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Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits.

Recently air pollutants and irritants have been labelled as possible exogenous risk factors for allergic disorders. Although the underlying causes of allergic disorders such as atopic dermatitis and asthma remain unclear, the T helper type 2 (Th2) cell-mediated allergic inflammatory cascade may contribute to their pathogenesis. In the last decade, it has been documented that one of the candidates for triggering Th2 commitment is thymic stromal lymphopoietin (TSLP), the expression of which is up-regulated in the lesions of allergic patients. Here, we describe TSLP function in a fluorescein isothiocyanate (FITC) -induced contact hypersensitivity (CHS) model. A cytokine profile indicated that the model was dominantly mediated by the Th2 milieu. Interestingly, TSLP was increased in the skin during the sensitization phase when stimulated by a solvent, dibutyl phthalate (DBP), but not by FITC hapten or another solvent, acetone. Ear swelling in FITC-induced CHS was totally abrogated by removing DBP from the sensitization or elicitation phase, and was restored by complementary injection of TSLP. Inversely, the ear swelling was suppressed by injection of small interfering RNA against TSLP during the sensitization phase, which was concomitant with decreasing expression of interleukin-4 at the swollen skin site. Taken together, DBP-induced TSLP during the sensitization phase plays a role in establishing FITC-induced CHS and may be one of the causes of Th2 commitment in the model, suggesting that certain environmental toxins, such as DBP, may endow pro-allergic and atopic predisposition in humans or animals.

The number of amino acid substitutions in the interferon sensitivity-determining region (ISDR) in the nonstructural 5A (NS5A) gene of hepatitis C virus (HCV) is closely associated with the interferon (IFN) response and viral load. Several HCV replicon-based studies have reported that ISDR sequences had an influence on viral replication in vitro. However, it is unclear as to how different ISDR sequences affect HCV replication. Various clinically observed ISDR sequences were introduced into HCV replicons and their contribution to viral replication was investigated using a colony formation assay and/or a transient replication assay. A mapping study of the ISDR was performed to identify the amino acid positions that critically affect replication. While no colonies were formed in the colony formation assay using HCV replicons with few mutations (0, 1 and 3) in the ISDR, numerous colonies (>200) appeared when using constructs with six mutations. Introduction of various distinct ISDR sequences with multiple mutations resulted in replication enhancement in transient assays. A mapping study identified several specific sites in the ISDR that critically affected replication, including codon 2209 which, in patients, was closely associated with a strong response to IFN. ISDR sequences associated with a clinical IFN response and viral load modulated the replication of HCV replicons, suggesting the importance of the ISDR sequence in HCV infection.

The difficulties Japanese sponsors experienced with Contract Research Organizations (CROs) (including Site Management Organizations (SMOs)) inside and outside Japan were analyzed to explore preventive measures from the viewpoint of the Japanese sponsor's quality assurance. The results of the analysis were grouped into four major service categories: monitoring, data management (DM), clinical laboratories and phase I sites. Characteristic issues were found in each category and there was also an indication of difficulties related to the difference in the interpretation of International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines between Japan and other countries. The corrective and preventive measures formulated in response to these issues were also discussed. Copyright © 2004 John Wiley & Sons, Ltd.

Due to advances in double-balloon endoscopy, various types of malignant lymphoma of the small intestine have been observed at very early stages. We report here that after remission of diffuse large B-cell lymphoma, follicular lymphoma recurred in the mucosa of the small intestine. Furthermore, these lesions were diagnosed by biopsy from normal mucosa as diminutive erosions and reddish looking. If a small intestinal lesion is suspected of being a malignant lymphoma, a double-balloon endoscopy should be carried out, and a biopsy should be taken and inspected.

Beckwith-Wiedemann syndrome is an inherited disorder most commonly characterized by prenatal or postnatal overgrowth, macroglossia, omphalocele, unusual earlobe creases, and increased risk of neoplasia. Several reported cases of this syndrome have been prenatally diagnosed, but no report has described the occurrence of this syndrome in association with a single umbilical artery. We report a case in which prenatal sonographic examination demonstrated fetal overgrowth, macroglossia, and omphalocele together with a single umbilical artery; our prenatal diagnosis of Beckwith-Wiedemann syndrome was confirmed after birth of the infant. The possibility of this syndrome should be considered when performing a detailed sonographic examination of a fetus with a single umbilical artery.

We evaluated the efficacy of loxoprofen sodium for refractory nocturia. Twelve men (mean age, 75.1 +/- 5.7) with nocturia were enrolled in this study. All patients received 60 mg loxoprofen sodium prior to sleeping at night for 14 days. Nine of 12 patients (75%) felt more satisfaction than previous treatments. Patients were grouped into a loxoprofen sodium-effective (n = 7) and ineffective groups (n = 5) based on the results of the frequency-volume chart. In the effective group, interestingly, night-time urine volume showed significant reduction (P < 0.05). On the other hand, the average single voided volume at night and 24-h urine volume showed no significant change. There was a statistically significant difference in the night-time urine volume after treatment between groups (P < 0.01). Loxoprofen sodium is an effective treatment for some patients with refractory nocturia. The main effect mechanism of loxoprofen sodium may involve the reduction of night-time urine production.

The distribution of neurotensin-containing cell bodies and fibers was examined in the central nervous system of the dog using light microscopic immunohistochemistry. A very large population of neurotensin-containing cell bodies was observed in the septal nuclei, nucleus accumbens septi, preoptic areas, bed nucleus of the stria terminalis, olfactory tubercle, entorhinal cortex, ventral subiculum, anterodorsal thalamic nucleus, anteroventral thalamic nucleus, nucleus reuniens, lateral habenular nucleus, parabrachial nucleus, and nucleus of the solitary tract. Extremely dense networks of neurotensin-containing fibers were found in the globus pallidus, hypothalamus, infundibular stalk, ventral tegmental area, periaqueductal gray, interpeduncular nucleus, and spinal nucleus of the trigeminal nerve and substantia gelatinosa. However, the cerebral neocortex and cerebellum were negative for neurotensin in the present study. When the present findings are compared with those in other animals, it is clear that the major species-specific differences in distribution involve three immunonegative regions and four immunopositive regions in the dog: The former are the cerebral neocortex, mammillary body, and hippocampus; the latter are the cell bodies in the pyramidal layer of the olfactory tubercle, the superficial and middle layers of the entorhinal cortex and ventral subiculum, and the nerve fibers in the interpeduncular nucleus. The present study indicates a rather extensive network of neurotensin neurons in the central nervous system of the dog.

We present two cases of transient abnormal myelopoiesis associated with trisomy 21 that had hypoechoic hepatomegaly during the late fetal period. Fetal chromosomal abnormality and fetal myeloproliferative disorder should be suspected in such cases.

A synthetic contact sapphire endoprobe attached to the quartz fiber of a neodymium:yttrium aluminum garnet (Nd:YAG) laser had been used in the transurethral treatment of bladder tumors. A total of 68 operations have been carried out in 48 patients. The contact probe was placed directly into the tumor under direct vision. Using 15-20 watts of laser energy, the tumor blanched and underwent necrosis. The technique was easy to apply, and bleeding was minimal. Damage to the ureteral orifice and ureter in the bladder wall at repeat cystoscopy appeared less than with conventional electrocautery or noncontact laser treatment. The technique of contact Nd:YAG laser surgery will have an important role in the transurethral treatment of bladder tumors.

Selective dehydrochlorination of 1,1,2-trichloroethane into 1,1-dichloroethylene was found to be catalysed by methylimidazole–HCl/SiO2, an acid-proof base, the selectivity being as high as 85%.