Neutrophil to lymphocyte ratio predicts disease progression following intra-arterial therapy of hepatocellular carcinoma.

BACKGROUND: Prospectively predicting response to intra-arterial therapy for hepatocellular carcinoma (HCC) is challenging. Neutrophil/lymphocyte ratio (NLR) is a serum biomarker that is associated with survival for multiple malignancies. It was hypothesized that increased NLR would be associated with early disease progression after intra-arterial therapy of HCC. METHODS: The outcomes of 86 treatment-naïve patients who had chemoembolization or radioembolization of HCC between July 2013-July 2014 were reviewed. Pre-treatment laboratory tests and imaging were used to measure NLR, Child-Pugh (CP) score, tumor number and tumor size. High/low NLR groups were defined as >3 and <3 respectively. Follow-up imaging at two months with assessed response using modified response criteria in solid tumors (mRECIST). RESULTS: NLR >3 was seen in 25/86 patients (range 3.0-21.6). NLR >3 patients had a significantly higher baseline CP score. Comorbidities were otherwise similar between groups as was tumor number/size. Disease control was significantly worse (p = 0.014) with NLR >3. Logistic regression for tumor response revealed NLR >3 as the best predictor of early progression (p < 0.0001). DISCUSSION: NLR may be a serologic biomarker of early progressive disease after intra-arterial therapy of HCC. Future research should focus on outcomes by treatment type or potentially combining arterial therapies with ablation and/or targeted biologic agents.

Sex differences in obesity development in pair-fed neuronal lipoprotein lipase deficient mice.

OBJECTIVE: Compared to men, postmenopausal women suffer from a disproportionate burden of many co-morbidities associated with obesity, e.g. cardiovascular disease, cancer, and dementia. The underlying mechanism for this sex difference is not well understood but is believed to relate to absence of the protective effect of estrogen through the action of estrogen receptor alpha (ERα) in the central nervous system. With the recently developed neuron-specific lipoprotein lipase deficient mice (NEXLPL-/-) (Wang et al., Cell Metabolism, 2011 [15]), we set to explore the possible role of lipid sensing in sex differences in obesity development. METHODS: Both male and female NEXLPL-/- mice and littermate WT controls were subjected to pair feeding (pf) where daily food amount given was adjusted according to body weight to match the food intake of ad libitum (ad) fed control WT mice. Food intake and body weight were measured daily, and pair feeding was maintained to 42 wk in male mice and to 38 wk in female mice. Various brain regions of the mice were harvested, and ERα gene expression was examined in both male and female NEXLPL-/- and WT control mice under both ad- and pf-fed conditions. RESULTS: Although both male and female NEXLPL-/- mice developed obesity similarly on standard chow, male NEXLPL-/- mice still developed obesity under with pair feeding, but on a much delayed time course, while female NEXLPL-/- mice were protected from extra body weight and fat mass gain compared to pair-fed WT control mice. Pair feeding alone induced extra fat mass gain in both male and female WT mice, and this was mostly driven by the reduction in physical activity. LPL deficiency resulted in an increase in ERα mRNA in the hypothalamus of ad-fed female mice, while pair feeding alone also resulted in an increase of ERα in both female WT control and NEXLPL-/- mice. The effect on increasing ERα by pair feeding and LPL deficiency was additive in pair-fed female NEXLPL-/- mice. ERα mRNA levels were not significantly modified in other brain regions examined, nor in the hypothalamus of male NEXLPL-/- mice compared to control mice. CONCLUSIONS: These results suggest that the mechanism underlying ERα regulation of body weight interacts with the LPL-dependent lipid processing in the hypothalamus in a sex specific way. ERα could provide the link between brain lipid sensing and sex differences in obesity development. This study has the potential important clinical implication to provide better management for women who suffer from obesity and obesity-related co-morbidities.

Obesity development in neuron-specific lipoprotein lipase deficient mice is not responsive to increased dietary fat content or change in fat composition.

We have previously reported that mice with neuron-specific LPL deficiency (NEXLPL-/-) become obese by 16weeks of age on chow. Moreover, these mice had reduced uptake of triglyceride (TG)-rich lipoprotein-derived fatty acids and lower levels of n-3 long chain polyunsaturated fatty acids (n-3 PUFAs) in the hypothalamus. Here, we asked whether increased dietary fat content or altered dietary composition could modulate obesity development in NEXLPL-/- mice. Male NEXLPL-/- mice and littermate controls (WT) were randomly assigned one of three synthetic diets; a high carbohydrate diet (HC, 10% fat), a high-fat diet (HF, 45% fat), or a HC diet supplemented with n-3 PUFAs (HCn-3, 10% fat, Lovaza, GSK®). After 42weeks of HC feeding, body weight and fat mass were increased in the NEXLPL-/- mice compared to WT. WT mice fed a HF diet displayed typical diet-induced obesity, but weight gain was only marginal in HF-fed NEXLPL-/- mice, with no significant difference in body composition. Dietary n-3 PUFA supplementation did not prevent obesity in NEXLPL-/- mice, but was associated with differential modifications in hypothalamic gene expression and PUFA concentration compared to WT mice. Our findings suggest that neuronal LPL is involved in the regulation of body weight and composition in response to either the change in quantity (HF feeding) or quality (n-3 PUFA-enriched) of dietary fat. The precise role of LPL in lipid sensing in the brain requires further investigation.

Prevalence of Hypertension in Pediatric Tibia Vara and Slipped Capital Femoral Epiphysis.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) and tibia vara (Blount disease) are associated with childhood obesity. However, the majority of obese children do not develop SCFE or tibia vara. Therefore, it is hypothesized that other obesity-related biological changes to the physis, in addition to increased biomechanical stress, potentiate the occurrence of SCFE and tibia vara. Considering that hypertension can impose pathologic changes in the physis similar to those observed in these obesity-related diseases we set out to determine the prevalence of hypertension in patients with SCFE and tibia vara. METHODS: Blood pressure measurements were obtained in 44 patients with tibia vara and 127 patients with SCFE. Body mass index and blood pressure were adjusted for age, sex, and height percentiles utilizing normative distribution data from the CDC. These cohorts were compared with age-matched and sex-matched cohorts derived from an obesity clinic who did not have either bone disease. A multivariable proportional odds model was used to determine association. RESULTS: The prevalence of prehypertension/hypertension was significantly higher in the tibia vara (64%) and SCFE cohort (64%) compared with respective controls (43%). Patients diagnosed with either SCFE or tibia vara had 2.5-fold higher odds of having high blood pressure compared with age-matched and sex-matched obese patients without bone disease. Sex, age, and race did not have a significant effect on a patient's blood pressure. CONCLUSIONS: This is the first study to establish that the obesity-related bone diseases, SCFE and tibia vara, are significantly associated with high blood pressure. These data have immediate clinical impact as they demonstrate that children with obesity-related developmental bone disease have increased prevalence of undiagnosed and untreated hypertension. Furthermore, this prevalence study supports the hypothesis that hypertension in conjunction with increased biomechanical forces together potentiate the occurrence of SCFE and tibia vara. If proven true, it is plausible that hypertension may represent a modifiable risk factor for obesity-related bone disease. LEVEL OF EVIDENCE: Level III-case-control study.

Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice.

Alterations in lipid metabolism have been found in several neurodegenerative disorders, including Alzheimer's disease. Lipoprotein lipase (LPL) hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system (CNS). Though many brain regions express LPL, the functions of this lipase in the CNS remain largely unknown. We developed mice with neuron-specific LPL deficiency that became obese on chow by 16 wks in homozygous mutant mice (NEXLPL-/-) and 10 mo in heterozygous mice (NEXLPL+/-). In the present study, we show that 21 mo NEXLPL+/- mice display substantial cognitive function decline including poorer learning and memory, and increased anxiety with no difference in general motor activities and exploratory behavior. These neurobehavioral abnormalities are associated with a reduction in the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor subunit GluA1 and its phosphorylation, without any alterations in amyloid ß accumulation. Importantly, a marked deficit in omega-3 and omega-6 polyunsaturated fatty acids (PUFA) in the hippocampus precedes the development of the neurobehavioral phenotype of NEXLPL+/- mice. And, a diet supplemented with n-3 PUFA can improve the learning and memory of NEXLPL+/- mice at both 10 mo and 21 mo of age. We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation.

Deficiency of lipoprotein lipase in neurons modifies the regulation of energy balance and leads to obesity.

Free fatty acids (FFAs) suppress appetite when injected into the hypothalamus. To examine whether lipoprotein lipase (LPL), a serine hydrolase that releases FFAs from circulating triglyceride (TG)-rich lipoproteins, might contribute to FFA-mediated signaling in the brain, we created neuron-specific LPL-deficient mice. Homozygous mutant (NEXLPL-/-) mice were hyperphagic and became obese by 16 weeks of age. These traits were accompanied by elevations in the hypothalamic orexigenic neuropeptides, AgRP and NPY, and were followed by reductions in metabolic rate. The uptake of TG-rich lipoprotein fatty acids was reduced in the hypothalamus of 3-month-old NEXLPL-/- mice. Moreover, deficiencies in essential fatty acids in the hypothalamus were evident by 3 months, with major deficiencies of long-chain n-3 fatty acids by 12 months. These results indicate that TG-rich lipoproteins are sensed in the brain by an LPL-dependent mechanism and provide lipid signals for the central regulation of body weight and energy balance.