Activation of natural killer cells by heat shock protein 70

Intracellular heat shock proteins (HSP) function as molecular chaperones, they support folding and transport mechanisms of other proteins under physiological conditions and following physical or chemical stress. More recently, extracellular localized HSP have been found to play key roles in the induction of a cellular immune response. Either they act as carrier molecules for immunogenic peptides that are presented on Antigen Presenting Cells (APC) to cytotoxic T-cells or they themselves act as activatory molecules for the innate immune system. Binding of uncomplexed HSP to HSP-receptors on APC has been found to induce the secretion of inflammatory cytokines. Furthermore, an unusual tumor-selective membrane-localization of non-conserved regions of the 72000Da HSP (Hsp70) has been found to act as a recognition structure for natural killer (NK) cells. In this review the interaction of NK cells with Hsp70 or peptides derived thereof will be eluciated in more detail.     

Fixation of distal femoral osteotomies with self-reinforced poly(L/DL)lactide 70 : 30 and self-reinforced poly(L/DL)lactide 70 : 30/bioactive glass composite rods. An experimental study on rabbits

Two self-reinforced poly(L/DL)lactide 70 : 30 or self-reinforced poly(L/DL)lactide 70 : 30/bioactive glass (SR-P(L/DL)LA/bioactive glass) composite rods (2 mm × 40 mm) were implanted into the dorsal subcutaneous tissue and osteotomies of the distal femur were fixed with these rods (2 mm × 26 mm) in 36 rabbits. The follow-up times varied from 3 to 100 weeks. After the animals were killed, three-point bending and shear tests and molecular weight measurements were performed for subcutaneously placed rods. Radiological, histological, histomorphometrical, microradiographic and oxytetracycline-fluorescence studies of the osteotomized and intact control femora were performed. After 12 weeks the SR-P(L/DL)LA rods had fragmented into pieces and the mechanical properties could not be measured. The SR-P(L/DL)LA/bioactive glass rods lost their mechanical properties slower, and at 24 weeks the bending strength had decreased by 39% and the shear strength by 50%. After that the mechanical properties of the SR-P(L/DL)LA/bioactive glass rods could not be measured. All osteotomies healed well, and no gross signs of inflammatory reactions were observed. One slight displacement was seen in the three-week follow-up group with SR-P(L/DL)LA rods. Signs of resorption of the implants were seen after 48 weeks in the SR-P(L/DL)LA group and after 24 weeks in the SR-P(L/DL)LA/bioactive glass group. The SR-P(L/DL)LA/bioactive glass rods were almost totally resorbed from the bone at 100 weeks. The present investigation showed that the mechanical strength and fixation properties of the SR-P(L/DL)LA and the SR-P(L/DL)LA/bioactive glass composite rods are suitable for fixation of cancellous bone osteotomies in rabbits.     

Intracellular antigens as targets for antibody based immunotherapy of malignant diseases

This review discusses the potential use of intracellular tumor antigens as targets of antibody‐based immunotherapy for the treatment of solid tumors. In addition, it describes the characteristics of the intracellular tumor antigens targeted with antibodies which have been described in the literature and have been identified in the authors'' laboratory. Finally, the mechanism underlying the trafficking of the intracellular tumor antigens to the plasma membrane of tumor cells are reviewed.     

Fracture resistance and 2-body wear of 3-dimensional–printed occlusal devices

Statement of problem

Polymeric material for 3-dimensional printing can be used to fabricate occlusal devices. However, information about fracture resistance and wear is scarce.

Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression

Mitochondrial dysfunction leads to reactive oxygen species (ROS) overload, exacerbating injury in myocardial infarction (MI). As a receptor for translocases in the outer mitochondrial membrane (Tom) complex, Tom70 has an unknown function in MI, including melatonin‐induced protection against MI injury. We delivered specific small interfering RNAs against Tom70 or lentivirus vectors carrying Tom70a sequences into the left ventricles of mice or to cultured neonatal murine ventricular myocytes (NMVMs). At 48 h post‐transfection, the left anterior descending coronary arteries of mice were permanently ligated, while the NMVMs underwent continuous hypoxia. At 24 h after ischemia/hypoxia, oxidative stress was assessed by dihydroethidium and lucigenin‐enhanced luminescence, mitochondrial damage by transmission electron microscopy and ATP content, and cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick‐end labeling and caspase‐3 assay. At 4 weeks after ischemia, cardiac function and fibrosis were evaluated in mice by echocardiography and Masson's trichrome staining, respectively. Ischemic/hypoxic insult reduced Tom70 expression in cardiomyocytes. Tom70 downregulation aggravated post‐MI injury, with increased mitochondrial fragmentation and ROS overload. In contrast, Tom70 upregulation alleviated post‐MI injury, with improved mitochondrial integrity and decreased ROS production. PGC‐1α/Tom70 expression in ischemic myocardium was increased with melatonin alone, but not when combined with luzindole. Melatonin attenuated post‐MI injury in control but not in Tom70‐deficient mice. N‐acetylcysteine (NAC) reversed the adverse effects of Tom70 deficiency in mitochondria and cardiomyocytes, but at a much higher concentration than melatonin. Our findings showed that Tom70 is essential for melatonin‐induced protection against post‐MI injury, by breaking the cycle of mitochondrial impairment and ROS generation.     

Arimoclomol: a potential therapy under development for ALS

Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.     

Heat Shock Protein-70 Expression in Vitiligo and its Relation to the Disease Activity

Background:Vitiligo is a progressive depigmenting disorder characterized by the loss of functional melanocytes from the epidermis. The etiopathogenesis of vitiligo is still unclear. Heat shock proteins (HSPs) are prime candidates to connect stress to the skin. HSPs were found to be implicated in autoimmune diseases such as rheumatoid arthritis and other skin disorders as psoriasis.Results:Our analysis revealed a significantly higher expression of HSP-70 mRNA in lesional skin biopsies from vitiligo patients compared to nonlesional skin biopsies from vitiligo patients (P < 0.001) and compared to skin biopsies from healthy controls (P < 0.001). The level of HSP-70 was not found to be correlated with age, sex, or disease duration. The expression of HSP-70 was correlated with the disease activity and patients with active vitiligo showed higher mean HSP-70 level compared to those with inactive disease.Conclusions:HSP-70 plays a role in the pathogenesis of vitiligo and may enhance the immune response in active disease.