Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression

Summary Interleukin-18 (IL-18, interferon [IFN]-gamma-inducing factor) is a proinflammatory cytokine converted to a biologically active molecule by interleukin (IL)-1beta converting enzyme (caspase-1). A wide range of normal and cancer cell types can produce and respond to IL-18 through a specific receptor (IL-18R) belonging to the toll-like receptor family. The activity of IL-18 is regulated by IL-18-binding protein (IL-18bp), a secreted protein possessing the ability to neutralize IL-18 and whose blood level is affected by renal function and is induced by IFNgamma. IL-18 plays a central role in inflammation and immune response, contributing to the pathogenesis and pathophysiology of infectious and inflammatory diseases. Because immune-stimulating effects of IL-18 have antineoplastic properties, IL-18 has been proposed as a novel adjuvant therapy against cancer. However, IL-18 increases in the blood of the majority of cancer patients and has been associated with disease progression and, in some cancer types, with metastatic recurrence risk and poor clinical outcome and survival. Under experimental conditions, cancer cells can also escape immune recognition, increase their adherence to the microvascular wall and even induce production of angiogenic and tumor growth-stimulating factors via IL-18-dependent mechanism. This is particularly visible in melanoma cells. Thus, the role of IL-18 in cancer progression and metastasis remains controversial. This review examines the clinical correlations and biological effects of IL-18 during cancer development and highlights recent experimental insights into prometastatic and proangiogenic effects of IL-18 and the use of IL-18bp against cancer progression.     

Intravenous delivery of a liposomal formulation of voriconazole improves drug pharmacokinetics,tissue distribution,and enhances antifungal activity

Voriconazole (VCZ), a triazole with a large spectrum of action is one of the most recommended antifungal agents as the first line therapy against several clinically important systemic fungal infections, including those by Candida albicans. This antifungal has moderate water solubility and exhibits a nonlinear pharmacokinetic (PK) profile. By entrapping VCZ into liposomes, it is possible to circumvent certain downsides of the currently available product such as a reduction in the rate of its metabolization into an inactive form, avoidance of the toxicity of the sulfobutyl ether-beta-cyclodextrin (SBECD), vehicle used to increase its solubility. PKs and biodistribution of VCZ modified by encapsulation into liposomes resulted in improved antifungal activity, due to increased specificity and tissue penetration. In this work, liposomal VCZ resulted in AUC_0–24/MIC ratio of 53.51?±?11.12, whereas VFEND^® resulted in a 2.5-fold lower AUC_0–24/MIC ratio (21.51?±?2.88), indicating favorable antimicrobial systemic activity. VCZ accumulation in the liver and kidneys was significantly higher when the liposomal form was used. Protection of the drug from biological degradation and reduced rate of metabolism leads to a 30% reduction of AUC of the inactive metabolite voriconazole-N-oxide (VNO) when the liposomal drug was administered. Liposomal VCZ presents an alternative therapeutic platform, leading to a safe and effective treatment against systemic fungal infections.     

Effect of Pursed-Lip Breathing in Patients With COPD: Linear and Nonlinear Analysis of Cardiac Autonomic Modulation

Objective: The aim of the present study was to evaluate the effect of pursed-lip breathing (PLB) on cardiac autonomic modulation in individuals with chronic obstructive pulmonary disease (COPD) while at rest. Methods: Thirty-two individuals were allocated to one of two groups: COPD (n = 17; 67.29 ± 6.87 years of age) and control (n = 15; 63.2 ± 7.96 years of age). The groups were submitted to a two-stage experimental protocol. The first stage consisted of the characterization of the sample and spirometry. The second stage comprised the analysis of cardiac autonomic modulation through the recording of R-R intervals. This analysis was performed using both nonlinear and linear heart rate variability (HRV). In the statistical analysis, the level of significance was set to 5% (p ≤ 0.05). Results: PLB promoted significant increases in the SD₁, SD₂, RMSSD and LF (ms²) indices as well as an increase in α₁ and a reduction in α₂ in the COPD group. A greater dispersion of points on the Poincaré plots was also observed. The magnitude of the changes produced by PLB differed between groups. Conclusion: PLB led to a loss of fractal correlation properties of heart rate in the direction of linearity in patients with COPD as well as an increase in vagal activity and impact on the spectral analysis. The difference in the magnitude of the changes produced by PLB between groups may be related to the presence of the disease and alterations in the respiration rate.     

Association of fixed partial denture and gingival prosthesis as alternative approach to recover esthetics and function in anterior maxillary region

Tooth replacement in the maxillary anterior region is especially difficult when the loss includes significant amounts of the residual ridge and the soft tissue. Several techniques are available, such as dental implants or fixed partial denture, and bone and gingival grafts or gingival prostheses, respectively. This article showed a clinical case of an elderly who was treated with a collarless metal-ceramic fixed partial denture and acrylic removable gingival prosthesis to recover the esthetics in the maxillary anterior region. The association of a metal-ceramic fixed denture and gingival prosthesis was an excellent alternative in cases when surgical procedures are contraindicated.     

Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer

The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.     

Effect of ionizing radiation after-therapy interval on bone: histomorphometric and biomechanical characteristics

Clinical Oral Investigations - This study aimed to evaluate the effects of radiotherapy on biomechanical, histomorphometric, and microstructural characteristics of bone, in diverse periods,...