Mature dendritic cells induce tumor-specific type 1 regulatory T cells

The aim of this study was to compare the tumor antigen-specific T-cell repertoire generated by transduced, human dendritic cells (DCs). The transductions were three commonly used antigen delivery procedures: adenovirus (AdV) infection, RNA electroporation, and liposome-mediated protein transfection. The DCs in each experimental group were transfected with similar efficacy and matured using TNF-alpha, anti-CD40, or lipopolysaccharide. Regardless of the gene transfer method or the maturation stimuli used, the DCs were indistinguishable with regard to surface phenotype and allostimulatory capacity. With the exception of the Adv transduced group, the T cells generated were tumor antigen specific, as characterized by high IFN-gamma production. The T cells generated upon stimulation with DCs subjected to AdV infection, and subsequently treated with TNF-alpha, exhibited tumor antigen specificity, but accompanied by reduced proliferation and IFNgamma production and increased IL-10 production. Moreover, these T cells exerted a suppressive effect on both autologous and allogeneic lymphocytes resembling type 1 regulatory T cells (Tr1). The authors show that mature DCs may induce tumor antigen-specific Tr1 cells by the appearance of high IL-10 and low IL-12. Similar results were also obtained with AdV-infected and TNF-matured DCs regardless of the transgene used. This work supports the conclusion that it can no longer be assumed that mature DCs induce only antitumor reactive T cells.     

Anionic linear aliphatic surfactants activate TRPV1: A possible endpoint for estimation of detergent induced eye nociception?

The transient receptor potential vanilloid type 1 (TRPV1) has been reported as one of the key components in the pain pathway. Activation of the receptor causes a Ca²⁺ influx in sensory C-fibres with secondary effects leading to neurogenic inflammation in the surrounding tissue. We have earlier reported specific activation of TRPV1 by surfactant-containing hygiene products. We have continued this project by investigating activation of the TRPV1 by shampoo and soap ingredients in low concentrations measured as intracellular Ca²⁺ influxes in stably TRPV1-expressing neuroblastoma SH-SY5Y cells. As a TRPV1 specific control, the TRPV1 antagonist capsazepine was used. The response was quantified as the product induced Ca²⁺ influx during 2 min in relation to the maximum response induced by the TRPV1 agonist capsaicin. The results show that anionic alkyl linear surfactant ingredients such as sodium lauryl sulphate, sodium laureth sulphate, ammonium lauryl sulphate, sodium C12-15 pareth sulphate and N-lauroylsarcosine concentration-dependently induced Ca²⁺ influx that could be addressed to TRPV1. The cationic surfactants benzalkonium chloride and cetylpyridinium chloride induced a Ca²⁺ influx that was not TRPV1 mediated as well as the zwitterionic surfactant cocamidopropyl betaine, the non-linear anionic surfactant sodium deoxycholate and the non-ionic surfactant Triton-X. These results reveal a new mechanistic pathway for surfactant-induced nociception.     

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

The size of affibody molecules makes them suitable as targeting agents for targeted radiotherapy with the alpha-emitter 211At, since their biokinetic properties match the short physical half-live of 211At. In this study, the potential for this approach was investigated in vivo. Two different HER-2 binding affibody molecules were radiolabeled with 211At using both the linker PAB (N-succinimidyl-para-astatobenzoate) and a decaborate-based linker, and the biodistribution in tumor-bearing nude mice was investigated. The influence of L-lysine and Na-thiocyanate on the 211At uptake in normal tissues was also studied. Based on the biokinetic information obtained, the absorbed dose was calculated for different organs. Compared with a previous biodistribution with 125I, the 211At biodistribution using the PAB linker showed higher uptake in lungs, stomach, thyroid and salivary glands, indicating release of free 211At. When the decaborate-based linker was used, the uptake in those organs was decreased, but instead, high uptake in kidneys and liver was found. The uptake, when using the PAB linker, could be significantly reduced in some organs by the use of L-lysine and/or Na-thiocyanate. In conclusion, affibody molecules have suitable blood-kinetics for targeted radionuclide therapy with 211At. However, the labeling chemistry affects the distribution in normal organs to a high degree and needs to be improved to allow clinical use.     

Radiation doses to the cell nucleus in single cells and cells in micrometastases in targeted therapy with (131)I labeled ligands or antibodies

PURPOSE: The aim of this study was to theoretically investigate how the radiation dose to cell nuclei depends on the subcellular position of (131)I. The influence of the size of the cells and crossfire irradiation in clusters of cells was also studied. METHODS AND MATERIAL: Using data describing the dose rate around a point source of (131)I, we calculated the dose distributions inside and around cell models of different sizes. The assumed positions of (131)I were on the cellular or nuclear membrane, in the cytoplasm, in the nucleus, or spread in the whole cell. The mean doses to the nucleus of the targeted cell and to the nuclei of its neighbors were calculated using the dose distributions. RESULTS: The dose distributions inside a single targeted cell showed very different distribution profiles depending on the subcellular position of the (131)I. Targeting the nucleus instead of the cellular membrane could increase the dose to the nucleus 10-fold. Crossfire irradiation can be the major contributor to the nuclear dose in clusters of more than six cells. CONCLUSIONS: Dosimetry without microscopic considerations is inadequate for targeted radionuclide therapy of disseminated or clustering tumor cells exposed to (131)I. Therapeutic doses could be achieved, even in single cells, when (131)I was positioned near, or inside the cell nucleus, or when the clusters were large enough.     

Treatment of malignant endocrine pancreatic tumors with a new long-acting somatostatin analogue, SMS 201-995

Ten patients with malignant endocrine pancreatic tumors were treated with SMS 201-995 at doses of 50 micrograms twice daily, administered subcutaneously. Four out of 10 patients (40%)-1 patient with the Zollinger-Ellison syndrome and 3 of 6 with the watery diarrhea syndrome--responded objectively with more than 50% reduction of peptide levels, with a median duration of 15.5 months. All four patients improved symptomatically, with decreasing dyspeptic symptoms and decreasing diarrhoea. Three additional patients had a clear relief of symptoms without an effect on tumor-secreted peptides. The disease progressed in three patients during treatment. No reduction of tumor mass was seen in any of the patients. The main side effect noted was a slight but maintained increase in fasting blood glucose in four patients. In conclusion, SMS 201-995 had a beneficial effect in more than half of the patients and seems to be a valuable adjunct to other causal therapy in this patient category, especially in acute situations and weak patients because of its very few side effects.     

Oral function in patients wearing fixed prosthesis on osseointegrated implants in the maxilla

Bite force, chewing efficiency and tactile sensibility were investigated in 21 subjects with OIB (Osseointegrated Implant bridges) in the maxilla or in both jaws. Recordings were performed before treatment, approximately 1 wk and finally 3-6 months after treatment. The bite force was recorded in the incisor, canine, and premolar areas and was tested at gentle biting, biting as when chewing, and maximal biting. In the chewing tests the chewing time, the chewing velocity, the time to swallowing, and the Ci (Chewing Efficiency Index) were calculated. The occlusal thickness perception was tested in the front with a 12.8 x 10(-3) mm thick plastic foil. The maximal bite force was more than doubled, the Ci improved about one index unit, and the occlusal thickness perception improved from on average 57.5 x 10(-3) mm to 18.7 x 10(-3) mm during the observation time. It is concluded that treatment with upper OIB has a very positive impact on oral function as reflected by improved bite force, chewing efficiency, and occlusal thickness perception.     

Nerve growth factor affects11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (Case Report)

Summary Based on animal research suggesting that nerve growth factor (NGF) can stimulate central cholinergic neurons, the known losses of cholinergic innervation of the cortices in Alzheimer's disease (AD), and our experience of infusing NGF to support adrenal grafts in parkinsonian patients, we have initiated clinical trials of NGF infusions into the brain of patients with AD. Here we report a follow-up of our first case, a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF during three months resulted in a marked transient increase in uptake and binding of¹¹C-nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects could be ascribed to the NGF infusion. Taken together, the results of this case study indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.     

Suicide in psychiatric patients. A prospective study of 67 cases without initial signs of severe depression or alcoholism

All cases from the county, who were subjected to post-mortem examination at the Department of Forensic Medicine, University of Lund with a diagnosis of suicide during 1949-1984, were compared with the inpatient register at the Department of Psychiatry, University Hospital, Lund during 1949-1969. During these years all patients were rated at discharge with a multidimensional schedule. All patients with initial ratings of severe depression/melancholia and alcoholism were analyzed separately and excluded from the present sample. The ratings of the suicide cases were compared with those of 8,046 other inpatients. There were 67 suicide cases, 36 men and 31 women. The suicide cases had higher frequencies of the item easily led/dependent/immature personality (34% versus 18%) and of attempted suicides (19% versus 8%). There were no differences in ratings of symptoms as slight depression and anxiety or of situational factors. Attempted suicide was related to suicides early in the course, while easily led/dependent/immature was not so related. At the time of the suicide there was a higher frequency of never married and a lower frequency of married subjects in the present series compared with suicides in severe depression/melancholia and alcoholism.