Jose M. Garcia

Update on Management of Cancer-Related Cachexia

Cachexia is a metabolic syndrome driven by inflammation and characterized by loss of muscle with or without loss of fat mass. In cancer cachexia, the tumor burden and host response induce increased inflammation, decreased anabolic tone, and suppressed appetite leading to the clinical presentation of reduced body weight and quality of life (QOL). There is no approved treatment for cancer cachexia, and commonly used nutritional and anti-inflammatory strategies alone have proven ineffective for management of symptoms. Several other pharmacological agents are currently in development and have shown promise as a clinical strategy in early-phase trials. Recently, it has been proposed that multimodal strategies, with an anabolic focus, initiated early in the disease/treatment progression may provide the most therapeutic potential for symptom management. Here we review the data from recent clinical trials in cancer cachexia including pharmacological, exercise, and nutritional interventions.

Ghrelin deletion protects against age-associated hepatic steatosis by downregulating the C/EBPα-p300/DGAT1 pathway

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. NAFLD usually begins as low‐grade hepatic steatosis which further progresses in an age‐dependent manner to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma in some patients. Ghrelin is a hormone known to promote adiposity in rodents and humans, but its potential role in hepatic steatosis is unknown. We hypothesized that genetic ghrelin deletion will protect against the development of age‐related hepatic steatosis. To examine this hypothesis, we utilized ghrelin knockout (KO) mice. Although no different in young animals (3 months old), we found that at 20 months of age, ghrelin KO mice have significantly reduced hepatic steatosis compared to aged‐matched wild‐type (WT) mice. Examination of molecular pathways by which deletion of ghrelin reduces steatosis showed that the increase in expression of diacylglycerol O‐acyltransferase‐1 (DGAT1), one of the key enzymes of triglyceride (TG) synthesis, seen with age in WT mice, is not present in KO mice. This was due to the lack of activation of CCAAT/enhancer binding protein‐alpha (C/EBPα) protein and subsequent reduction of C/EBPα‐p300 complexes. These complexes were abundant in livers of old WT mice and were bound to and activated the DGAT1 promoter. However, the C/EBPα‐p300 complexes were not detected on the DGAT1 promoter in livers of old KO mice resulting in lower levels of the enzyme. In conclusion, these studies demonstrate the mechanism by which ghrelin deletion prevents age‐associated hepatic steatosis and suggest that targeting this pathway may offer therapeutic benefit for NAFLD.

Deletion of ghrelin prevents aging-associated obesity and muscle dysfunction without affecting longevity.

During aging, decreases in energy expenditure and locomotor activity lead to body weight and fat gain. Aging is also associated with decreases in muscle strength and endurance leading to functional decline. Here, we show that lifelong deletion of ghrelin prevents development of obesity associated with aging by modulating food intake and energy expenditure. Ghrelin deletion also attenuated the decrease in phosphorylated adenosine monophosphate‐activated protein kinase (pAMPK) and downstream mediators in muscle, and increased the number of type IIa (fatigue resistant, oxidative) muscle fibers, preventing the decline in muscle strength and endurance seen with aging. Longevity was not affected by ghrelin deletion. Treatment of old mice with pharmacologic doses of ghrelin increased food intake, body weight, and muscle strength in both ghrelin wild‐type and knockout mice. These findings highlight the relevance of ghrelin during aging and identify a novel AMPK‐dependent mechanism for ghrelin action in muscle.

Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways

Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like receptor 4 (TLR4) mediates cancer-induced muscle wasting by directly activating muscle catabolism as well as stimulating an innate immune response in mice bearing Lewis lung carcinoma (LLC), and targeting TLR4 alone effectively abrogate muscle wasting. Utilizing specific siRNAs we observed that LLC cell-conditioned medium (LCM)-treated C2C12 myotubes underwent a rapid catabolic response in a TLR4-dependent manner, including activation of the p38 MAPK−C/EBPβ signaling pathway as well as the ubiquitin-proteasome and autophagy-lysosome pathways, resulting in myotube atrophy. Utilizing a reporter cell-line it was confirmed that LCM activated TLR4. These results suggest that LLC-released cachexins directly activate muscle catabolism via activating TLR4 on muscle cells independent of immune responses. Critically, LLC tumor-bearing TLR4−/− mice were spared from muscle wasting due to a blockade in muscle catabolic pathways. Further, tumor-induced elevation of circulating TNFα and interleukin-6 (IL-6) was abolished in TLR4−/− mice. These data suggest that TLR4 is a central mediator and therapeutic target of cancer-induced muscle wasting.

Use of growth hormone, IGF-I, and insulin for anabolic purpose: Pharmacological basis, methods of detection, and adverse effects

Hormones with anabolic properties such as growth hormone (GH), insulin-like growth factor-1 (IGF-I), and insulin are commonly abused among professional and recreational athletes to enhance physical ability. Performance enhancing drugs (PEDs) such as these are also commonly used by recreational athletes to improve body aesthetics. The perception of increased muscle mass due to supraphysiologic hormone supplementation, or doping, is widespread among PED users despite a paucity of evidence-based data in humans. Even still, athletes will continue to abuse PEDs in hopes of replicating anecdotal results. It is important to educate the general public and potential treating physicians of the risks of PED use, including the dangers of polypharmacy and substance dependence. It will also be important for the research community to address the common challenges associated with studying PED use such as the ethical considerations of PED administration, the general reticence of the PED-using community to volunteer information, and the constant need to improve or create new detection methods as athletes continually attempt to circumvent current methods. This review highlights the anabolic mechanisms and suggestive data implicating GH, IGF-I, and insulin for use as PEDs, the specific detection methods with cutoff ranges that may be utilized to diagnose abuse of each substance, and their respective side effects.

Sex Differences in Muscle Wasting

With aging and other muscle wasting diseases, men and women undergo similar pathological changes in skeletal muscle: increased inflammation, enhanced oxidative stress, mitochondrial dysfunction, satellite cell senescence, elevated apoptosis and proteasome activity, and suppressed protein synthesis and myocyte regeneration. Decreased food intake and physical activity also indirectly contribute to muscle wasting. Sex hormones also play important roles in maintaining skeletal muscle homeostasis. Testosterone is a potent anabolic factor promoting muscle protein synthesis and muscular regeneration. Estrogens have a protective effect on skeletal muscle by attenuating inflammation; however, the mechanisms of estrogen action in skeletal muscle are less well characterized than those of testosterone. Age- and/or disease-induced alterations in sex hormones are major contributors to muscle wasting. Hence, men and women may respond differently to catabolic conditions because of their hormonal profiles. Here we review the similarities and differences between men and women with common wasting conditions including sarcopenia and cachexia due to cancer, end-stage renal disease/chronic kidney disease, liver disease, chronic heart failure, and chronic obstructive pulmonary disease based on the literature in clinical studies. In addition, the responses in men and women to the commonly used therapeutic agents and their efficacy to improve muscle mass and function are also reviewed.

Selective Serotonin Reuptake Inhibitors Reduce Longitudinal Growth in Risperidone-Treated Boys

Objectives To examine whether selective serotonin reuptake inhibitors (SSRIs) inhibit longitudinal growth in children and adolescents, particularly in the early stages of puberty, using a sample of convenience comprising risperidone‐treated boys. Study design Data from four clinic‐based studies in risperidone‐treated 5‐ to 17‐year‐old boys with no general medical conditions were combined for this analysis. Anthropometric measurements and psychotropic treatment history were extracted from the medical and pharmacy records. Linear mixed effects regression analyses examined the association between SSRI use and change in age‐sex‐specific height and body mass index z scores, after adjusting for relevant confounders. Results Risperidone‐treated boys (n = 267; age: 12.7 ± 2.7 years), 71% of whom had ever taken an SSRI, contributed to the analysis. After adjusting for age, psychostimulant and antipsychotic use, and time in the study, both the duration of SSRI use as well as the cumulative dose were inversely associated with height z score after age 11 years (P < .0001). After adjusting for baseline height, duration of SSRI use was most strongly inversely associated with height z score in Tanner stages 3 and 4 boys who took SSRIs continuously (r = −0.69, P < .009). No association was observed with body mass index z score. Conclusions In risperidone‐treated boys, SSRI use is associated with reduced longitudinal growth, particularly in those undergoing puberty. Whether adult height or other metabolic or psychological outcomes are affected remains to be determined.

The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study: The Role of the Habenula in Cancer-Associated Weight Loss

Little is known about the brain mechanisms underlying cancer‐associated weight loss (C‐WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that patients with C‐WL have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward.

Erratum to: Update on Management of Cancer-Related Cachexia

The original version of this article, published in Current Oncology Reports, Volume 19, Issue 1, January 2017, contained misinterpreted data within the paragraph entitled “Nutritional Supplementation” on page 2 of the article. The authors offer their sincerest apologies regarding the incorrect statements in reference to Kapoor et al. 2016 [1]. It was pointed out that the definition of cachexia was not provided; however, the definition should be “weight loss of more than 5% from pretreatment weight, bodymass index less than 20 kg/m along with hemoglobin level less than 12 g/dL, and energy intake of less than 1500 kcal/d were considered eligible for participation” [1]. It was also noted that the experimental supplementation consisted of a wheat flour mix when wheat was not included as an ingredient. Finally, it was suggested that the baseline differences in energy intake “may have contributed to” the resultant changes in body composition; however, baseline data was adjusted for in the Kapoor et al. 2016 analyses which revealed increased energy intake in the experimental group. The amended paragraph provided is now correct.

Factors affecting bleedthrough of phenolic resin adhesive in hardwood plywood

SummarySome variables affecting the bleedthrough of phenolic resin adhesives in hardwood plywood were studied quantitatively. Variables included resin age, age of adhesive mix, extender/water ratio, amount of glue spread, aseembly time, veneer moisture content, species differences, grain angle, platen pressure, pressure cycle, platen temperature and rate of temperature rise.A technique was developed for evaluating bleedthrough numerically. This permitted the use of statistical analysis in a series of two- and three-factor experiments that resulted in some conclusions about the important interactions of variables, the combinatinos of which affect the amount of bleedthrough. Generally those combinations of variables that result in a high volume of glue in the glueline at the time of pressing, with a minimum of penetration into the veneer surfaces, permitted the phenolic adhesive to move through open vessel segments, that were inclined to the panel surface during the period of highest fluidity, when a pronounced lowering of viscosity is caused by the temperature rise in the glueline. These results generally confirmed other research on bleedthrough where urea resin adhesives were used as well as a different evaluating technique. A general concept of the mechanism of glue bond development in the manufacture of plywood is proposed in the light of the experimental results.ZusammenfassungVerschiedene Faktoren, die das Durchschlagen von Phenolharzleimen bei der Herstellung von Sperrholz aus Laubhölzern verursachen, wurden quantitativ untersucht. Sie betrafen das Alter des Harzes, das Alter der Leimmischung, das Verhältnis Streckmittel zu Wasser, die Menge des Leimauftrages, die Zeit zwischen Leimauftrag und Erreichen des Preßdruckes, den Feuchtigkeitsgehalt des Furniers, die Unterschiede zwischen den verschiedenen Holzarten, den Faserrichtungswinkel, den Preßdruck, den Preßzyklus, die Preßplattentemperatur und die Temperatur-Anstiegsgeschwindigkeit. Ein Verfahren zur numerischen Bewertung des Durchschlages wurde entwickelt. Dadurch konnte eine statistische Analyse bei einer Reihe von Versuchen mit zwei oder drei Einflußgrößen angewendet werden, die Stärke des Durchschlagens Wechselwirkungen zwischen Faktoren gaben, die gemeinsam die Stärke des Durchschlagens bestimmen. Im allgemeinen ließen jene Faktoren-Kombinationen, die durch eine große Leimmenge kurz vor dem Verpressen, bei gliechzeitig verhältnismäßig geringer Leimeindringung in die Furnieroberfläche gekennzeichnet waren, den Phenolharzleim durch die schräg durch das Furnier hindurchlaufenden, angeschnittenen Gefäße hindurchtreten. Dies geschah zum Zeitpunkt der höchsten Leim-Verflüssigung, d. h. dann, wenn die Leim-Viskosität durch die erhöhte Temperatur in der Leimfuge am niedrigsten war. Diese Ergebnisse bestätigten andere Forschungsergebnisse, bie denen Harnstoffharzleime, aber auch ein anderes Bewertungsschema verwendet wurden. Aufgrund der experimentellen Ergebnisse wird eine allgemeine Hypothese über die Entstehung der Leimverbindung bei der Sperrholzerzeugung aufgestellt.