Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia

BackgroundCancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-κB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-κB inhibitor that targets the IκB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy.MethodsUsing a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses.ResultsOf the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p < 0.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered—changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius’ baseline metabolic profile.ConclusionsThe findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF-kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics.Electronic supplementary materialThe online version of this article (doi:10.1007/s13539-012-0101-7) contains supplementary material, which is available to authorized users

Characterization of Postoperative Changes in Nasal Airflow Using a Cadaveric Computational Fluid Dynamics Model: Supporting the Internal Nasal Valve

Collapse or compromise of the internal nasal valve (INV) results in symptomatic nasal obstruction; thus, various surgical maneuvers are designed to support the INV

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism

Characterization of Postoperative Changes in Nasal Airflow Using a Cadaveric Computational Fluid Dynamics Model

IMPORTANCE: Collapse or compromise of the internal nasal valve (INV) results in symptomatic nasal obstruction; thus, various surgical maneuvers are designed to support the INV. OBJECTIVE: To determine the effect on nasal airflow after various surgical techniques focused at the level of the INV and lateral nasal sidewall. DESIGN AND SETTING: A fresh cadaver head was obtained and underwent suture and cartilage graft techniques directed at the level of the INV using an external approach. Preoperative and postoperative digital nasal models were created from the high-resolution, fine-cut, computed tomographic imaging after each intervention. Isolating the interventions to the level of the INV, we used computational fluid dynamic techniques to calculate nasal resistance, nasal airflow, and nasal airflow partitioning for each intervention. INTERVENTION: Suture and cartilage graft techniques. MAIN OUTCOMES AND MEASURES: Nasal airflow, nasal resistance, and partitioning of airflow. RESULTS: Using the soft-tissue elevation model as baseline, computational fluid dynamic analysis predicted that most of the suture and cartilage graft techniques directed toward the nasal valve improved nasal airflow and partitioning while reducing nasal resistance. Specifically, medial and modified flare suture techniques alone improved nasal airflow by 16.9% and 15.1%, respectively. The combination of spreader grafts and modified flare suture improved nasal airflow by 13.2%, whereas spreader grafts alone only improved airflow by 5.9%. The largest improvements in bilateral nasal resistance were achieved using the medial and modified flare sutures, outperforming the combination of spreader grafts and modified flare suture. CONCLUSIONS AND RELEVANCE: Techniques directed at supporting the INV have tremendous value in the treatment of nasal obstruction. The use of flare sutures alone can address dynamic valve collapse or upper lateral cartilage incompetence without gross disruption of the nasal architecture. Using computational fluid dynamic techniques, this study suggests that flare sutures alone may improve flow and reduce resistance when placed medially, surpassing spreader grafts alone or in combination with flare sutures. The longevity of these maneuvers can only be assessed in the clinical setting. Studies in additional specimens and clinical correlation in human subjects deserve further attention and investigation. LEVEL OF EVIDENCE: NA

Predicting Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer by Using MR Imaging and Quantitative 1H MR Spectroscopy

Purpose: To compare changes in the concentration of choline-containing compounds (tCho) and in tumor size at follow-up after neoadjuvant chemotherapy (NAC) between patients who achieved pathologic complete response (pCR) and those who did not (non-pCR)