Renal tubular dysgenesis: the first case reported in Japan

Renal tubular dysgenesis (RTD) is a fatal congenital disease characterized by a defect in the differentiation of the proximal and distal convoluted tubules. This disorder is clinically associated with oligohydramnios, intrauterine growth retardation, and acute renal failure, and the diagnosis is made only at autopsy. We report a very low birth-weight infant with RTD. The infant was delivered at 32 weeks of gestation by cesarian section, because of fetal distress, and weighed 631 g. She had no micturition after birth and developed acute renal failure on day 3 of life. Because ultrasound scan did not show any abnormalities of the kidneys, she was treated aggressively with various blood purification procedures, but she died of sepsis and disseminated intravascular coagulation (DIC) on day 13 after birth. Postmortem examination of the kidneys showed glomerular crowding and undifferentiated tubules. Positive staining of tubular epithelial cells for epithelial membrane antigen supported a diagnosis of RTD. When renal failure occurs in a neonate without any gross morphological abnormalities of the kidneys on ultrasound imaging, RTD should be considered. A review of the literature showed that this is the first case of RTD reported in Japan. Received: June 4, 2001 / Accepted: June 25, 2001     

Unventilated Airway Is Time-dependently Constricted in Paralyzed Dogs

Background : Apnea has been reported to produce bronchoconstriction and to cause hypoxia, hypercapnia, and modulation of vagal afferent nerves, which also change airway tone. In this study, the authors determined the mechanism of apnea-induced bronchoconstriction.

Methods : Twenty-eight dogs anesthetized and paralyzed were assigned to four groups (n = 7 each): apnea after artificial ventilation with 50% and 100% O2 groups (apnea-50% O2 and apnea-100% O2 groups, respectively), an apnea plus vagotomy group (fraction of inspired oxygen [Fio2] = 1.0), and a one-lung ventilation group (Fio2 = 1.0). The trachea was intubated with a single- or double-lumen tube in the three apnea groups or the one-lung ventilation group, respectively. The bronchial cross-sectional area (BCA) was assessed by the authors' bronchoscopic method. In the apnea-100% O2 and apnea plus vagotomy groups, a respirator was turned off for 5 min to produce apnea. In the apnea-50% O2 group, apnea was produced for 3 min. In the one-lung ventilation group, the right lumen was blocked for 5 min, and 15 min later, the left lumen was blocked for 5 min. BCA, arterial oxygen tension (Pao2), and arterial carbon dioxide tension (Paco2) were assessed every minute.

Results : The BCA in intact dogs time-dependently decreased by approximately 20% and 40% at 3 and 5 min after apnea started, respectively, whereas they did not in vagotomized dogs. In the apnea-50% O2 and apnea-100% O2 groups, bronchoconstriction could occur without hypoxemia, although hypercapnia was observed in all dogs. In the one-lung ventilation group, despite the fact that Paco2 increased by only 2 mmHg without hypoxemia, unventilated BCA time-dependently decreased by 33.6 +/- 10.3%, whereas ventilated BCA did not.     

Histogenesis of the intravitreal membrane and secondary vitreous in the mouse

PURPOSE: The intravitreal membrane (IVM) is a membranous structure between the primary and secondary vitreous bodies in developing mammalian eyes. In this study, for the first time the histogenesis of the IVM and the relationship between the hyaloid vasculature and the IVM was characterized in newborn mice. METHODS: Eyes of mice less than 12 days old were fixed and embedded. From these, serial paraffin-embedded sections were made for lectin histochemistry, immunohistochemistry, and picrosirius red (PSR) staining, and ultrathin sections were made for transmission electron microscopy (TEM). Eight biotinylated lectins and antibodies for laminin and type IV collagen were used. RESULTS: Among the eight lectins tested, concanavalin A (Con A) agglutinin, Ricinus communis agglutinin I, and wheat germ agglutinin demonstrated strong positive staining in the IVM and vitreous fibrils of the primary and secondary vitreous bodies. They also bound to the internal limiting membrane (ILM) of the retina. At postgestational day 4, the secondary vitreous first appeared between the ILM and the vasa hyaloidea propria (VHP). Immunohistochemical staining revealed that the IVM consists of extracellular matrix components including laminin and type IV collagen, whereas PSR staining and TEM showed that collagen fibrils in the IVM are bundled and continuous with the basement membrane of hyaloid capillaries or the VHP. CONCLUSIONS: Lectin histochemistry and immunohistochemistry provided good methods for visualizing the structures of the IVM and vitreous fibrils. These results suggest that the IVM is separated from the basement membrane of the retinal ILM along with the vascular network of the VHP when the secondary vitreous begins to form.     

Stanniocalcin 2 overexpression in castration-resistant prostate cancer and aggressive prostate cancer

Prostate cancer is usually androgen-dependent and responds well to androgen ablation therapy based on castration. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype where they progress aggressively and show very poor response to any anticancer therapies. To characterize the molecular features of these clinical castration-resistant prostate cancers, we previously analyzed gene expression profiles by genome-wide cDNA microarrays combined with microdissection and found dozens of trans -activated genes in clinical castration-resistant prostate cancers. Among them, we report the identification of a new biomarker, stanniocalcin 2, as an overexpressed gene in castration-resistant prostate cancer cells. Real-time polymerase chain reaction and immunohistochemical analysis confirmed overexpression of stanniocalcin 2, a 302-amino-acid glycoprotein hormone, specifically in castration-resistant prostate cancer cells and aggressive castration-naïve prostate cancers with high Gleason scores (8–10). The gene was not expressed in normal prostate, nor in most indolent castration-naïve prostate cancers. Knockdown of stanniocalcin 2 expression by short interfering RNA in a prostate cancer cell line resulted in drastic attenuation of prostate cancer cell growth. Concordantly, stanniocalcin 2 overexpression in a prostate cancer cell line promoted prostate cancer cell growth, indicating its oncogenic property. These findings suggest that stanniocalcin 2 could be involved in aggressive phenotyping of prostate cancers, including castration-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers. ( Cancer Sci 2009; 100: 914–919)     

Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity

Objective  Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 (⁹⁰Y)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of ⁹⁰Y-MAb 92-13. Methods  FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with ⁹⁰Y-MAb 92-13 in vitro. Biodistribution study of indium-111 (¹¹¹In)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with ⁹⁰Y-MAb 92-13 (100, 150, and 200 μCi), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor. Results  Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of ¹¹¹In-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0 ± 4.2 and 22.0 ± 4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with ⁹⁰Y-MAb 92-13 (tumor volume decreased to less than 0.1 cm³ at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with ⁹⁰Y-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor. Conclusions  The therapeutic efficacy of RIT seems to largely depend on the tumor radiosensitivity.     

Association of T-cell receptor Vβ haplotypes with dry skin in DS-Nh mice

Background.  Although dry skin and T cell-dependent disease exacerbation are characteristic features of atopic dermatitis (AD), the involvement of T cells in the development of dry skin remains unclear.
Aims.  We aimed to elucidate the role of T cells in the development of dry skin in DS- Nh mice as a model for AD, and to evaluate this skin condition pharmacologically.
Methods.  We prepared DS- Nh mice harbouring a T-cell receptor (TCR)Vβ^a haplotype with a central deletion in the TCRBV gene segments, and mice harbouring a TCRVβ^b haplotype without any deletion. We analysed the TCRVβ chain usage and cytokine response to antimouse CD3 monoclonal antibodies in the splenocytes from the two mouse substrains. Transepidermal water loss (TEWL) was measured, and histochemical examination of these mice was carried out. Finally, a pharmacological analysis using loratadine was also performed to evaluate the features of spontaneous dry skin in DS- Nh mice as a model of AD.
Results.  Although the deletion of TCRBV gene segments in the TCRVβ^a haplotype yielded different representations of each TCRVβ mRNA, this deletion did not evoke distinct cytokine profiles in the splenocytes compared with those of mice with the TCRVβ^b haplotype. Furthermore, our results indicated that the onset of dry skin occurred earlier in mice with TCRVβ^b than in those with TCRVβ^a. Pharmacologically, AD-like dry skin in DS- Nh with TCRVβ^b mice is susceptible to an H1 blocker.
Conclusions.  A specific lymphocyte subpopulation bearing T-cell receptors may be responsible for loratadine-responsive dermatitis in DS- Nh mice.     

Osteopontin is involved in the formation of malignant pleural effusion in lung cancer

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.     

Continuous arterial infusion therapy for severe acute pancreatitis: correlation between CT arteriography and therapeutic effect

PURPOSE: This study evaluates the relationship between the therapeutic effect of arterial infusion therapy for severe acute pancreatitis and drug distribution on CT-arteriography (CTA). MATERIALS AND METHODS: Eleven patients with severe acute pancreatitis were treated by arterial infusion with use of protease inhibitor and antibiotics. Ten patients had an inflammation of the entire pancreas, while one had pancreatitis localized to the body and tail of the pancreas. The arterial infusion drugs were infused into the celiac artery, splenic artery, inferior pancreaticoduodenal artery, and common hepatic artery. The drug distributions were evaluated by CTA in 10 patients. The duration of arterial infusion ranged from 3 to 39 days. The relationship between the distribution on the CTA and the change in clinical grading of pancreatitis as evaluated by an APACHE II score was studied. RESULTS: Of the nine patients with inflammation of the entire pancreas, six showed the distribution of contrast material to the entire area of pancreatic inflammation (a good distribution) on the CTA, and the remaining three did not show the distribution of contrast material to cover the entire area of pancreatic inflammation (a poor distribution). One patient with localized pancreatitis showed a good distribution. In seven patients with a good distribution, the APACHE II score was decreased from 11.7 points to 4.3 points during follow-up. In the remaining three patients with a poor distribution, the APACHE II score was decreased from 12.3 points to nine points, but was decreased to five points after the additional interventions. One patient without CTA showed a marked improvement in the APACHE II score. No clinically important complications were observed. CONCLUSION: The present study findings suggest that arterial infusion is effective in the treatment of severe acute pancreatitis. A good drug distribution to the area of inflammation is needed to ensure a proper therapeutic effect.     

LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers

Autophagy is a bulk protein and organelle degradation process essential for cell maintenance and viability. Microtubule-associated protein 1 light chain 3 (LC3), the mammalian homologue of yeast Atg8, is involved in autophagosome formation during autophagy. The aim of this study was to investigate LC3 expression in gastrointestinal cancers to elucidate the role of autophagy in human cancer development. We evaluated LC3 expression by immunohistochemistry in 163 gastrointestinal cancers including 106 esophageal, 38 gastric and 19 colorectal cancers. Seventy precancerous intraepithelial neoplasias were found in esophageal cancer specimens. LC3 expression was compared with Ki-67 staining and expression of carbonic anhydrase (CA) IX, a hypoxic marker. LC3 was expressed in the cytoplasm of cancer cells, but not in noncancerous epithelial cells. A high expression of LC3 was observed in 53% of esophageal, 58% of gastric and 63% of colorectal cancers. LC3 immunoreactive score gradually increased during early esophageal carcinogenesis in low- and high-grade intraepithelial neoplasia and T1 carcinoma, while it did not change in later cancer progression (T2-T4 carcinomas). In early esophageal carcinogenesis, LC3 expression correlated with Ki-67 labeling index (p=0.0001), but showed no significant association with CAIX expression. In esophageal cancers, LC3 expression did not correlate with various clinicopathological factors, including survival. LC3 is upregulated in various gastrointestinal cancers and partly associated with Ki-67 index. Our results suggest that LC3 expression is advantageous to cancer development especially in early-phase carcinogenesis.