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Somatostatin receptors type 2 (sst2) are expressed in high concentration on numerous neudoendocrine tumors. The successful use of radiolabeled somatostatin analogs in imaging promoted further studies in utilizing them in radiopeptide therapy. The somatostatin analog [⁹⁰Y–DOTA–D-Phe¹–Try3]octreotide (DOTATOC) (DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N",N‴-tetraacetic acid) possesses favorable characteristic for its therapeutic use; shows high affinity for sst2, moderately high affinity for sst5, and intermediate affinity for sst3; high hydrophilicity; stable and facile labeling with ¹¹¹ In and ⁹⁰ Y. In this article we report our experience with ⁹⁰Y–DOTATOC in neuroendocrine tumors. Eighty-seven patients with neuroendocrine tumors were treated with a cumulated activity ranging from 7.4 to 20.2 GBq. Most patients responded with stabilization of disease (48%); however, objective responses were observed in 28% of patients (5% complete response). No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The dose limiting was bone marrow toxicity and the maximal tolerated dose was defined as 5.18 GBq. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 393–398, 2002

The molecular mechanism leading to the imprinted expression of genes is poorly understood. While no conserved cis-acting elements have been identified within the known loci, many imprinted genes are located near directly repetitive sequence elements, suggesting that such repeats might play a role in imprinted gene expression. The maternally expressed mouse H19gene is located approximately 1.5 kb downstream from a 461-bp G-rich repetitive element. We have used a transgenic model to investigate whether this element is essential for H19imprinting. Previous results demonstrated that a transgene, which contains 14 kb of H19sequence, exhibits parent-of-origin specific expression and methylation analogous to the endogenous H19imprinting pattern. Here, we have generated transgenes lacking the G-rich repeat. One transgene, containing a deletion of the G-rich repetitive element but which includes an additional 1.7 kb of 5’H19sequence, is imprinted similarly to the endogenous H19gene. To determine whether the G-rich repeat is conserved in other imprinted mammalian H19homologues, additional 5’ flanking sequences were cloned from the rat and human. This element is conserved in the rat but not in human DNA. These results suggest that the 461-bp G-rich repetitive element is not essential for H19imprinting.

Inclusion complex formation between pyridoxine and β- and γ-cyclodextrins in aqueous solution has been investigated by1H NMR and UV spectroscopy. Both complexes exhibited a 1:1 stoichiometry and the inclusion process has been shown to perturb the equilibrium between the lactim and the lactam tautomer of pyridoxine, with a preferential inclusion of the former, less polar tautomer.

Differentially methylated sequences associated with imprinted genes are proposed to control genomic imprinting. A 2-kb region located 5' to the imprinted mouse H19 gene is hypermethylated on the inactive paternal allele throughout development. To determine whether this differentially methylated domain (DMD) is required for imprinted expression at the endogenous locus, we have generated mice harboring a 1.6-kb targeted deletion of the DMD and assayed for allelic expression of H19 and the linked, oppositely imprinted Igf2 gene. H19 is activated and Igf2 expression is reduced when the DMD deletion is paternally inherited; conversely, upon maternal transmission of the mutation, H19 expression is reduced and Igf2 is activated. Consistent with the DMD's hypothesized role of setting up the methylation imprint, the mutation also perturbs allele-specific methylation of the remaining H19 sequences. In conclusion, these experiments show that the H19 hypermethylated 5' flanking sequences are required to silence paternally derived H19. Additionally, these experiments demonstrate a novel role for the DMD on the maternal chromosome where it is required for the maximal expression of H19 and the silencing of Igf2. Thus, the H19 differentially methylated sequences are required for both H19 and Igf2 imprinting.

Background and objective: The clinical effectiveness of noninjectable routes for specific immunotherapy has been demonstrated in many studies, but no data are available on the kinetics of allergens administered by these routes. Therefore we studied the kinetics of the radiolabeled purified major Parietaria judaica allergen (Par j 1) after sublingual, oral, and intranasal administration to healthy human beings. Methods: After tracer administration (10 to 12.5 @mg of Par j 1 labeled with iodine 123) to nonallergic volunteers, scintigraphic images were recorded at various times. Blood samples were also obtained at serial intervals to evaluate the absorption and distribution of radioactivity in plasma and to identify circulating radioactive species by molecular exclusion gel chromatography. Results: When the sublingual route was used, no circulating radioactivity was detected until the tracer was kept under the tongue. The labeled allergen was rapidly degraded and absorbed in the gastrointestinal tract after swallowing. Plasma radioactivity peaked at about 1.5 to 3 hours and was mostly represented by free radioiodine and small radiolabeled peptides. Some activity not caused by free ^1^2^3I remained associated with the oral mucosa up to 18 to 20 hours after administration. When the oral route was used, the results were similar to those observed after swallowing the sublingually administered allergen but without any persistence of the tracer in the mouth. When the intranasal route was used, the pattern of plasma radioactivity mimicked that of the sublingual and oral routes, with absorption of activity from the radiolabeled allergen occurring in the gastrointestinal tract after transport to the pharynx by mucociliary cle arance. A relevant fraction of the tracer was retained on the nasal mucosa up to 48 hours after administration. Conclusion: The data in this study provide the first experimental basis for exploring the in vivo kinetics of allergen administered through noninjectable routes for specific immunotherapy in human beings. (J Allergy Clin Immunol 1997;100:122-9.)