Interleukin 6-independent metabolic reprogramming as a driver of cancer-related fatigue.

Fatigue is a common and debilitating symptom of cancer with few effective interventions. Cancer-related fatigue (CRF) is often associated with increases in inflammatory cytokines, however inflammation may not be requisite for this symptom, suggesting other biological mediators also play a role. Because tumors are highly metabolically active and can amplify their energetic toll via effects on distant organs, we sought to determine whether CRF could be explained by metabolic competition exacted by the tumor. We used a highly metabolically active murine E6/E7/hRas model of head and neck cancer for this purpose. Mice with or without tumors were submitted to metabolic constraints in the form of voluntary wheel running or acute overnight fasting and their adaptive behavioral (home cage activity and fasting-induced wheel running) and metabolic responses (blood glucose, ketones, and liver metabolic gene expression) were monitored. We found that the addition of running wheel was necessary to measure activity loss, used as a surrogate for fatigue in this study. Tumor-bearing mice engaged in wheel running showed a decrease in blood glucose levels and an increase in lactate accumulation in the skeletal muscle, consistent with inhibition of the Cori cycle. These changes were associated with gene expression changes in the livers consistent with increased glycolysis and suppressed gluconeogenesis. Fasting also decreased blood glucose in tumor-bearing mice, without impairing glucose or insulin tolerance. Fasting-induced increases in wheel running and ketogenesis were suppressed by tumors, which was again associated with a shift from gluconeogenic to glycolytic metabolism in the liver. Blockade of IL-6 signaling with a neutralizing antibody failed to recover any of the behavioral or metabolic outcomes. Taken together, these data indicate that metabolic competition between the tumor and the rest of the organism is an important component of fatigue and support the hypothesis of a central role for IL-6-independent hepatic metabolic reprogramming in the pathophysiology of CRF.

Biological sex and DNA repair deficiency drive Alzheimer's disease via systemic metabolic remodeling and brain mitochondrial dysfunction.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polß haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

Lipocalin-2 is dispensable in inflammation-induced sickness and depression-like behavior.

RATIONALE: While the relationship between inflammation and depression is well-established, the molecular mechanisms mediating this relationship remain unclear. RNA sequencing analysis comparing brains of vehicle- and lipopolysaccharide-treated mice revealed LCN2 among the most dysregulated genes. As LCN2 is known to be an important regulator of the immune response to bacterial infection, we investigated its role in the behavioral response to lipopolysaccharide. OBJECTIVE: To explore the role of LCN2 in modulating behavior following lipopolysaccharide administration using wild type (WT) and lcn2-/- mice. METHODS: Using a within-subjects design, mice were treated with 0.33 mg/kg liposaccharide (LPS) and vehicle. Primary outcome measures included body weight, food consumption, voluntary wheel running, sucrose preference, and the tail suspension test. To evaluate the inflammatory response, 1 week later, mice were re-administered either vehicle or LPS and terminated at 6 h. RESULTS: While lcn2-/- mice had increased baseline food consumption and body weight, they showed a pattern of reduced food consumption and weight loss similar to WT mice in response to LPS. WT and lcn2-/- mice both recovered voluntary activity on the fourth day following LPS. LPS induced equivalent reductions in sucrose preference and TST immobility in the WT and lcn2-/- mice. Finally, there were no significant effects of genotype on inflammatory markers. CONCLUSIONS: Our data demonstrate that lcn2 is dispensable for sterile inflammation-induced sickness and depression-like behavior. Specifically, lcn2-/- mice displayed sickness and immobility in the tail suspension test comparable to that of WT mice both in terms of intensity and duration.

Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase.

Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1-/- mice underwent behavioral tests of antidepressant activity (e.g., forced swim test) and motivated behavior, including assessment of (1) reward expectancy using a food-related anticipatory activity task, (2) willingness to work for reward using a progressive ratio schedule of food reinforcement, (3) effort allocation using a concurrent choice task, and (4) ability to associate environmental cues with reward using conditioned place preference. LPS- and SNI-induced deficits in behavioral tests of antidepressant activity in WT but not Ido1-/- mice. Further, LPS decreased food related-anticipatory activity, reduced performance in the progressive ratio task, and shifted effort toward the preferred reward in the concurrent choice task. These effects were observed in both WT and Ido1-/- mice. Finally, SNI mice developed a conditioned place preference based on relief from pain in an IDO1-independent manner. These findings demonstrate that the motivational effects of inflammation do not require IDO1. Further, they indicate that the motivational component of inflammation-induced depression is mechanistically distinct from that measured by behavioral tests of antidepressant activity.

Bioresorbable everolimus-eluting vascular scaffold for the treatment of chronic total occlusions: CTO-ABSORB pilot study.

AIMS: We sought to assess the safety and performance of the Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) in percutaneous chronic total occlusion (CTO) revascularisation guided by intracoronary imaging. The feasibility of using the BVS in CTO lesions is unknown. METHODS AND RESULTS: Thirty-five consecutive true CTO lesions (EuroCTO Club definition) were included in this prospective registry. After mandatory predilatation and IVUS analysis, all target lesions were treated with BVS and no other stents were deployed. Optical coherence tomography (OCT) was performed after BVS implantation. Multislice computed tomography (MSCT) was performed at baseline and at six to eight months. The mean age was 60.7±9.7 years; 80% were male; 20% were diabetic; 37% had a previous PCI. The most frequently treated vessel was the RCA (46%). According to the Japanese-CTO (J-CTO) complexity score, most lesions were classified as intermediate (49%) or difficult-very difficult (26%); 34% were moderate-severely calcified. Most cases (86%) were treated with an anterograde strategy, 60% by radial or biradial approach. In 71% a cutting balloon was used. The total scaffold length implanted per lesion was 52.5±22.9 mm. All scaffolds were successfully delivered and deployed. Post-dilatation was undertaken in 63%. By OCT, final minimum scaffold area and lumen stenosis were 7.1±1.5 mm2 and 11.7±6.6%, without areas of significant strut malapposition. At complete six-month follow-up, no major adverse events were observed. MSCT identified two cases of scaffold reocclusion. CONCLUSIONS: BVS for CTO recanalisation demonstrates excellent feasibility and safety as well as midterm efficacy. Appropriate lesion preparation is key to aiding adequate expansion of these scaffolds in this setting.

Intracoronary thrombolysis in patients with ST-segment elevation myocardial infarction presenting with massive intraluminal thrombus and failed aspiration.

AIM: Massive intracoronary thrombus is associated with adverse procedural results including failed aspiration and unfavourable reperfusion. In this scenario the best treatment remains unknown. We aim to evaluate the effect of low dose intracoronary thrombolysis in patients with ST-segment elevation myocardial infarction (STEMI) presenting with a large thrombus burden and failed aspiration. METHODS AND RESULTS: In this study 30 STEMI patients with a large thrombus burden and failed manual aspiration were included in the registry. Local fibrinolysis with low dose (one-third of systemic) tenecteplase (27%) or alteplase (73%) was administered via a 6F-infusion catheter. A thrombus was qualified as large when its maximal dimension was ≥2 vessels (thrombolysis in myocardial infarction (TIMI) thrombus grade 4 and 5). Altogether 33% of patients received delayed invasive therapy (>12 h) guided by the presence of recurrent symptoms and/or ischaemia. A total of 17% of patients presented with cardiogenic shock and half of the population received glycoprotein IIb/IIIa inhibitors. A post-lysis thrombus grade 4-5 was found in just one patient. TIMI flow grade improved from 0/1 at baseline (93%) to ≥2 in most patients (97%). Blush grade 2-3 was observed in 85% and we observed a similar percentage (82%) of more than 50% ST-segment resolution. In-hospital mortality was 10% (three patients with cardiogenic shock). No major bleeding events were observed. At a median follow-up of 14 (6-35) months, only one new clinical event was reported (1 target lesion revascularization, (TLR)). CONCLUSIONS: In STEMI patients with a large thrombus burden and failed manual aspiration, administration of low dose intracoronary thrombolysis is safe and reduces trhombus burden, as a result improving in epicardial flow and myocardial reperfusion.

Enfermedad de chagas sistémico en fase aguda por transmisión oral: diagnóstico integral de un caso autopsiado / Acute phase of systemic chagas disease due to oral transmission: integral diagnosis of an autopsied case

Se presenta el primer caso autopsiado en Venezuela con enfermedad de Chagas por transmisión oral. Se trata de una joven de 24 años de edad con 8 semanas de embarazo quien contrajo la enfermedad conjuntamente con 71 niños y 14 adultos, la mayoría integrantes de la comunidad escolar “Rómulo Monasterios” en la localidad de Chichiriviche de la costa Vargas, donde ocurrió el segundo brote agudo de enfermedad de Chagas por transmisión oral registrado en Venezuela. El diagnóstico epidemiológico, clínico, serológico y parasitológico en sangre y líquido pleural extraídos en vida, fueron confirmados con los hallazgos histopatológicos y moleculares (PCR) de los tejidos. Se plantearon las características peculiares del caso así como algunos aspectos de la transmisión oral, ampliamente estudiados en nuestro país en animales de experimentación.

This first autopsy case with Chagas disease by oral transmissions in Venezuela is presented. This is a 24 year old girl with 8 weeks of pregnancy who contracted the disease together with 71 and 14 adults, the majority members of the school community “Romulo Monasterios” in the town of Vargas State, where occurred the second acute Chagas disease outbreak by oral transmission in Venezuela.The epidemiological, clinical, serological and parasitological diagnosis in the blood and pleural fluid extracted in life, were confirmed with the histopathology and molecular (PCR) finding in the tissues, Special features of the case are shown, as well as, some aspects of oral transmission widely studied in our country in experimental animals.