shared responsibility. CONCLUSIONS: Women surgeons are more likely to be partnered with a full-time working spouse and to be primarily responsible for managing their households. Additional consideration for improvement in recruitment and retention strategies for surgeons might address barriers to equalizing these gender disparities.
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Centros Médicos Académicos/estadística & datos numéricos , Movilidad Laboral , Docentes Médicos/estadística & datos numéricos , Satisfacción en el Trabajo , Cirujanos/estadística & datos numéricos , Equilibrio entre Vida Personal y Laboral/estadística & datos numéricos , Centros Médicos Académicos/organización & administración , Docentes Médicos/organización & administración , Docentes Médicos/psicología , Femenino , Humanos , Indiana , Modelos Lineales , Masculino , Estado Civil/estadística & datos numéricos , Análisis Multivariante , Factores Sexuales , Esposos/estadística & datos numéricos , Cirujanos/organización & administración , Cirujanos/psicología , Encuestas y CuestionariosRESUMEN
Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.
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Proteínas Morfogenéticas Óseas/farmacología , Caquexia/inducido químicamente , Factores de Diferenciación de Crecimiento/farmacología , Corazón/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Miocardio/patología , Animales , Masculino , Ratones , Ratones DesnudosRESUMEN
BACKGROUND & AIMS: Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. METHODS: Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. RESULTS: Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (â¼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. CONCLUSIONS: Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse.
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Fibras Musculares Esqueléticas/clasificación , Fibras Musculares Esqueléticas/patología , Neoplasias/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares Esqueléticas/química , Fibras Musculares de Contracción Lenta/patología , Atrofia Muscular/etiología , Atrofia Muscular/patología , Cadenas Pesadas de Miosina/análisis , Neoplasias/complicaciones , Neoplasias/fisiopatología , Pronóstico , Pérdida de PesoRESUMEN
This invited article reviews the grant process to include the following objectives: (1) to provide an understanding of otolaryngology funding mechanisms in the context of career progression; (2) to outline key components of a well-written grant; (3) to highlight vital members of a successful research team, with emphasis on the mentor-mentee relationship; and (4) to clarify grant scoring with emphasis on common pitfalls to avoid. Current otolaryngology funding mechanisms and up-to-date resources are provided. The review is aimed to assist otolaryngology residents, faculty new to the grant process, as well as experienced researchers striving to improve their grant review scores.
Asunto(s)
Investigación Biomédica/economía , Organización de la Financiación/métodos , Otolaringología/economía , Escritura/normas , HumanosRESUMEN
Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (µCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.
RESUMEN
Cachexia is a profoundly debilitating wasting syndrome that affects patients with head and neck cancer and often contributes to their demise. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, CINAHL, and the Google search engine. For the meta-analyses, pooled prevalence estimates were calculated with a confidence interval of 95% (95% CI) by using random effects modeling. In this review, we outlined the unique challenges of cancer cachexia among patients with head and neck cancer by reviewing its impacts on quality of life (QOL), morbidity, and mortality. We explored the prevalence of different clinical markers of cachexia at the time of diagnosis and before and after treatment. Finally, we present updates regarding the diagnosis of cancer cachexia and recent findings, such as cardiac dysfunction that warrant clinical attention to more carefully identify patients at risk and potentially lead to better outcomes.