Baylor Research Institute

Morvaridzadeh, M., M. Sepidarkish, F. Farsi, A. Akbari, R. Mostafai, A. Omidi, E. Potter and J. Heshmati (2020). “Effect of Cashew Nut on Lipid Profile: A Systematic Review and Meta-Analysis.” Complement Med Res.

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INTRODUCTION: Nuts are one of the dietary components which appear to have beneficial effects on cardiovascular disease biomarkers. Studies demonstrate beneficial effects of cash-ews on serum lipids concentration, but results in the literature remain inconclusive. We conducted a review to examine the effects of cashew nut supplementation on serum lipid profile. METHODS: Two reviewers independently searched PubMed, Web of Science, Cochrane Library, Scopus, and EMBASE electronic databases from inception until June 2019 without language limitation. Random- and fixed-effects models were used to calculate 95% confidence intervals (CI) for studies. RESULTS: Six randomized clinical trials comprising 531 participants were included in this systematic review. Three studies were included in the meta-analysis model. There were no significant changes for total cholesterol (TC) (standardized mean difference [SMD]: -0.02, 95% CI: -0.32, 0.28), triglycerides (TG) (SMD: -0.01, 95% CI: -0.22, 0.20), high-density lipoprotein (HDL) cholesterol (SMD: 0.09, 95% CI: -0.16, 0.34), or low-density lipoprotein (LDL) cholesterol (SMD: -0.18, 95% CI: -0.75, 0.39). CONCLUSION: The results of this analysis demonstrate that treatment with cashew nut supplementation alone did not significantly change serum levels of LDL, HDL, TC, or TG.

Kirby, T., D. C. Walters, M. Brown, E. Jansen, G. S. Salomons, C. Turgeon, P. Rinaldo, E. Arning, P. Ashcraft, T. Bottiglieri, J. B. Roullet and K. M. Gibson (2020). “Post-mortem tissue analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD). I. Metabolomic outcomes.” Metab Brain Dis Mar 14. [Epub ahead of print].

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Metabolomic characterization of post-mortem tissues (frontal and parietal cortices, pons, cerebellum, hippocampus, cerebral cortex, liver and kidney) derived from a 37 y.o. male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) was performed in conjunction with four parallel series of control tissues. Amino acids, acylcarnitines, guanidino- species (guanidinoacetic acid, creatine, creatinine) and GABA-related intermediates were quantified using UPLC and mass spectrometric methods that included isotopically labeled internal standards. Amino acid analyses revealed significant elevation of aspartic acid and depletion of glutamine in patient tissues. Evidence for disruption of short-chain fatty acid metabolism, manifest as altered C4OH, C5, C5:1, C5DC (dicarboxylic) and C12OH carnitines, was observed. Creatine and guanidinoacetic acids were decreased and elevated, respectively. GABA-associated metabolites (total GABA, gamma-hydroxybutyric acid, succinic semialdehyde, 4-guanidinobutyrate, 4,5-dihydroxyhexanoic acid and homocarnosine) were significantly increased in patient tissues, including liver and kidney. The data support disruption of fat, creatine and amino acid metabolism as a component of the pathophysiology of SSADHD, and underscore the observation that metabolites measured in patient physiological fluids provide an unreliable reflection of brain metabolism.

Correction to: Treatment of Psoriasis with Secukinumab in Challenging Patient Scenarios: A Review of the Available Evidence.

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Upon publication, it was noted that five of the on-line supplementary figures had incorrect figure: figure legend associations. These were supplementary Figs. 6, 7, 14, 15, and 23.

Plichta, J. K., M. L. Sebastian, L. A. Smith, C. S. Menendez, A. T. Johnson, S. M. Bays, D. M. Euhus, E. J. Clifford, M. Jalali, S. H. Kurtzman, W. A. Taylor and K. S. Hughes (2019). “Germline Genetic Testing: What the Breast Surgeon Needs to Know.” Ann Surg Oncol Apr 2. [Epub ahead of print].

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PURPOSE: The American Society of Breast Surgeons (ASBrS) sought to provide educational guidelines for breast surgeons on how to incorporate genetic information and genomics into their practice. METHODS: A comprehensive nonsystematic review was performed of selected peer-reviewed literature. The Genetics Working Group of the ASBrS convened to develop guideline recommendations. RESULTS: Clinical and educational guidelines were prepared to outline the essential knowledge for breast surgeons to perform germline genetic testing and to incorporate the findings into their practice, which have been approved by the ASBrS Board of Directors. RECOMMENDATIONS: Thousands of women in the USA would potentially benefit from genetic testing for BRCA1, BRCA2, and other breast cancer genes that markedly increase their risk of developing breast cancer. As genetic testing is now becoming more widely available, women should be made aware of these tests and consider testing. Breast surgeons are well positioned to help facilitate this process. The areas where surgeons need to be knowledgeable include: (1) identification of patients for initial breast cancer-related genetic testing, (2) identification of patients who tested negative in the past but now need updated testing, (3) initial cancer genetic testing, (4) retesting of patients who need their genetic testing updated, (5) cancer genetic test interpretation, posttest counseling and management, (6) management of variants of uncertain significance, (7) cascade genetic testing, (8) interpretation of genetic tests other than clinical cancer panels and the counseling and management required, and (9) interpretation of somatic genetic tests and the counseling and management required.

McKenna Iii, J., D. Kapfhamer, J. M. Kinchen, B. Wasek, M. Dunworth, T. Murray-Stewart, T. Bottiglieri, R. A. Casero, Jr. and M. J. Gambello (2018). “Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex.” Hum Mol Genet. Apr 9. [Epub ahead of print].

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Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and the quintessential disorder of mTORC1 dysregulation. Loss of either causative gene, TSC1 or TSC2, leads to constitutive mTORC1 kinase activation and a pathologically anabolic state of macromolecular biosynthesis. Little is known about the organ-specific metabolic reprogramming that occurs in TSC-affected organs. Using a mouse model of TSC in which Tsc2 is disrupted in radial glial precursors and their neuronal and glial descendants, we performed an unbiased metabolomic analysis of hippocampi to identify Tsc2-dependent metabolic changes. Significant metabolic reprogramming was found in well-established pathways associated with mTORC1 activation, including redox homeostasis, glutamine/TCA cycle, pentose and nucleotide metabolism. Changes in two novel pathways were identified: transmethylation and polyamine metabolism. Changes in transmethylation included reduced methionine, cystathionine, S-adenosylmethionine (SAM – the major methyl donor), reduced SAM/SAH ratio (cellular methylation potential), and elevated betaine, an alternative methyl donor. These changes were associated with alterations in SAM-dependent methylation pathways and expression of the enzymes methionine adenosyltransferase 2A (MAT2A) and cystathionine beta synthase (CBS). We also found increased levels of the polyamine putrescine due to increased activity of ornithine decarboxylase, the rate-determining enzyme in polyamine synthesis. Treatment of Tsc2+/- mice with the ornithine decarboxylase (ODC) inhibitor 2-difluoromethylornithine (DFMO), to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAM-dependent methylation reactions and polyamine metabolism in TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.

Majtan, T., E. M. Bublil, I. Park, E. Arning, T. Bottiglieri, F. Glavin and J. P. Kraus (2018). “Pharmacokinetics and pharmacodynamics of PEGylated truncated human cystathionine beta-synthase for treatment of homocystinuria.” Life Sci 200: 15-25. May 1.

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AIMS: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. In this communication, we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice, wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials. MAIN METHODS: Animal models received single or multiple doses of PEG-CBS. Activity of PEG-CBS and sulfur amino acid metabolites were determined in plasma and used to determine PK and PD. KEY FINDINGS: The plasma half-lives of PEG-CBS after a single subcutaneous (SC) injection were approximately 20, 44 and 73h in mouse, rat and monkey, respectively. The SC administration of PEG-CBS resulted in a significant improvement or full correction of metabolic imbalance in both blood and tissues of homocystinuric mice. The PD of PEG-CBS in mouse was dose-dependent, but less than dose-proportional, with the maximal efficacy achieved at 8mg/kg. PEG-CBS was well-tolerated in mice and monkeys, but resulted in dose-dependent minimal-to-moderate inflammation at the injection sites and vacuolated macrophages in rats. Allometric scaling of animal data was linear and the estimated human efficacious dose was determined as 0.66mg/kg administered once a week. SIGNIFICANCE: These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.