Edward A. Medina

Conjugated linoleic acid supplementation in humans: effects on circulating leptin concentrations and appetite.

Conjugated linoleic acid (CLA) has been demonstrated to reduce body fat in animals. However, the mechanism by which this reduction occurs is unknown. Leptin may mediate the effect of CLA to decrease body fat. We assessed the effects of 64 d of CLA supplementation (3 g/d) on circulating leptin, insulin, glucose, and lactate concentrations in healthy women. Appetite was assessed as a physiological correlate of changes in circulating leptin levels. Analysis of plasma leptin concentrations adjusted for adiposity by using fat mass as a covariate showed that CLA supplementation significantly decreased circulating leptin concentrations in the absence of any changes of fat mass. Mean leptin levels decreased over the first 7 wk and then returned to baseline levels over the last 2 wk of the study in the CLA-treated group. Appetite parameters measured at around the time when the greatest decreases in leptin levels were observed showed no significant differences between supplementation and baseline determinations in the CLA-supplemented group or between the CLA and placebo-supplemented groups. There was a nonsignificant trend for mean insulin levels to increase toward the end of the supplementation period in CLA-treated subjects. CLA did not affect plasma glucose and lactate over the treatment period. Thus, 64 d of CLA supplementation in women produced a transient decrease in leptin levels but did not alter appetite. CLA did not affect these parameters in a manner that promoted decreases of adiposity.

Micronutrients and Innate Immunity

Micronutrients such as zinc, selenium, iron, copper, beta-carotene, vitamins A, C, and E, and folic acid can influence several components of innate immunity. Select micronutrients play an important role in alteration of oxidant-mediated tissue injury, and phagocytic cells produce reactive oxidants as part of the defense against infectious agents. Thus, adequate micronutrients are required to prevent damage of cells participating in innate immunity. Deficiencies in zinc and vitamins A and D may reduce natural killer cell function, whereas supplemental zinc or vitamin C may enhance their activity. The specific effects of micronutrients on neutrophil functions are not clear. Select micronutrients may play a role in innate immunity associated with some disease processes. Future studies should focus on issues such as age-related micronutrient status and innate immunity, alterations of micronutrients in disease states and their effect on innate immunity, and the mechanisms by which micronutrients alter innate immunity.

Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response to Francisella tularensis Live Vaccine Strain

An inadequate innate immune response appears to contribute to the virulence of Francisella tularensis following pulmonary infection. Studies in mice suggest that this poor response results from suppression of proinflammatory cytokine production early during infection, but the mechanisms involved are not understood. PI3K is known to regulate proinflammatory cytokine expression, but its exact role (positive versus negative) is controversial. We sought to clarify the role of PI3K in regulating proinflammatory signaling and cytokine production during infection with F. tularensis live vaccine strain (LVS). In this study, we demonstrate that the induction of TNF and IL-6 expression by LVS in mouse bone marrow-derived macrophages was markedly enhanced when PI3K activity was inhibited by either of the well-known chemical inhibitors, wortmannin or LY294002. The enhanced cytokine expression was accompanied by enhanced activation of p38 MAPK and ERK1/2, both of which were critical for LVS-induced expression of TNF and IL-6. LVS-induced MAPK activation and cytokine production were TLR2- and MyD88- dependent. PI3K/Akt activation was MyD88-dependent, but was surprisingly TLR2-independent. LVS infection also rapidly induced MAPK phosphatase-1 (MKP-1) expression; PI3K and TLR2 signaling were required. Peak levels of MKP-1 correlated closely with the decline in p38 MAPK and ERK1/2 phosphorylation. These data suggest that infection by LVS restrains the TLR2-triggered proinflammatory response via parallel activation of PI3K, leading to enhanced MKP-1 expression, accelerated deactivation of MAPKs, and suppression of proinflammatory cytokine production. This TLR2-independent inhibitory pathway may be an important mechanism by which Francisella suppresses the host’s innate immune response.

Anaplastic large cell lymphoma: twenty-five years of discovery.

CONTEXT The year 2010 commemorates the 25th year since the seminal publication by Karl Lennert and Harald Stein and others in Kiel, West Germany, describing an unusual large cell lymphoma now known as anaplastic large cell lymphoma (ALCL). Investigators at many universities and hospitals worldwide have contributed to our current in-depth understanding of this unique peripheral T-cell lymphoma, which in its systemic form, principally occurs in children and young adults. OBJECTIVE To summarize our current knowledge of the clinical and pathologic features of systemic and primary cutaneous ALCL. Particular emphasis is given to the biology and pathogenesis of ALCL. DATA SOURCES Search of the medical literature (Ovid MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE: 1950 to Present [National Library of Medicine]) and more than 20 years of diagnostic experience were used as the source of data for review. CONCLUSIONS Based on immunostaining for activation antigen CD30 and the presence of dysregulation of the anaplastic lymphoma kinase gene (2p23), the diagnosis of ALCL has become relatively straightforward for most patients. Major strides have been made during the last decade in our understanding of the complex pathogenesis of ALCL. Constitutive NPM-ALK signaling has been shown to drive oncogenesis via an intricate network of redundant and interacting pathways that regulate cell proliferation, cell fate, and cytoskeletal modeling. Nevertheless, pathomechanistic, therapeutic, and diagnostic challenges remain that should be resolved as we embark on the next generation of discovery.

Effects of tumor necrosis factor alpha on leptin secretion and gene expression: Relationship to changes of glucose metabolism in isolated rat adipocytes

OBJECTIVE: Our objective was to determine the effects of prolonged exposure to tumor necrosis factor-alpha (TNF-α) on leptin secretion from and leptin (OB) gene expression in isolated adipocytes. Because glucose uptake and the metabolism of glucose beyond lactate are important determinants of leptin production in adipocytes, we examined the effects of TNF-α on glucose uptake and lactate production and their relationship to leptin secretion.DESIGN AND METHODS: Isolated rat adipocytes were anchored in a defined matrix of basement membrane components and cultured with media containing 5 mM glucose, 0.16 nM insulin and several concentrations of TNF-α. Leptin secretion, steady-state levels of leptin mRNA levels, glucose uptake, and lactate production were assessed over 96 h.RESULTS: TNF-α at concentrations of 0.024, 0.24, 2.4 and 24 ng/ml did not affect leptin secretion over 24 h. TNF-α at concentrations of 0.24 to 24 ng/ml significantly inhibited leptin secretion over 96 h by 19–60%. TNF-α at concentrations of 0.024 to 24 ng/ml significantly decreased steady-state levels of leptin mRNA after 96 h by 32–95%. In addition, TNF-α at concentrations of 2.4 and 24 ng/ml significantly increased glucose uptake and lactate production over 96 h by 30–57%. TNF-α at a concentration of 0.024 ng/ml did not affect leptin secretion, glucose uptake or lactate production. Overall, for the TNF-α concentrations tested, leptin secretion was inversely related to the percent of glucose carbon released as lactate; however, TNF-α did not induce a proportional increase of lactate production from glucose.CONCLUSION: Short-term (24 h) exposure of isolated adipocytes to TNF-α does not affect leptin secretion. Prolonged exposure to TNF-α produces a concentration-dependent inhibition of leptin secretion and gene expression. This suggests that the acute effect of TNF-α to increase circulating leptin levels in vivo may be indirect. TNF-α at higher concentrations increases glucose uptake, but does not increase the conversion of glucose to lactate. Therefore, TNF-α appears to induce a dissociation between adipocyte glucose metabolism and leptin production.

PKA/AMPK signaling in relation to adiponectin's antiproliferative effect on multiple myeloma cells

Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin’s ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.

Immune reconstitution inflammatory syndrome after cessation of the tumor necrosis factor α blocker adalimumab in cryptococcal pneumonia

Tumor necrosis factor alpha antagonists have proven efficacious for a variety of autoimmune-mediated diseases. However, recent data have highlighted the risk of invasive fungal infections with their use. These agents are typically discontinued when infectious complications occur during therapy; however, the immune reconstitution inflammatory syndrome (IRIS) may be seen after drug cessation. We describe the 1st case of IRIS secondary to cryptococcal pneumonia after cessation of adalimumab.

Is mTOR inhibitor good enough for treatment all tumors in TSC patients

Tuberous sclerosis complex (TSC) is an autosomal dominant and multi-system genetic disorder in humans. TSC affects around 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders. TSC is caused by defects or mutations in two genes, TSC1 and TSC2. Loss of TSC1/TSC2 leads to dysregulation of mTOR, resulting in aberrant cell differentiation and development, and abnormal enlargement of cells. TSC is characterized by the development of benign and/or malignant tumors in several organs including renal/liver angiomyolipomas, facial angiofibroma, lymphangiomyomatosis, cardiac rhabdomyomas, retinal astrocytic, renal cell carcinoma, and brain subependymal giant cell astrocytomas (SEGA). In addition, TSC disease causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Particularly problematic are the development of renal angiomyolipomas, which tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. In addition, SEGA block the flow of fluid within the brain, causing a buildup of fluid and pressure that leads to blurred vision and seizures. In the current review, we describe the pathology of TSC disease in key organs and summarize the use of mTOR inhibitors to treat tumors in TSC patients.

The Diagnostic Value of Adiponectin Multimers in Healthy Men Undergoing Screening for Prostate Cancer

Background: Adiponectin has been reported to have a prohibitory effect on prostate cancer. The goal of this study was to evaluate the diagnostic value of adiponectin multimers for prostate cancer. Methods: Total adiponectin, high- and low-molecular-weight (HMW, LMW), ratios of these measures, and body mass index (BMI) were compared in a prospective prostate cancer–screened cohort. Multivariable logistic regression was used to assess the association between adiponectin measures, their interaction with BMI, and risk of prostate cancer and Gleason score upgrading from biopsy to prostatectomy. Results: A total of 228 prostate cancer cases and 239 controls were analyzed: 72 (31.6%) of the cancer cases were high grade (Gleason grade ≥7). Only percent HMW had a statistically significant relationship with prostate cancer (P = 0.04). Among normal and overweight men, the risk of prostate cancer increased as percent HMW increased [OR = 1.24 for a doubling of percent HMW, 95% confidence interval (CI), 0.41–3.75 and OR = 1.81; 95% CI, 1.02–3.20, respectively], whereas among obese men, the risk of prostate cancer decreased (OR = 0.62; 95% CI, 0.32–1.18). Among 97 patients who underwent radical prostatectomy, there was no association between Gleason score upgrading and any of the adiponectin multimers. Conclusion: This study was unable to confirm the utility of total adiponectin as a biomarker for prostate cancer risk. For the adiponectin multimers, only HMW showed increases with prostate cancer but not in all weight classes. Impact: Although adiponectin may play a role in the pathogenesis of prostate cancer, our results do not support adiponectin multimers as biomarkers of detection. Cancer Epidemiol Biomarkers Prev; 23(2); 309–15. ©2013 AACR.

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer

Loss of Von Hippel‐Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia‐inducible factor (HIF‐α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5‐aminoimidazole‐4‐carboxamide‐riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF‐2α expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of HIF‐2α to the Akt promoter and effected formation of the DNA‐protein complex in nuclear extracts from 786‐O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, AICAR, and rapamycin+AICAR decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p‐Akt, HIF‐2α, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre‐clinical trials in patients with kidney cancer.