Fatty acid composition of muscle and heart tissue of Nile perch,Lates niloticus,and Nile tilapia,Oreochromis niloticus,from various populations in Lakes Victoria and Kioga,Uganda

The fatty acid composition in the heart tissue and muscle tissue of the Nile perch, Lates niloticus, and Nile tilapia, Oreochromis niloticus populations from Lakes Kioga and Victoria was determined by methanolysis and gas chromatography of the resulting fatty acid methyl esters. The analytical data were treated by multivariate principal component analysis. The most abundant individual fatty acids were palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1n9), vaccenic acid (18:1n7), arachidonic acid (20:4n6) and docosahexaenoic acid (22:6n3). Due to high levels of both n6 and n3 fatty acids, the ratios of n3 to n6 were between 1 and 2, typical for freshwater fish species. Two Lake Victoria and one Lake Kioga populations of Nile tilapia and Nile perch were distinguished by the fatty acid profiles in their heart and muscle tissue. The heart tissue showed better separation than muscle tissue, due to dominance of polar phospholipids. It is rationalised that genetics are more important than diet in determining the fatty acid composition of the tissues.     

A systems biology approach to identify molecular pathways altered by HDAC inhibition in osteosarcoma

Osteosarcoma (OS) is the most common primary tumor in humans and dogs affecting the skeleton, and spontaneously occurring OS in dogs serves as an extremely useful model. Unacceptable toxicities using current treatment protocols prevent further dose-intensification from being a viable option to improve patient survival and thus, novel treatment strategies must be developed. Histone deacetylase inhibitors (HDACi) have recently emerged as a promising class of therapeutics demonstrating an ability to enhance the anti-tumor activity of traditional chemotherapeutics. To date, gene expression analysis of OS cell lines treated with HDACi has not been reported, and evaluation of the resultant gene expression changes may provide insight into the mechanisms that lead to success of HDACi. Canine OS cells, treated with a clinically relevant concentration of the HDACi valproic acid (VPA), were used for expression analysis on the Affymetrix canine v2.0 genechip. Differentially expressed genes were grouped into pathways based upon functional annotation; pathway analysis was performed with MetaCore and Ingenuity Pathways Analysis software. Validation of microarray results was performed by a combination of qRT-PCR and functional/biochemical assays revealing oxidative phosphorylation, cytoskeleton remodeling, cell cycle, and ubiquitin-proteasome among those pathways most affected by HDACi. The mitomycin C-bioactivating enzyme NQ01 also demonstrated upregulation following VPA treatment, leading to synergistic reductions in cell viability. These results provide a better understanding of the mechanisms by which HDACi exert their effect in OS, and have the potential to identify biomarkers that may serve as novel targets and/or predictors of response to HDACi-containing combination therapies in OS.     

A Network Meta‐Analysis of Short and Long‐Term Efficacy of Targeted Therapy With Single or Double‐Drug Regimens in the Treatment of Stage III/IV Malignant Melanoma Based on 16 Randomized Controlled Trials

For the treatment of stage III/IV malignant melanoma (MM), a network meta‐analysis (NMA) was conducted to compare the short and long‐term efficacy of targeted therapy with single or double‐drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double‐drug regimens for treatment of stage III/IV MM were also analyzed. To group the treatments according to their similarity with regards to both outcomes, cluster analyses were performed. Ultimately, 16 RCTs were incorporated for this NMA. The NMA revealed that the overall response rate (ORR) values of single‐drug regimens (Vemurafenib [Vem], Dabrafenib [Dab], and Nivolumab [Niv]) were higher than those of Dacarbazine (Dac). Also the ORR values of double‐drug regimens (Dab + Trametinib [Dab + Tra], Niv + Ipilimumab [Niv + Ipi], and Vem + Cobimetinib [Vem + Cob]) were moderately higher than those of Dac. The results of the SUCRA showed that short‐term efficacy of single‐drug regimens (Vem and Dab) were better, while the short‐term efficacy of double‐drug regimens (Dab + Tra and Vem + Cob) were relatively better. It was determined that Vem, Dab, and Niv might be the best choice in evaluating the treatment of stage III/IV MM among different single‐drug targeted therapy regimens, while Dab + Tra, Niv + Ipi, and Vem + Cob might have better short‐term efficacy among different double‐drug targeted therapy regimens. J. Cell. Biochem. 119: 640–649, 2018. © 2017 Wiley Periodicals, Inc.     

Efficacy Comparison of Six Chemotherapeutic Combinations for Osteosarcoma and Ewing's Sarcoma Treatment: A Network Meta‐Analysis

This study aimed to address the insufficiency of traditional meta‐analysis and provide improved guidelines for the clinical practice of osteosarcoma treatment. The heterogeneity of the fixed‐effect model was calculated, and when necessary, a random‐effect model was adopted. Furthermore, the direct and indirect evidence was pooled together and exhibited in the forest plot and slash table. The surface under the cumulative ranking curve (SUCRA) value was also measured to rank each intervention. Finally, heat plot was introduced to demonstrate the contribution of each intervention and the inconsistency between direct and indirect comparisons. This network meta‐analysis included 32 trials, involving a total of 5,626 subjects reported by 28 articles. All the treatments were classified into six chemotherapeutic combinations: dual agent with or without ifosfamide (IFO), multi‐agent with or without IFO, and dual agent or multi‐agent with IFO and etoposide. For the primary outcomes, both overall survival (OS) and event‐free survival (EFS) rates were considered. The multi‐agent integrated with IFO and etoposide showed an optimal performance for 5‐year OS, 10‐year OS, 3‐year EFS, 5‐year EFS, and 10‐year EFS when compared with placebo. The SUCRA value of this treatment was also the highest of these six interventions. However, multi‐drug with IFO alone had the highest SUCRA value of 0.652 and 0.516 when it came to relapse and lung‐metastasis. It was efficient to some extent, but no significant difference was observed in both outcomes. Chemotherapy, applied as induction or adjuvant treatment with radiation therapy or surgery, is able to increase the survival rate of patients, especially by combining multi‐drug with IFO and etoposide, which demonstrated the best performance in both OS and EFS. As for relapse and the lung‐metastasis, multiple agents with IFO alone seemed to have the optimal efficiency, although no significant difference was observed here. J. Cell. Biochem. 119: 250–259, 2018. © 2017 Wiley Periodicals, Inc.     

Simulation Based Investigation of Deleterious nsSNPs in ATXN2 Gene and Its Structural Consequence Toward Spinocerebellar Ataxia

Spinocerebellar degeneration, termed as ataxia is a neurological disorder of central nervous system, characterized by limb in‐coordination and a progressive gait. The patient also demonstrates specific symptoms of muscle weakness, slurring of speech, and decreased vibration senses. Expansion of polyglutamine trinucleotide (CAG) within ATXN2 gene with 35 or more repeats, results in spinocerebellar ataxia type‐2. Protein ataxin‐2 coded by ATXN2 gene has been reported to have a crucial role in translation of the genetic information through sequestering the histone acetyl transferases (HAT) resulting in a state of hypo‐acetylation. In the present study, we have evaluated the outcome for 122 non synonymous single nucleotide polymorphisms (nsSNPs) reported within ATXN2 gene through computational tools such as SIFT, PolyPhen 2.0, PANTHER, I‐mutant 2.0, Phd‐SNP, Pmut, MutPred. The apo and mutant (L305V and Q339L) form of structures for the ataxin‐2 protein were modeled for gaining insights toward 3D spatial arrangement. Further, molecular dynamics simulations and structural analysis were performed to observe the brunt of disease associated nsSNPs toward the strength and secondary properties of ataxin‐2 protein structure. Our results showed that, L305V is a highly deleterious and disease causing point substitution. Analysis based on RMSD, RMSF, Rg, SASA, number of hydrogen bonds (NH bonds), covariance matrix trace, projection analysis for eigen vector demonstrated a significant instability and conformation along with rise in mutant flexibility values in comparison to the apo form of ataxin‐2 protein. The study provides a blue print of computational methodologies to examine the ataxin‐blend SNPs. J. Cell. Biochem. 119: 499–510, 2018. © 2017 Wiley Periodicals, Inc.     

Efficacy and Toxicity of Different Chemotherapy Regimens in the Treatment of Advanced or Metastatic Pancreatic Cancer: A Network Meta‐Analysis

Objective A network meta‐analysis was conducted to compare the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic pancreatic cancer (PC). PubMed, Cochrane Library and EMBASE databases from inception to June 2016 were searched. A combination of direct and indirect evidences was referred to for calculating the weighted mean difference (WMD) or the odds ratio (OR) and to establish surface under the cumulative ranking (SUCRA) curves, so as to evaluate the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic PC. Twenty randomized controlled trials were enrolled. Twelve chemotherapy regimens included Gemcitabine, S‐1 (Tegafur), Gemcitabine + Cisplatin, Gemcitabine + Capecitabine, Gemcitabine + S‐1, Gemcitabine + 5‐FU (5‐fluorouracil), Gemcitabine + Exatecan, Gemcitabine + Irinotecan, Gemcitabine + Nab‐paclitaxel, FOLFIRINOX (Oxaliplatin + Irinotecan + Fluorouracil + Leucovorin), Gemcitabine + Oxaliplatin, and Gemcitabine + Pemetrexed. Higher overall response rate (ORR) was observed in patients treated with the gemcitabine + S‐1 and FOLFIRINO regimens. Thrombocytopenia reduced in patients treated with the S‐1 regimen. The Gemcitabine + S‐1 and FOLFIRINO regimens had better short‐ and long‐term efficacies than the other regimens; S‐1 regimen had the lowest hematologic toxicity, while Gemcitabine + Nab‐paclitaxel, FOLFIRINOX, and Gemcitabine + Pemetrexed regimens had higher incidence of non‐hematologic toxicity among twelve chemotherapy regimens. The efficacy of Gemcitabine + S‐1 and FOLFIRINOX regimens may be better in treating patients with advanced or metastatic pancreatic cancer, while FOLFIRINOX and Gemcitabine + Pemetrexed regimens may have relatively higher incidence of toxicity than other regimens. J. Cell. Biochem. 119: 511–523, 2018. © 2017 Wiley Periodicals, Inc.     

The Role of Serum High Mobility Group Box 1 and Interleukin‐6 Levels in Acute Pancreatitis: A Meta‐Analysis

The purpose of this meta‐analysis was to comprehensively investigate the correlation between high mobility group box 1 (HMGB1) and interleukin‐6 (IL‐6) in relation to acute pancreatitis. A highly regulated exploration of various electronic databases, supplemented by manual searching methods, was performed in an attempt to identify pertinent articles of a useful nature. Subsequently, high‐quality cohort studies that were deemed to comply with the arduous inclusion and exclusion criteria were selected for our meta‐analysis. The extensive data analyses reported in our meta‐analysis were conducted in connection with the Comprehensive Meta‐analysis 2.0 (CMA 2.0). A total of 395 studies (135 Chinese studies and 260 English studies) were initially retrieved. 27 of those studies were selected for our meta‐analysis, comprising of 896 cases of mild acute pancreatitis (MAP), 700 cases of severe acute pancreatitis (SAP) as well as 312 healthy controls. Pooled data suggested that serum HMGB1 and IL‐6 levels of SAP and MAP patients were higher than in healthy controls. Moreover, serum HMGB1 and IL‐6 levels of SAP patients exhibited significantly higher levels than in that of MAP patients. Based on the rigorous investigation of our meta‐analysis, it was concluded that serum HMGB1 and IL‐6 levels might be used as effective indicators for pancreatic lesions as well as the degree of inflammatory response, owing ultimately to the observations and data analyses, suggesting that serum HMGB1 and IL‐6 levels share a close correlation with the severity of pancreatitis. J. Cell. Biochem. 119: 616–624, 2018. © 2017 Wiley Periodicals, Inc.