Targeting of antigens to activated dendritic cells in vivo cures metastatic melanoma in mice

Anti (alpha)-DEC-205 antibodies target to the DEC-205 receptor that mediates antigen presentation to T cells by dendritic cells. To exploit these properties for immunization purposes, we conjugated the melanoma antigen tyrosinase-related protein (TRP)-2 to alphaDEC-205 antibodies and immunized mice with these conjugates together with dendritic cell-activating oligonucleotides (CpG). Upon injection of the melanoma cell line B16, alphaDEC-TRP immunized mice were protected against tumor growth. Even more important for clinical applications, we were able to substantially slow the growth of implanted B16 cells by injection of alphaDEC-TRP2 conjugates into tumor bearing hosts. Approximately 70% of the animals were cured from existing tumors by treatment with alphaDEC conjugates carrying two different melanoma antigens (TRP-2 and gp100). This protection was due to induction of melanoma-specific CD4 and CD8 responses. Thus, these data show that targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity.     

Sporadic Creutzfeldt–Jakob disease

To investigate a possible relationship between the severity of pathological and radiological lesions in diffusion–weighted MRI (DWI) we compared DWI findings from 6 sequential brain MRI scans with pathological features of numerous tissue blocks of different cortical and subcortical regions in a case of autopsy–proven sporadic CJD. Whereas DWI and pathological examination revealed multifocal, cortical and deep hyperintensities at corresponding localizations, no correlation between the degree of severity of radiologically visible and pathological damage was found.The characteristic focal involvement and extension of lesions of the cortex and the basal ganglia bilaterally shown by DWI may be an argument for the spreading of the disease per contiguitatem.     

Hashimoto's encephalopathy presenting with bipolar affective disorder

OBJECTIVE: We report on a rare case of Hashimoto's encephalopathy associated with a bipolar affective disorder. CASE REPORT: A 32-year-old woman presented with a bipolar affective disorder and Hashimoto's thyroiditis. Neurological investigations (magnetic resonance imaging of the brain and cerebrospinal fluid) did not reveal any pathological findings except for a pathological electroencephalogram (EEG). Despite consequent antidepressant treatment, the patient remitted only in conjunction with normalization of the EEG after short-term treatment with high doses of prednisolone. CONCLUSION: In treatment resistant courses of disorders, the thorough clinical and laboratory investigation of our patient revealed a very efficient treatment strategy. Cases of Hashimoto's encephalopathy associated with the occurrence of a manic episode and hence with bipolar disorder are rare; this is the first reported case. However, clinicians should be alert to this possibility.     

Processing of sub-syllabic speech units in the posterior temporal lobe: an fMRI study

The objective of this study was to investigate phonological processing in the brain by using sub-syllabic speech units with rapidly changing frequency spectra. We used isolated stop consonants extracted from natural speech consonant-vowel (CV) syllables, which were digitized and presented through headphones in a functional magnetic resonance imaging (fMRI) paradigm. The stop consonants were contrasted with CV syllables. In order to control for general auditory activation, we used duration- and intensity-matched noise as a third stimulus category. The subjects were seventeen right-handed, healthy male volunteers. BOLD activation responses were acquired on a 1.5-T MR scanner. The auditory stimuli were presented through MR compatible headphones, using an fMRI paradigm with clustered volume acquisition and 12 s repetition time. The consonant vs. noise comparison resulted in unilateral left lateralized activation in the posterior part of the middle temporal gyrus and superior temporal sulcus (MTG/STS). The CV syllable vs. noise comparison resulted in bilateral activation in the same regions, with a leftward asymmetry. The reversed comparisons, i.e., noise vs. speech stimuli, resulted in right hemisphere activation in the supramarginal and superior temporal gyrus, as well as right prefrontal activation. Since the consonant stimuli are unlikely to have activated a semantic-lexical processing system, it seems reasonable to assume that the MTG/STS activation represents phonetic/phonological processing. This may involve the processing of both spectral and temporal features considered important for phonetic encoding.     

Comparative in vitro activity of ceftobiprole against staphylococci displaying normal and small-colony variant phenotypes

The antistaphylococcal activity of ceftobiprole was compared with those of cefuroxime, linezolid, and moxifloxacin by using the agar dilution method. Apart from three strains with small-colony variant phenotypes, all Staphylococcus aureus isolates tested were inhibited by < or =2 microg/ml of ceftobiprole. This compound exhibited an excellent antistaphylococcal activity, comparable to that of linezolid.     

Duration of symptoms: impact on outcome of radiotherapy in glottic cancer patients

PURPOSE: To study the relationship between the durations of symptoms before the start of radiotherapy and treatment outcome in Stage I-III glottic cancer. METHODS AND MATERIALS: From 1965 to 1997, 611 glottic cancer patients from the Southern Region of Denmark were treated with primary radiotherapy. A total of 544 patients fulfilled the criteria for inclusion to the study (Stage I-III glottic cancer, a duration of symptoms less than or equal to 36 months, primary radiotherapy with at least 50 Gy and sufficient data for analysis). The total radiation dose ranged from 50.0 to 71.6 Gy in 22 to 42 fractions, and the median dose per fraction was 2.00 Gy (range, 1.56-2.29 Gy). All patients had 5 years of follow-up, and the 5-year recurrence-free survival rate was used as the primary endpoint. RESULTS: The 5-year recurrence-free survival rate was 74%. In a multivariate Cox regression analysis, duration of symptoms was a significant factor (p < 0.0001) with a hazard ratio of 1.045 (95% CI 1.023, 1.069). Other significant factors included tumor stage and radiation dose, whereas duration of treatment time was borderline significant (p = 0.06). CONCLUSIONS: The duration of symptoms was statistically significantly related to a decrease in recurrence-free survival. One-month delay from onset of symptoms to start of radiotherapy was equivalent to a 4.5% decrease in recurrence-free survival.     

Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors.

PURPOSE: Bladder tumors develop through different molecular pathways. Recent reports suggest activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene as marker for the "papillary" pathway with good prognosis, in contrast to the more malignant "carcinoma in situ" (CIS) pathway. The aim of this clinical follow-up study was to investigate the role of FGFR3 mutations in bladder cancer development in a longitudinal study. EXPERIMENTAL DESIGN: We selected 85 patients with superficial bladder tumors, stratified into early (stage T(a)/grade 1-2, n = 35) and more advanced (either stage T(1) or grade 3, n = 50) developmental stages. The patients were followed prospectively, and metachronous tumors were included. We did screening for FGFR3 and TP53 mutations by direct bidirectional sequencing and for genome-wide molecular changes with microarray technology. RESULTS: A total of 43 of 85 cases (51%) showed activating mutations of FGFR3. The mutations were associated with papillary tumors of early developmental stage. However, after stratifying for developmental stage, FGFR3-mutated tumors showed the same malignant potential as wild-type tumors. Tumors with concomitant CIS were generally FGFR3 wild type. They were characterized by different patterns of chromosomal changes and gene expression signatures compared with FGFR3-mutated tumors, indicating different molecular pathways. CONCLUSIONS: FGFR3 mutations seem to have a central role in the early development of papillary bladder tumors. These tumors follow a common molecular pathway, which is different from tumors with concomitant CIS. FGFR3 mutations do not seem to play a role in bladder cancer progression.     

Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer

BACKGROUND AND AIMS: Genomewide expression profiling has identified a number of genes expressed at higher levels in colorectal cancer (CRC) than in normal tissues. Our objectives in this study were: 1) to test whether genes were also distinct on the protein level; 2) to evaluate these biomarkers in a series of well-characterized CRCs; and 3) to apply hierarchical cluster analysis to the immunohistochemical data. METHODS: Tissue microarrays (TMAs) comprising 351 CRC specimens from 270 patients were constructed to evaluate the genes Adam10, Cyclin D1, Annexin II, NFKB, Casein kinase 2 beta (CK2B), YB-1, P32, Rad51, c-fos, IGFBP4, and Connexin26 (Cx26). In total, 3,797 samples were analyzed. RESULTS: Unsupervised hierarchical clustering discovered subgroups of CRC that differed by tumor stage and survival. Kaplan-Meier analysis showed that reduced Cx26 expression was significantly associated with shorter patient survival and higher tumor grade (G1/G2 vs G3, P = .02), and Adam10 expression with a higher tumor stage (pT1/2 vs pT3/4, P = .04). CONCLUSIONS: Our study highlights the potential of TMAs for a higher-dimensional analysis by evaluating serial sections of the same tissue core (three-dimensional TMA analysis). In addition, it endorses the use of immunohistochemistry supplemented by hierarchical clustering for the identification of tumor subgroups with diagnostic and prognostic signatures.     

Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation

The development of new direct compression excipients should include a comprehensive and rapid determination of deformation properties. The aim of this study was to characterize StarLac, a new coprocessed compound for direct compression based on lactose and maize starch. For this purpose, the effects of the base materials (maize starch and spraydried lactose) were considered and the influence of the spray-drying process was investigated. This was performed by comparing the physical mixture of starch and spray-dried lactose at the same ratio as for StarLac. For analysis of the deformation behavior, the 3-D model and the Walker equation were applied; for verification, the Heckel equation and the pressure time function (a modified Weibull equation) were used. The advantages of StarLac are its good flowability depending on the spray-drying process, an acceptable crushing force due to its lactose content, its rapid disintegration depending on starch, and a brilliant fast release of an active ingredient, such as theophylline monohydrate. The volume-pressure deformation properties of StarLac were dependent on the lactose properties. Only at high maximum relative density (varrho(rel,max)) did the influence of starch cause a change in these properties. A network-like structure can be observed using scanning electron microscopy pictures. Overall, StarLac deformed plastically with a low portion of elasticity. The physical mixture exhibited a more elastic behavior than StarLac. However, the part of the powder that was irreversibly compressed was much lower than was observed for the single substances. This behavior is caused by an interaction between the components, which in StarLac is prevented by spray drying.