Cachectic muscle wasting in acute myeloid leukaemia: a sleeping giant with dire clinical consequences

Acute myeloid leukaemia (AML) is a haematological malignancy with poor survival odds, particularly in the older (>65 years) population, in whom it is most prevalent. Treatment consists of induction and consolidation chemotherapy to remit the cancer followed by potentially curative haematopoietic cell transplantation. These intense treatments are debilitating and increase the risk of mortality. Patient stratification is used to mitigate this risk and considers a variety of factors, including body mass, to determine whether a patient is suitable for any or all treatment options. Skeletal muscle mass, the primary constituent of the body lean mass, may be a better predictor of patient suitability for, and outcomes of, AML treatment. Yet skeletal muscle is compromised by a variety of factors associated with AML and its clinical treatment consistent with cachexia, a life-threatening body wasting syndrome. Cachectic muscle wasting is associated with both cancer and anticancer chemotherapy. Although not traditionally associated with haematological cancers, cachexia is observed in AML and can have dire consequences. In this review, we discuss the importance of addressing skeletal muscle mass and cachexia within the AML clinical landscape in view of improving survivability of this disease

The paradoxical effect of parp inhibitor bgp-15 on irinotecan-induced cachexia and skeletal muscle dysfunction

Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI-and IRI+BGP-treated mice, while IRI+BGP treatment also decreased β-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15’s capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization

Sodium nitrate co-supplementation does not exacerbate low dose metronomic doxorubicin-induced cachexia in healthy mice

The purpose of this study was to determine whether (1) sodium nitrate (SN) treatment progressed or alleviated doxorubicin (DOX)-induced cachexia and muscle wasting; and (2) if a more-clinically relevant low-dose metronomic (LDM) DOX treatment regimen compared to the high dosage bolus commonly used in animal research, was sufficient to induce cachexia in mice. Six-week old male Balb/C mice (n = 16) were treated with three intraperitoneal injections of either vehicle (0.9% NaCl; VEH) or DOX (4 mg/kg) over one week. To test the hypothesis that sodium nitrate treatment could protect against DOX-induced symptomology, a group of mice (n = 8) were treated with 1 mM NaNO3 in drinking water during DOX (4 mg/kg) treatment (DOX + SN). Body composition indices were assessed using echoMRI scanning, whilst physical and metabolic activity were assessed via indirect calorimetry, before and after the treatment regimen. Skeletal and cardiac muscles were excised to investigate histological and molecular parameters. LDM DOX treatment induced cachexia with significant impacts on both body and lean mass, and fatigue/malaise (i.e. it reduced voluntary wheel running and energy expenditure) that was associated with oxidative/nitrostative stress sufficient to induce the molecular cytotoxic stress regulator, nuclear factor erythroid-2-related factor 2 (NRF-2). SN co-treatment afforded no therapeutic potential, nor did it promote the wasting of lean tissue. Our data re-affirm a cardioprotective effect for SN against DOX-induced collagen deposition. In our mouse model, SN protected against LDM DOX-induced cardiac fibrosis but had no effect on cachexia at the conclusion of the regimen

Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle For Myopathy But Does Not Cause Cachexia

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU

Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?

BACKGROUND: Pharmacological corticosteroid therapy is the standard of care in Duchenne Muscular Dystrophy (DMD) that aims to control symptoms and slow disease progression through potent anti-inflammatory action. However, a major concern is the significant adverse effects associated with long term-use. MAIN: This review discusses the pros and cons of standard of care treatment for DMD and compares it to novel data generated with the new-wave dissociative corticosteroid, vamorolone. The current status of experimental anti-inflammatory pharmaceuticals is also reviewed, with insights regarding alternative drugs that could provide therapeutic advantage. CONCLUSIONS: Although novel dissociative steroids may be superior substitutes to corticosteroids, other potential therapeutics should be explored. Repurposing or developing novel pharmacological therapies capable of addressing the many pathogenic features of DMD in addition to anti-inflammation could elicit greater therapeutic advantages

Avaliação genômica para características ligadas à eficiência alimentar em bovinos da raça Angus.

Seleção Genômica; Provas de Eficiência Alimentar; Características Avaliadas; Consumo Alimentar Residual; Consumo Matéria Prima; Como Interpretar as Avaliações Genômicas Diferença Esperada na Progênie; Acurária (AC); Percentil (%); ResultadosPublicado também como impresso. ODS 2, ODS 12

Is the exchange transfusion a possibile specific treatment for neonatal hemochromatosis?

Neonatal hemochromatosis is a rare congenital disorder of the liver associated to a poor prognosis. Liver transplantation is often required, since no effective medical treatment has been found. Despite mounting evidence of an alloimmune etiology of this condition, exchange transfusion has never been proposed as a specific treatment for neonatal hemochromatosis. Here we describe two siblings affected by neonatal hemochromatosis. The first, a female, died at 18 days of severe coagulopathy and acute renal failure, diagnosed as affected by neonatal hemochromatosis only when the second sibling was suspected as being affected by the same disease. The second child showed a rapidly worsening coagulopathy which was treated with two exchange transfusions, followed by rapid clinical and laboratory improvement, before reaching a definite diagnosis of neonatal hemochromatosis. He is healthy at present after a follow-up of 12 months. Although exchange transfusion has never been considered as treatment for neonatal hemochromatosis, this case suggests that it could be a feasible treatment option for children affected by this disease, as for other alloimmune condition