Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients.

PURPOSE: To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays. RESULTS: The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation. CONCLUSION: We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.     

The influence of cochlear implantation on some voice parameters

OBJECTIVE: Some of the voice characteristics of deaf people differ considerably from those of speakers with normal hearing. After a cochlear implantation, auditory control of voice production is possible and the quality of the voice is improved. The aim of this study was to investigate the changes in some of the voice parameters in deaf children after cochlear implantation. METHODS: Thirty-one prelingually deafened children implanted unilaterally at the age of 2.5-13 years were included in the study. For all of the children an acoustic analysis (Multi-Dimensional Voice Program, Kay Elemetrics Corp., USA) of the Slovene vowel 'a' was performed before cochlear implantation and 6, 12 and 24 months after the implantation. The fundamental frequency (F0), jitter, shimmer and noise-to-harmonic ratio (NHR) were compared before and after the implantation. The results of the acoustic analyses were compared for the children who were implanted before or at the age of 4 years and the children who were implanted after the age of 4 years. RESULTS: After the cochlear implantation the fundamental frequency did not change significantly. However, an improvement was noticed in the measurements of jitter (p=0.006) and shimmer (p=0.021) as early as 6 months after the implantation. The noise-to-harmonic ratio improved (p=0.013) 24 months after the implantation. The children implanted before or at the age of 4 years showed a significant improvement in jitter (p=0.003) and shimmer (p=0.004) as early as 6 months and in noise-to-harmonic ratio (p=0.021) 12 months after the implantation. In the children implanted after the age of 4 years the only significant change was detected in F0 (p=0.045), 12 months after the implantation, and in Shimmer (p=0.017), 24 months after the implantation. CONCLUSION: The results of the present study have confirmed that cochlear implantation enables auditory moment-to-moment control of pitch and loudness. The determination of jitter and shimmer in the vowel 'a' sample proved to be a good and early indicator of improved phonation control, even in young children. The deaf children who were implanted before the age of 4 years improved their voice control more quickly and to a greater extent than the children implanted after the age of 4 years.     

Blastocyst development after sperm selection at high magnification is associated with size and number of nuclear vacuoles

Spermatozoa selection at high magnification before intracytoplasmic sperm injection seems to be positively associated with pregnancy rates after day 3 embryo transfers. The aim was to demonstrate an association between the presence of vacuoles in sperm nuclei and the competence of embryos to develop to day 5. Grading of spermatozoa at x 6000-x 12,500 magnification: grade I, no vacuoles; grade II, or=1 large vacuole; grade IV, large vacuoles with other abnormalities. The outcome of embryo development in a group of 25 patients after sibling oocyte injection with the four different grades of spermatozoa showed no significant difference in embryo quality up to day 3. However, the occurrence of blastocyst formation was 56.3 and 61.4% with grade I and II spermatozoa respectively, compared with 5.1% with grade III and 0% with grade IV respectively (P < 0.001). Spermatozoa selection at high magnification using Nomarski interference contrast is useful to identify more precisely the size and the number of nuclear vacuoles that greatly exert a negative effect on embryo development to the blastocyst stage. These observations confirm previous studies pointing to possible 'early and late paternal effects', both of which may have an impact on early embryonic development.     

Aerucyclamides A and B: isolation and synthesis of toxic ribosomal heterocyclic peptides from the cyanobacterium Microcystis aeruginosa PCC 7806

Two new modified hexacyclopeptides, aerucyclamides A and B, were isolated from the toxic freshwater cyanobacterium Microcystis aeruginosa PCC 7806. The constitution was assigned by spectroscopic methods, and the configuration determined by chemical degradation and analysis by Marfey's method combined with chemical synthesis. Synthetic aerucyclamide B was obtained through oxidation of aerucyclamide A (MnO2, benzene). The aerucyclamides were found to be toxic to the freshwater crustacean Thamnocephalus platyurus, exhibiting LC50 values for congeners A and B of 30.5 and 33.8 microM, respectively.     

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