The Effect of a Western Diet on Hepatic Autophagy in Age Accelerated SAMP8 Mice

Non-alcoholic steatohepatitis (NASH) is characterized as a dysregulation of hepatic lipid metabolism and a chronic inflammatory state. It is hypothesized the link between lipid dysregulation and inflammation may be due in part to defective hepatic autophagy and reduced mitochondrial capacity to oxidize fatty acids. It remains to be determined; however, the effects of a Western diet on hepatic autophagy and mitochondrial function during aging. PURPOSE: The purpose of this study was to determine the effect of a high-fat high fructose diet (HFF) on markers of hepatic autophagy and mitochondrial function in an age accelerated mouse model. METHODS: Twenty week old, male and female, SAMP8 mice (n=49) were randomly assigned, matching for gender, to either a standard chow (SC) or HFF (45% fat, 24% fructose) diet for 32 weeks. Liver tissue was analyzed for mRNA expression of autophagic (BNIP3, Beclin 1, p62, and Atg7) and mitochondrial (PGC1α and COXIV) genes. Differences between gender and dietary groups were identified by a 2 x 2 ANOVA and statistical significance was set at p\u3c0.05. RESULTS: Following 32 weeks of feeding, male mice fed the HFF diet were significantly heavier than male mice in the SC group (31.6 g vs 26.5 g; p=0.001); however, no difference was observed between diet groups for female mice. The HFF diet resulted in higher autophagic activity as observed by Beclin 1 (+36%; p=0.001) and BNIP3 (+40%; P=0.003) expression. Despite the higher autophagic activity, p62 was higher (+31%; p\u3c0.001) in the HFF compared to the SC group, suggesting impaired autophagic flux. In addition, mitochondrial COXIV expression was elevated (+43%; P\u3c0.001) in the HFF group compared to the SC group suggesting increased β-oxidation. Overall, the expression of all autophagic and mitochondrial markers was higher in male compared to female mice; however, both sexes responded similarly to the HFF diet. CONCLUSION: Despite the higher expression of autophagic and mitochondrial genes, elevated expression of p62 suggests an impaired autophagic flux in age accelerated mice following a Western diet

Mapping the business systems of 61 major economies: a taxonomy and implications for varieties of capitalism and business systems research

Efforts to build a universal theory of the world’s business systems require empirical grounding in an understanding of the variety that need explaining. To support such theorizing, we analyzed the institutional structures of 61 major economies, accounting for 93.5% of 2013 world GDP at purchasing power parity. We found nine main types of business systems: Highly Coordinated, Coordinated Market, Liberal Market, European Peripheral, Advanced Emerging, Advanced City, Arab Oil-Based, Emerging, and Socialist Economies. Our findings illustrate the need to go beyond the Varieties of Capitalism and Business Systems frameworks; provide empirical support for the CME versus LME dichotomy for part of the OECD; identify some of the business systems proposed recently as sub-types of larger clusters; indicate that institutional diversity may increase with development level; and cast doubt on the notions of state-led and family-led capitalism as types of business systems. Our discussion further suggests numerous avenues for theory development and empirical research

Dietary Enrichment of Fish-Oils Attenuates Diet-Induced Obesity and Hepatic Steatosis

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess hepatic fat, exceeding 5% of total liver mass. NAFLD is present in one-third of Americans and up to 90% in those who are obese. NAFLD develops largely in part to consumption of a Western diet, defined as 40-60% kcal from saturated fats; however, a diet rich in fish-oils may prevent and reverse the development of steatosis. PURPOSE: To determine the effects of fish oils on the development of NAFLD. METHODS: C57BL/6 (n=91) mice were randomly assigned to four dietary groups for 32-weeks: 10% lard (LFL), 10% fish-oil (LFFO), 41% lard (HFL), or 41% fish-oil (HFFO) diet. Significant differences (p\u3c0.05) between groups were identified by a one-way ANOVA. RESULTS: When compared to HFFO, mice in the HFL group saw an greater (Table 1) body mass and net glucose AUC by 13% (p\u3c0.001) and 24% (p=0.08), respectively. No significant difference was observed between LFL and LFFO for body mass, net glucose AUC or HOMA-IR. This is interesting given no significant difference was observed between groups for the mean weekly caloric intake. HFFO mice showed an 86% lower (p\u3c0.001) total hepatic lipid and 4.8-fold lower (p\u3c0.001) hepatic triglyceride concentration when compared to HFL. HFFO mice also saw a 32% lower (p\u3c0.001) total hepatic cholesterol when compared to HFL. There was no significant difference in total hepatic lipids between LFL and LFFO. CONCLUSION: Despite for no significant difference in caloric intake between high-fat diet groups, consumption of a high-fat diet rich in fish-oils prevented dietary induced obesity, insulin resistance and hepatic steatosis. These results suggest that a diet rich in fish-oils have preventative effects on the development of NAFLD

Fish-oils Increase BAMBI Expression to Protect Against Fibrotic Activity in LPS Stimulated Hepatic Tissue

Non-alcoholic steatohepatitis (NASH), defined as excess hepatic lipid and chronic inflammation, provides an environment prone for the development of hepatic fibrosis. Recent evidence suggests that the antifibrotic protein BAMBI (BMP-Activin membrane bound inhibitor) is downregulated in the presence of inflammation, and may be central to the development of fibrosis. Diets rich in omega-3 (w-3) fatty acids are known to provide anti-inflammatory effects; however, the effects of w-3 fatty acids on hepatic fibrosis are not well-established. PURPOSE: To determine the effects of fish-oils on the hepatic fibrosis signaling cascade, following 32-weeks of high-fat feeding in a LPS-induced model of NASH. METHODS: Male C57BL/6 mice were randomly assigned to one of four diets for 32 weeks (n=9/group): low-fat lard based (LFL, 10% kcal fat), low-fat fish-oil based (LFFO, 10% kcal fat), high-fat lard based (HFL, 41% kcal fat), or high-fat fish-oil based (HFFO, 41% kcal fat). Following in situ LPS stimulation, liver mRNA expression of CD14, TLR4, MyD88, BAMBI, and TGF-β1 was quantified using quantitative RT-PCR. Differences between diets were identified using a one-way ANOVA with statistical significance set at p\u3c0.05. RESULTS: Following LPS stimulation, CD14 was increased 2.5 fold (p=0.020) in HFFO when compared to HFL. Despite the increase in CD14, TLR4 showed no difference between groups. In contrast, MyD88 was 2.8 fold greater (p\u3c0.001) in HFL compared to HFFO. In comparison to untreated tissue, BAMBI was 1.7 fold (p=0.017) higher in the HFFO LPS-stimulated tissue, which best explained the 1-fold (p=0.004) lower expression of TGF-β1 in HFFO when compared to HFL post-LPS stimulation. CONCLUSION: Despite the increase in extracellular LPS signaling receptor CD14, the consumption of fish-oils produced a protective intracellular response as observed by an increase in BAMBI and decrease in TGF-β1. These results suggest that a diet high in w-3 fatty acids may protect against the development of hepatic fibrosi

Diet and Sex Differences Induce Unique Alterations of Markers for Blood Brain Barrier Integrity in Age-Accelerated Mice

The role of diet on brain health has received significant attention, with the Western diet (WD) contributing to cerebrovascular alterations and neurodegenerative disease. The blood-brain barrier (BBB) may play a particularly important role as it forms the interface between the peripheral circulation and the central nervous system. The WD has been shown to negatively impact the BBB. Whether there are sex specific differences with diet on BBB integrity remains unclear. PURPOSE: To determine the effect of diet and sex on the mRNA expression of markers of BBB integrity in an age-accelerated mouse model. METHODS: Male and female Senescence Accelerated Mouse-Prone 8 (SAMP8) mice were randomly assigned to a standard diet (SD) or WD formula for a 32-week period, matched for sex, ending at 12-months of age (n=10-14/group). At 12-months of age, cortical brain tissue was evaluated for the expression of mRNA for targets associated with BBB integrity (Cldn-1, Cldn-3, Cldn-5, Cldn-12, F11r, Lsr, Msfd2a, Ocln, Tjp) using quantitative RT-PCR. A two-way ANOVA was used to identify whether mRNA expression of these targets differed with sex, diet, and their interaction. RESULTS: A significant (pCONCLUSION: Overall, female mice presented with higher expression of mRNA markers for BBB integrity, which may be a protective factor. Furthermore, mice fed the WD had lower mRNA expression of markers of BBB integrity suggesting that a Western diet may accelerate the pathogenesis of the disease state

Omega-3-Fatty Acids Hold Therapeutic Potential for the Prevention and Treatment of Diabetic Neuropathy

Diabetic neuropathy is a debilitating complication of diabetes, affecting over 50% of diabetic patients. Overweight humans display manifestations of diabetic neuropathy before developing overt diabetes and mice fed a high fat diet exhibit signs of neuropathy including mechanical hindpaw hypersensitivity and neuronal inflammation, suggesting fat diet-induced inflammation may play a role in the development of neuropathy. Omega-3 (n-3) fatty acids have anti-inflammatory properties and may hold therapeutic potential as a preventative treatment for prediabetic and diabetic patients at risk for neuropathy. PURPOSE: Investigate the impact of diet composition on signs of neuropathy. We hypothesized that a diet rich in n-3 fatty acids would attenuate hindpaw hypersensitivity during prolonged feeding of a high fat diet. METHODS: C57BL/6 mice were randomized into four diet groups (n = 12/group) for 32 weeks: 10% low fat-fish oil (LFFO), 41% high fat-fish oil (HFFO), 10% low fat-lard (LFL), or 41% high fat-lard (HFL). Neuropathy was characterized at baseline and every other week thereafter using the von Frey behavioral test for hindpaw mechanical sensitivity. A glucose tolerance test was performed at end study, and total area under the curve (AUC) was calculated using the trapezoidal method. RESULTS: At end study, body weight was greater in HFL compared to all other groups. Body weight was also greater in HFFO compared to LFFO. Fasting glucose and glucose AUC were higher in HFL compared to LFFO and HFFO. Following the same pattern as body weight, fasting glucose was higher in HFFO compared to LFFO. Although percent paw withdrawal was greater in HFL compared to HFFO and LFFO, there were no significant differences for LF vs. HF for fish oil or lard. CONCLUSION: A HFL diet induced signs of neuropathy including hindpaw hypersensitivity, whereas a fish oil diet was protective against hindpaw hypersensitivity. Moreover, omega-3-fatty acids may hold therapeutic potential for neuropathy prevention in nondiabetic and diabetic patients

Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma

PURPOSE: BRAF V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory BRAF V600-mutant HGG. METHODS: This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600-mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety. RESULTS: A total of 41 pediatric patients with previously treated BRAF V600-mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation. CONCLUSION: In relapsed/refractory BRAF V600-mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory BRAF V600-mutant HGG

1964: Abilene Christian College Bible Lectures - Full Text

LEADERSHIP IN THE CHURCH” Being the Abilene Christian College Annual Bible Lectures 1964 Price: $3.95 Published by ABILENE CHRISTIAN COLLEGE STUDENTS EXCHANGE ACC Station Abilene, Texa

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth