New pharmacological strategies in the treatment of nonsmall cell lung cancer

According to the number of deaths lung cancer is the leading cancer type, and non-small cell lung carcinoma (NSCLC) is the most frequent subtype. Because of high NSCLC morbidity the aim of this paper is to discuss the appearance of new pharmacological possibilities in the lung cancer therapy. In the research field of new drugs there are two approaches that differ from the standard chemotherapy. According to one approach targeted therapy against specific molecules in the cancer cells is considered, like inhibitors of growth factors, or inhibitors of cell signalling (e.g. tyrosine kinase inhibitors, serine-threonine inhibitors), while on the other hand, drugs that could induce immune system in order to destroy lung cancer (like inhibitors of programmed death receptors, their ligands, or MAGE-A3 antagonists) are on the way to be discovered. Some of these drugs are approved by the U.S. Food and Drug Administration, while the others are in the first phases of clinical trials

Differentiated thyroid carcinomas - epidemiology, etiopathogenesis, diagnostics and therapy

© 2014, Serbian Medical Society. All rights reserved. Differentiated thyroid carcinomas (DTCs) present more than 90% of all thyroid tumours and include papillary and follicular carcinomas. Females suffer 2-3 times more often than men. Radiation is considered to be one of the most important etiological factors for the appearance of differentiated thyroid carcinomas, especially papillary carcinomas. DTCs may have a hereditary character in about 3% of cases. Disease usually presents in the form of slow growing thyroid nodules. The diagnostics is based on clinical examination, completed with ultrasonography and fine needle aspiration biopsy with cytological findings. DTCs patients require multidisciplinary therapeutic approach including total or near-total thyreoidectomy with postoperative application of radioactive iodine 131 for ablation of residual tumor as well as normal thyroid tissue. After that, the administration of L-thyroxine is required, at dose which inhibits the secretion of TSH. All patients require continuous monitoring, which also includes the determination of serum concentration of thyroglobulin. The prognosis is generally good, and the ten-year survival rate is over 90%. Recurrence is present in 10-15% of all patients, mainly in the neck, lymph nodes or thyroid region

Protein and lipid concentrations in patients with differentiated thyroid cancer treated with radioactive iodine-131

© 2014 University of Kragujevac, Faculty of Science. All rights reserved. Short-term, overt hypothyroidism in patients with differentiated thyroid cancer (DTC) before radioiodine (131-I) therapy might be accompanied by a number of metabolic changes, including altered protein and lipid metabolism. Protein concentrations and their relationship to lipids in the serum of DTC patients have not been fully elucidated. Th e aim of our study was to evaluate the protein and lipid concentrations in 24 DTC patients before and 3 and 7 days after 131-I therapy compared with those of 20 healthy control subjects. After radioiodine therapy, the mean protein concentration (78.71 -} 6.71 g/L vs. 87.16 -} 6.04 g/L; p = 0.003) and cholesterol level (8.12 ±} 2.13 mmol/L vs. 8.84 -} 2.09 mmol/L; p = 0.001) were lower 3 days after therapy; this persisted up to 7 days after therapy, whereas triglyceride concentrations were higher 3 days after therapy (2.44 -} 1.07 mmol/L vs. 2.26 -} 1.08 mmol/L; p = 0.041) and returned towards the pretreatment values at 7 days after 131-I therapy. Th ere was an indirect correlation between the protein and triglyceride concentrations 3 days after 131-I therapy in patients over 50 years old (Spearman’s r =-0.583, p = 0.048) but not in patients under 50 years old (Pearson’s r =-0.277, p = 0.384). Radioiodine therapy of DTC patients led to decreased serum protein and cholesterol concentrations, accompanied by increased triglyceride levels; these changes were especially evident in older subjects with metastases

Differential immunometabolic phenotype in Th1 and Th2 dominant mouse strains in response to high-fat feeding

© 2015 Jovicic et al. Immune reactivity plays an important role in obesity-associated metabolic disorders. We investigated immunometabolic phenotype of C57Bl/6 and BALB/c mice, prototypical Th1 and Th2-type strains, fed chow or high-fat diet (HFD) for 24 weeks. In comparison to C57Bl/ 6 mice, chow-fed BALB/c mice had higher body weight and weight gain, lower glycemia, more pronounced liver steatosis, but less inflammation and collagen deposition in liver. In response to HFD C57Bl/6 mice exhibited higher weight gain, higher glycemia, HbA1c and liver glycogen content, increased amount of visceral adipose tissue (VAT) and number of VAT associated CD3+CXCR3+ T cells, CD11c+ dendritic cells (DCs) and F4/80+ macrophages than BALB/c mice. More numerous CD3+ and CD8+ T lymphocytes, myeloid DCs, proinflammatory macrophages (F4/80+CD11b+CD11+ and F4/80+IL-1β+) and CD11b+ Ly6Chigh monocytes and higher levels of proinflammatory IL-6, TNF-α and IFN-γ were present in liver in HFD-fed C57Bl/6 mice compared with diet-matched BALB/c mice. As opposed to C57Bl/6 mice, HFD induced marked liver steatosis and upregulated the hepatic LXRα and PPARγ genes in BALB/c mice. C57Bl/6 mice fed HFD developed liver fibrosis and increased hepatic procollagen and TGF-β mRNA expression, and IL-33, IL-13 and TGF-β levels in liver homogenates, while BALB/c mice fed HFD had scarce collagen deposition in liver. The obtained results suggest inherent immunometabolic differences in C57Bl/6 and BALB/c mice. Moreover, HFD Th1-type mice on high fat diet regimen are more susceptible to adiposity, liver inflammation and fibrosis, while Th2-type mice to liver steatosis, which is associated with differential immune cell composition in metabolic tissues. Strain-dependent differences in immunometabolic phenotype may be relevant for studies of obesity-associated metabolic diseases in humans

Galectin-3 deletion enhances visceral adipose tissue inflammation and dysregulates glucose metabolism in mice on a high-fat diet

© 2016, University of Kragujevac, Faculty of Science. All rights reserved. Obesity and type 2 diabetes mellitus (T2DM) constitute major health problems worldwide. Increased visceral adiposity enhances the risk of insulin resistance and type 2 diabetes. The mechanisms involved in obesity-associated chronic inflammation in metabolic tissues (metaflammation) that lead to insulin resistance and dysregulated glucose metabolism are incompletely defined. Galectin-3 (Gal-3), a β-galactosidebinding lectin, modulates immune/inflammatory responses and specifically binds to metabolic danger molecules. To dissect the role of Gal-3 in obesity and diabetes, Gal-3-deficient (LGALS3-/-) and wild-type (WT) C57Bl/6 male mice were placed on a high-fat diet (HFD, 60% kcal fat) or a standard chow diet (10% kcal fat) for 6 months and metabolic, histological and immunophenotypical analyses of the visceral adipose tissue were performed. HFD-fed LGALS3-/- mice had higher body weights and more body weight gain, visceral adipose tissue (VAT), hyperglycaemia, hyperinsulinemia, insulin resistance and hyperlipidemia than diet-matched WT mice. Compared to WT mice, the enlarged VAT in obese LGALS3-/- mice contained larger adipocytes. Additionally, we demonstrate enhanced inflammation in the VAT of LGALS3-/- mice compared with diet-matched WT mice. The VAT of LGALS3-/- mice fed a HFD contained more numerous dendritic cells and proinflammatory F4/80+CD11c+CD11b+ and F4/80high macrophages. In contrast to WT mice, the numbers of CXCR3+ and CD8+ T cells were increased in the VAT of Gal-3-deficient mice after 6 months of high-fat feeding. We provide evidence that Gal-3 ablation results in enhanced HFD-induced adiposity, inflammation in the adipose tissue, insulin resistance and hyperglycaemia. Thus, Gal-3 represents an important regulator of obesity-associated immunometabolic alterations

ST2 deficiency ameliorates high fat diet-induced liver steatosis in BALB/c mice

© 2015 University of Kragujevac, Faculty of Science. All right reserved. Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but the molecular mechanisms of liver steatosis and its progression to non-alcoholic steatohepatitis and fibrosis are incompletely understood. Immune reactivity plays an important role in the pathogenesis of NAFLD. The IL-33/ST2 axis has a protective role in adiposity and atherosclerosis, but its role in obesity-associated metabolic disorders requires further clarification. To investigate the unresolved role of IL-33/ST2 signalling in NAFLD, we used ST2-deficient (ST2-/-) and wild type (WT) BALB/c mice maintained on a high-fat diet (HFD) for 24 weeks. HFDfed ST2-/- mice exhibited increased weight gain, visceral adipose tissue weight and triglyceridaemia and decreased liver weight compared with diet-matched WT mice. Compared with WT mice on an HFD, ST2 deletion significantly reduced hepatic steatosis, liver inflammation and fibrosis and downregulated the expression of genes related to lipid metabolism in the liver. The frequency of innate immune cells in the liver, including CD68+ macrophages and CD11c+ dendritic cells, was lower in HFD-fed ST2-/- mice, accompanied by lower TNFα serum levels compared with dietmatched WT mice. Less collagen deposition in the livers of ST2-/- mice on an HFD was associated with lower numbers of profibrotic CD11b+Ly6clow monocytes and CD4+IL-17+ T cells in the liver, lower hepatic gene expression of procollagen, IL-33 and IL-13, and lower serum levels of IL-33 and IL-13 compared with diet-matched WT mice. Our findings suggest that the IL-33/ST2 axis may have a complex role in obesity-associated metabolic disorders. Although it is protective in HFD-induced adiposity, the IL-33/ ST2 pathway promotes hepatic steatosis, inflammation and fibrosis

Blood cells in thyroid cancer patients: A possible influence of apoptosis

© 2016 Olgica B. Vrndic. The side effects of radioactive iodine (131-I) treatment of differentiated thyroid cancer (DTC) patients include reduction of peripheral blood cell counts. The aim of this study was to analyze some potential changes in blood cell counts of DTC patients after 131-I therapy, especially CD3-positive, CD19-positive, and CD56-positive peripheral blood lymphocytes (PBL), as well as the possible role of apoptosis in selected lymphocyte populations. The study group included 24 thyroid cancer patients and 24 control subjects. Peripheral blood samples from patients and controls were analyzed using 5-color flow cytometry. Apoptotic cells were detected using an Annexin V-FITC/7-AAD kit. There was a statistically significant decrease of all blood cells after the 131-I therapy. The CD19+ B lymphocyte population was the most affected (5.82 ± 3.21% before therapy vs. 3.93 ± 2.60% after therapy, p = 0.008). This decrease was correlated with the degree of apoptosis of peripheral blood lymphocytes (Spearman's r = 0.563, p = 0.013). We concluded that 131-I therapy of DTC patients led to a decrease of all peripheral blood cells, especially CD19+ B lymphocytes. This directly correlated with apoptosis of PBLs, indicating that radiation damage to B cells leads to subsequent elimination by apoptosis

Galectin-3 Deletion Enhances Visceral Adipose Tissue Inflammation and Dysregulates Glucose Metabolism in Mice on a High-Fat Diet

Obesity and type 2 diabetes mellitus (T2DM) constitute major health problems worldwide. Increased visceral adiposity enhances the risk of insulin resistance and type 2 diabetes. The mechanisms involved in obesity-associated chronic inflammation in metabolic tissues (metaflammation) that lead to insulin resistance and dysregulated glucose metabolism are incompletely defined. Galectin-3 (Gal-3), a β-galactoside-binding lectin, modulates immune/inflammatory responses and specifically binds to metabolic danger molecules. To dissect the role of Gal-3 in obesity and diabetes, Gal-3-deficient (LGALS3-/-) and wild-type (WT) C57Bl/6 male mice were placed on a high-fat diet (HFD, 60% kcal fat) or a standard chow diet (10% kcal fat) for 6 months and metabolic, histological and immunophenotypical analyses of the visceral adipose tissue were performed. HFD-fed LGALS3-/- mice had higher body weights and more body weight gain, visceral adipose tissue (VAT), hyperglycaemia, hyperinsulinemia, insulin resistance and hyperlipidemia than diet-matched WT mice. Compared to WT mice, the enlarged VAT in obese LGALS3-/- mice contained larger adipocytes. Additionally, we demonstrate enhanced inflammation in the VAT of LGALS3-/- mice compared with diet-matched WT mice. The VAT of LGALS3-/- mice fed a HFD contained more numerous dendritic cells and proinflammatory F4/80+CD11c+CD11b+ and F4/80high macrophages. In contrast to WT mice, the numbers of CXCR3+ and CD8+ T cells were increased in the VAT of Gal-3-deficient mice after 6 months of high-fat feeding. We provide evidence that Gal-3 ablation results in enhanced HFD-induced adiposity, inflammation in the adipose tissue, insulin resistance and hyperglycaemia. Thus, Gal-3 represents an important regulator of obesity-associated immunometabolic alterations

ST2 Deficiency Ameliorates High Fat Diet-Induced Liver Steatosis In BALB/c Mice

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but the molecular mechanisms of liver steatosis and its progression to non-alcoholic steatohepatitis and fibrosis are incompletely understood. Immune reactivity plays an important role in the pathogenesis of NAFLD. The IL-33/ST2 axis has a protective role in adiposity and atherosclerosis, but its role in obesity-associated metabolic disorders requires further clarification. To investigate the unresolved role of IL-33/ST2 signalling in NAFLD, we used ST2-deficient (ST2-/-) and wild type (WT) BALB/c mice maintained on a high-fat diet (HFD) for 24 weeks. HFD-fed ST2-/- mice exhibited increased weight gain, visceral adipose tissue weight and triglyceridaemia and decreased liver weight compared with diet-matched WT mice. Compared with WT mice on an HFD, ST2 deletion significantly reduced hepatic steatosis, liver inflammation and fibrosis and downregulated the expression of genes related to lipid metabolism in the liver. The frequency of innate immune cells in the liver, including CD68+ macrophages and CD11c+ dendritic cells, was lower in HFD-fed ST2-/- mice, accompanied by lower TNFα serum levels compared with diet-matched WT mice. Less collagen deposition in the livers of ST2-/- mice on an HFD was associated with lower numbers of profibrotic CD11b+Ly6clow monocytes and CD4+IL-17+ T cells in the liver, lower hepatic gene expression of procollagen, IL-33 and IL-13, and lower serum levels of IL-33 and IL-13 compared with diet-matched WT mice