Occupational exposure of platinum-based anti-cancer drugs: five-year monitoring of hair and environmental samples in a single hospital.

BACKGROUND: Occupational exposure to chemotherapeutic agents in hospitals is a critical issue. Here, we focused on occupational exposure to platinum-based anti-cancer drugs (PDs) by evaluating platinum concentrations in hair and environmental workplace samples to monitor the risk among workers. METHODS: Hospital workers who dealt with or without PDs, patients treated with PDs, and non-medical office workers outside the hospital donated hair samples and completed a questionnaire regarding their history of handling PDs, including any incidents. Hair samples were collected and surface wipe sampling was performed in July 2010 and April 2015, before and after moving to a new building and introducing a revised safety program in August 2010. Samples were analyzed by inductively coupled plasma-mass spectrometry. RESULTS: Platinum concentrations in hair from PDs-handling workers was significantly higher than in non-PDs-handling workers (P = 0.045), although 50 times lower than that from PDs-treated patients. Platinum concentrations in the hospital environment had decreased at the second survey 5 years later but had not changed significantly in the hair samples from hospital workers. CONCLUSION: Platinum concentrations in hair are likely dependent on the frequency of handling PDs. Reduced environmental contamination from PDs did not influence platinum levels in hospital workers' hair. Continuous monitoring by measuring platinum concentrations in the environment and in hair would provide information regarding these issues.

Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy. The drug-DNA interaction causes DNA crosslinks and subsequent cytotoxicity. Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin. Here, using an interdisciplinary approach, we reveal that the cytotoxic mechanism of 5-H-Y is distinct from that of cisplatin. 5-H-Y inhibits DNA replication and also RNA transcription, arresting cells in the S/G2 phase, and are effective against cisplatin-resistant cancer cells. Moreover, it causes much less DNA crosslinking than cisplatin, and induces chromatin folding. 5-H-Y will expand the clinical applications for the treatment of chemotherapy-insensitive cancers.

Chromatin compaction protects genomic DNA from radiation damage.

Genomic DNA is organized three-dimensionally in the nucleus, and is thought to form compact chromatin domains. Although chromatin compaction is known to be essential for mitosis, whether it confers other advantages, particularly in interphase cells, remains unknown. Here, we report that chromatin compaction protects genomic DNA from radiation damage. Using a newly developed solid-phase system, we found that the frequency of double-strand breaks (DSBs) in compact chromatin after ionizing irradiation was 5-50-fold lower than in decondensed chromatin. Since radical scavengers inhibited DSB induction in decondensed chromatin, condensed chromatin had a lower level of reactive radical generation after ionizing irradiation. We also found that chromatin compaction protects DNA from attack by chemical agents. Our findings suggest that genomic DNA compaction plays an important role in maintaining genomic integrity.

Scanning protein analysis of electrofocusing gels using X-ray fluorescence.

Recently, "metallomics," in addition to genomics and proteomics, has become a focus as a novel approach to identify sensitive fluctuations in homeostasis that accompany metabolic processes, such as stress responses, differentiation, and proliferation. Cellular elements and associated protein behavior provide important clues for understanding cellular and disease mechanism(s). It is important to develop a system for measuring the native status of the protein. In this study, we developed an original freeze-dried electrofocusing native gel over polyimide film (native-gel film) for scanning protein analysis using synchrotron radiation excited X-ray fluorescence (SPAX). To our knowledge, this is the first report detailing the successful mapping of metal-associated proteins of electrofocusing gels using X-ray fluorescence. SPAX can provide detection sensitivity equivalent to that of LA-ICP-MS. In addition to this increased sensitivity, SPAX has the potential to be combined with other X-ray spectroscopies. Our system is useful for further applications in proteomics investigating cellular element-associated protein behaviors and disease mechanisms.

Evaluation of selective tumor detection by clinical magnetic resonance imaging using antibody-conjugated superparamagnetic iron oxide.

Active targeting by monoclonal antibodies (mAbs) combined with nanosize superparamagnetic iron oxide (SPIO) is a promising technology for magnetic resonance imaging (MRI) diagnosis. However, the clinical applicability of this technology has not been investigated using appropriate controls. It is important to evaluate the targeting technology using widely used clinical 1.5-Tesla MRI in addition to the high-Tesla experimental MRI. In this study, we measured mAb-conjugated dextran-coated SPIO nanoparticles (CMDM) in vivo using clinical 1.5-Tesla MRI. MRI of tumor-bearing mice was performed using a simple comparison between positive and negative tumors derived from the same genetic background in each mouse. The system provided significant tumor-targeting specificity of the target tumor. To the best of our knowledge, this is the first report on the specific detection of target tumors by mAb-conjugated SPIO using clinical 1.5-Tesla MRI. Our observations provide clues for reliable active targeting using mAb-conjugated SPIO in clinical applications.

[A case of focal spared area of segment VIII in the liver].

We report a case of focal spared area of segment VIII in fatty liver. The patient was a 73-year-old man. Abdominal ultrasonography showed focal hypo-echogenicity with an irregular margin in segment VIII. Abdominal computed tomography and enhanced computed tomography showed a high-density mass in segment VIII of the right lobe. MRI examination revealed that the mass in S8 was high-intense on the T1 out of phase image and iso-intense on the T1 in phase image. The lesion was not observed on T2 weight images. He had a sigmoid colon cancer and was performed a sigmoidectomy and partial resection of the liver. A microscopic examination of the liver specimen revealed normal hepatic parenchymal cells, while the surrounding liver had a fat deposition.

Subserosal variceal ligation for gastric varices.

BACKGROUND/AIMS: From the experience of endoscopic examination showing residual gastric varices (GV) after paragastroesophageal devascularization and splenectomy (GEDS) for GV, it was considered that GV could be immediately cleared by additional subserosal variceal ligation (SSVL) after GEDS. We reviewed the outcome of all patients who underwent this surgical technique. METHODOLOGY: GEDS with SSVL was performed for GV on eight consecutive patients whose esophageal varices had already been treated by endoscopy. After intraoperative endoscopic examination revealed residual GV just after GEDS, the serosal surface was carefully incised by a knife, and GV were exposed, ligated by 3-0 silk and buried by interrupted seromuscular suture (3-0 silk). RESULTS: In all eight patients, endoscopic examination that was carried out just after SSVL, and after discharge, revealed no intraluminal bleeding and complete disappearance of GV. CONCLUSIONS: It was concluded that SSVL in addition to GEDS was a simple procedure and was effective for immediate disappearance of GV.

Brain abscess in which Porphyromonas gingivalis was detected in cerebrospinal fluid.

In this paper, we report one case of severe brain abscess in which Porphyromonas gingivalis was detected in the spinal fluid.

Specific CTL activity of CD8+ TCR Vbeta14+ T cell in mouse 2, 4, 6-trinitrobenzene sulfonic acid-induced colitis.

We analyzed the functional role of CD8+ T-cell receptor (TCR) Vbeta14+ T cells, which increased specifically in the lamina propria in 2,4,6-trinitrobenzene sulfonic acid (TNBS) -induced colitis. Cytotoxic activity and cytokine production in CD8+ TCR Vbeta14+ T-cell clones were analyzed by 51Cr release assay and enzyme-linked immunosorbent assay, respectively. Cell transfer studies using these clones were performed. Established T-cell clones showed specific cytotoxic activity against TNBS-conjugated self spleen cells, and this cytotoxicity was completely inhibited by anti-TCR Vbeta14 monoclonal antibody. These clones produced interferon (IFN) - gamma in their culture supernatant, but neither interleukin (IL) - 2 nor IL-4. Histological findings of the colon in mice, which received clone transfer after enema with suboptimal doses of TNBS, showed massive colitis. Our results indicate that CD8+ TCR Vbeta14+ T cells had a cytotoxic T-lymphocyte function induced by Th-1 T-cell response and played a pathogenic role in the development of TNBS-induced colitis.

Helper T-cell type 1 or type 2 function of xeno-MHC-restricted T-cell clones in a direct xenoantigen recognition.

There have been several reports that xeno-MHC-restricted T-cells have a cytotoxic function through a direct xenoantigen recognition, but yet no report that they have a helper function. Previously we showed that both xeno-MHC-restricted CD4(+) and CD8(+) T-cells recognized xenoantigens directly in a mouse anti-rat combination. In this study, we investigated whether or not xeno-MHC-restricted T-cells had a helper function. Mouse T-cell clones recognizing rat antigens directly were derived from T-cell lines using the limiting dilution method. Phenotype, cytotoxic activity and cytokine production of these clones were analyzed by flow cytometry, 51Cr release assay and ELISA, respectively. Rat-MHC class I-restricted mouse CD8(+) T-cell clones showed a specific cytotoxic activity against rat antigens. One CD4(+) clone produced IL-4 and IL-10, and the other CD4(+) clone produced not T-helper (Th) 2 cytokine but TNF-alpha. Our results suggested that xeno-MHC class I-restricted CD8(+) T-cells should have a cytotoxic function, and xeno-MHC class II-restricted CD4(+) T-cells should have either Th1 or Th2 function.