Improved Stability and Practicality for Synthesis of 4-Borono-2-[18F]fluoro-l-phenylalanine by Combination of [18O]O2 Single-Use and [18F]CH3COOF Labeling Agents

Purpose4-Borono-2-[¹⁸F]fluoro-l-phenylalanine ([¹⁸F]FBPA) synthesized with [¹⁸F]F₂, produced using the ¹⁸O(p, n)¹⁸F reaction, has been reported for increasing radioactivity. However, a dedicated system and complex procedure is required to reuse the costly [¹⁸O]O₂ gas; also, the use of [¹⁸F]F₂ as a labeling agent reduces the labeling rate and radiochemical purity. We developed a stable and practical method for [¹⁸F]FBPA synthesis by combining [¹⁸F]F₂, produced using a [¹⁸O]O₂ single-use system, and a [¹⁸F]CH₃COOF labeling agent.MethodsThe produced [¹⁸F]F₂ was optimized, and then [¹⁸F]FBPA was synthesized. For passivation of the target box, 0.5% F₂ was pre-irradiated in argon. Gaseous products were discarded; the target box was filled with [¹⁸O]O₂ gas, and then irradiated (first irradiation). Then, the [¹⁸O]O₂ gas was discarded, 0.05–0.08% F₂ in argon was fed into the target box, and it was again irradiated (second irradiation). The [¹⁸F]F₂ obtained after this was passed through a CH₃COONa column, converting it into the [¹⁸F]CH₃COOF labeling agent, which was then used for [¹⁸F]FBPA synthesis.ResultsThe mean amount of as-obtained [¹⁸F]F₂ was 55.0 ± 3.3 GBq and that of as-obtained [¹⁸F]CH₃COOF was 21.6 ± 1.4 GBq after the bombardment. The radioactivity and the radiochemical yield based on [¹⁸F]F₂ of [¹⁸F]FBPA were 4.72 ± 0.34 GBq and 12.2 ± 0.1%, respectively. The radiochemical purity and molar activity were 99.3 ± 0.1% and 231 ± 22 GBq/mmol, respectively.ConclusionWe developed a method for [¹⁸F]FBPA production, which is more stable and practical compared with the method using [¹⁸O]O₂ gas-recycling and [¹⁸F]F₂ labeling agent.     

Medial temporal lobe activation during context-dependent relational processes in episodic retrieval: an fMRI study. Functional magnetic resonance imaging

Previous studies have reported that the medial temporal lobe (MTL) structures contribute to the processing of relations among multiple stimuli in episodic encoding. There have been few studies, however, on the episodic retrieval requiring processing of relations among multiple components that was involved in our events. We used functional magnetic resonance imaging (fMRI) to investigate neural activities during the retrieval of relations within an organized episode and the recognition of an episodic component. Healthy, normal participants memorized 50 four-scene comic strips before fMRI scanning. In the retrieval phase with fMRI scanning, participants were engaged in three tasks: a visual identification (VI) task, a story recall (SR) task, and a picture recognition (PRe) task. In the VI task, participants were asked to judge whether they could identify at least one female character in the two scenes presented vertically. In the SR task, participants were shown the first and last scenes from strips memorized previously and asked to judge whether or not the two scenes were from the same strip. In the PRe task, participants were shown two scenes and asked to judge whether they both belonged to the memorized scenes. The two contrasts of SR with VI and PRe with VI demonstrated some commonly activated areas, such as the bilateral middle frontal gyrus and cerebellum. More importantly, the SR task differentially activated the bilateral parahippocampal gyrus, whereas the PRe task differentially activated right prefrontal areas, including the inferior frontal and precentral gyri. The results suggest that the activity of the MTL structures may be strongly associated with episodic memory retrieval requiring context-dependent relational processing.     

Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB

Malignant peripheral nerve sheath tumor (MPNST) is rare, highly aggressive, resistant to radiochemotherapy, and associated with poor prognosis. Basic research to develop new treatment regimes is critically needed. This study was designed to identify motogenic factor(s) involved in MPNST cell invasion and inhibitor(s) of such invasive activity. We profiled the invasion-inducing activities of eight motogenic growth factors on two human MPNST cell lines, FU-SFT8611 and 9817, using in vitro Matrigel invasion assays. Platelet-derived growth factor-BB (PDGF-BB) was identified as the most effective MPNST cell invasion-inducing factor. Epidermal growth factor (EGF) and hepatocyte growth factor (HGF) also stimulated invasion in one MPNST cell line. Expressions of PDGF-BB and EGF receptors (PDGFR-beta and EGFR) mRNAs were detected more frequently and their proteins were expressed at higher levels in MPNST tissues than benign peripheral nerve sheath tumors (schwannomas and neurofibromas). In both MPNST cell lines, PDGF-BB induced tyrosine phosphorylation of PDGFR-beta but not of PDGFR-alpha, and specific PDGFR-beta inhibition by small interfering RNA to the receptor inhibited PDGF-BB-stimulated MPNST cell invasion, suggesting the predominant role of PDGFR-beta. Inhibition of PDGFR-beta phosphorylation by pretreatment with herbimycin A and imatinib mesylate effectively suppressed basement membrane invasion and cell growth in vitro. No mutations were present in exons 12 and 18 of PDGFR-beta in both MPNST cell lines and 10 human MPNST tissues examined. Our results indicated that PDGF-BB enhanced the invasive activity of MPNST cells through PDGFR phosphorylation and that imatinib inhibited such activity. The results provide the ground for further assessment of the therapeutic potential of imatinib in suppressing the invasion and growth of MPNST.     

An invasion-independent pathway of blood-borne metastasis: a new murine mammary tumor model

It is generally believed that active invasion by cancer cells is essential to the metastatic process. In this report, we describe a murine mammary tumor (MCH66) model of metastasis that does not require invasion into the vascular wall of both the primary tumor and the target organ, in this case, the lung. The process involves intravasation of tumor nests surrounded by sinusoidal blood vessels, followed by intravascular tumor growth in the lung, without penetration of the vascular wall during the process. Comparative studies using a nonmetastatic MCH66 clone (MCH66C8) and another highly invasive metastatic cell line (MCH416) suggested that high angiogenic activity and sinusoidal remodeling of tumor blood vessels were prerequisites for MCH66 metastasis. Differential cDNA analysis identified several genes that were overexpressed by MCH66, including genes for the angiogenesis factor pleiotrophin, and extracellular matrix-associated molecules that may modulate the microenvironment toward neovascularization. Our analyses suggest that tumor angiogenesis plays a role in the induction of invasion-independent metastasis. This model should prove useful in screening and development of new therapeutic agents for cancer metastasis.     

A der(13)t(7;13)(p13;q14) with monoallelic loss of RB1 and D13S319 in myelodysplastic syndrome

Deletions or translocations of chromosome band 13q14, the locus of the retinoblastoma gene (RB1), have been observed in a variety of hematological malignancies including myelodysplastic syndrome (MDS). We describe here a novel unbalanced translocation der(13)t(7;13)(p13;q14) involving 13q14 in a patient with MDS. A 66-year-old woman was diagnosed as having MDS, refractory anemia with excess of blasts (RAEB-1) because of 7.4% blasts and trilineage dysplasia in the bone marrow cells. G-banding and spectral karyotyping analyses showed complex karyotypes as follows: 46,XX,der(6)t(6;7)(q11;?),der(7)del(7)(?p13)t(6;7)(q?;q11)t(6;13)(q?;q?),der(13)t(7;13)(p13;q14). Fluorescence in situ hybridization (FISH) analyses demonstrated that one allele of the RB1 gene and the microsatellite locus D13S319, located at 13q14 and telomeric to the RB1 gene, was deleted. Considering other reported cases, our results indicate that submicroscopic deletions accompanying 13q14 translocations are recurrent cytogenetic aberrations in MDS. The RB1 gene or another tumor suppressor gene in the vicinity of D13S319, or both, may be involved in the pathogenesis of MDS with 13q14 translocations by monoallelic deletion.     

Osteopontin affects the persistence of beta-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms

Osteopontin (OPN) plays a pivotal role in various immune responses and inflammatory diseases. OPN is expressed in various granulomatous diseases; however, the cellular and molecular role of OPN in these diseases is not well known. We analyzed the role of OPN in a beta-glucan-induced hepatic granuloma model. First, we found that neither OPN deficiency nor overexpression of OPN affected the number and the size of hepatic granulomas at day 7, indicating that OPN is not involved in the formation of hepatic granulomas at the early stages. Importantly, OPN did not influence the liver tissue damage as defined by alanine aminotransferase and aspartate aminotransferase levels at early stages. Second, OPN deficiency resulted in the reduction of IL-12 and IFN-gamma production at early stages. Third, at late stages, OPN deficiency resulted in a decrease in the number and size of hepatic granulomas, and a reduction of liver tissue injury. This was due to the reduction of the cellular recruitment including macrophages, CD4 T cells and dendritic cells into the liver, and the reduction of tumor necrosis factor (TNF)-alpha production in the liver. In contrast, overexpression of OPN resulted in the persistence of granuloma formation. These data suggest that OPN affects the persistence of hepatic granuloma formation. Our results indicate that OPN up-regulates the production of IL-12 and IFN-gamma within the granulomas at early stages, and OPN has an additional role in the regulation of cellular recruitment and TNF-alpha production at late stages that determine the severity of liver tissue injury.     

Pathological analyses of long-term intracoronary Palmaz-Schatz stenting; Is its efficacy permanent?

BACKGROUND: Angiographic regression of luminal narrowing occurs 6 months to 3 years poststenting. However, after 4 years lesions progressed gradually and late restenosis was observed in 28% of 179 Palmaz-Schatz-stented lesions during the past 10 years. Elucidating its pathogenesis is pivotal to developing preventive strategies. METHODS AND RESULTS: Histopathological and immunohistochemical studies were performed in 19 stented coronary arteries obtained from 19 patients autopsied after noncardiac death 2-7 years poststenting. The quality/severity of chronic inflammatory cells (T lymphocytes, macrophages and multinucleated giant cells) infiltration around the stent struts that is observed even in the absence of restenosis depended on the time elapsed from stenting: a) 2 years postprocedure, in spite of angiographic regression during the first year and pathologically expressed as maturation of the neointimal scar, there was chronic inflammatory response evidence: neovascularization and lymphocyte infiltration, b) > or = 3 years: the neointimal smooth muscle cells were sparse with abundant proliferation of collagen fibers. Presence of slight helper/inducer T lymphocytes and mild macrophage infiltration around the stent struts was evident immunohistochemically, c) > or = 4 years: prominent infiltration by lipid-laden macrophages with strong collagen-degrading matrix metalloproteinase immunoreactivity was observed around the struts. In two of these arteries, the surface contacting the stent was focally disrupted and covered by nonocclusive mural thrombi. CONCLUSIONS: Stainless steel stents evoke a remarkable foreign-body inflammatory reaction to the metal. These persistent peri-strut chronic inflammatory cells may accelerate new indolent atherosclerotic changes and consequent plaque vulnerability.