Multiple free-radical scavenging (MULTIS) capacity in cattle serum.

Multiple free-radical scavenging (MULTIS) activity in cattle and human sera was evaluated with electron spin resonance spectroscopy. Scavenging rates against six active species, namely hydroxyl radical, superoxide anion, alkoxyl radical, alkylperoxyl radical, methyl radical, and singlet oxygen were quantified. The difference in the electron spin resonance signal intensity in the presence and absence of the serum was converted into the scavenging rates. Comparative MULTIS measurements were made in sera from eight beef cattle, three fetal calves and fifteen healthy human volunteers. Further, we determined the MULTIS value of albumin, the most abundant component in serum. MULTIS values in cattle sera indicated higher scavenging activity against most free radical species tested than human sera. In particular, cattle serum scavenging activities against superoxide and methyl radical were higher than human serum by 2.6 and 3.7 fold, respectively. In cattle serum, albumin appears to play a dominant role in MULTIS activity, but in human serum that is not the case. Previous data indicated that the abundance of uric acid in bovine blood is nearly 80% less than humans; however, this difference does not explain the deviation in MULTIS profile.

The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption.

BACKGROUND: Glioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB). METHODS: Reproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [(14)C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth. RESULTS: Doranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [(14)C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas. CONCLUSIONS: Our results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects.

Successful Treatment of Central Nervous System Lymphoma with Combination Therapy of Nimustine and Prednisolone in Two Dogs.

Of intracranial tumors, primary central nervous system lymphoma (PCNSL) is rare in dogs. Herein, we describe our experience with two dogs (a 3-year-old intact female toy poodle and a 5-year-old spayed female toy poodle) that developed neurological symptoms. Magnetic resonance imaging (MRI) revealed intracranial disseminated lesions. Cerebrospinal fluid (CSF) examination revealed pleocytosis and B-cell monoclonal proliferation in both cases. PCNSL or secondary central nervous system lymphoma (SCNSL) was diagnosed on the basis of MRI findings and CSF examinations. Nimustine (ACNU) is a nitrosourea alkylating agent, a class of drugs that includes lomustine. Nimustine is mainly used to treat human intracranial neoplasia because of its high permeability across the blood-brain barrier. The dogs in this study were treated with combined chemotherapy comprising nimustine and prednisolone, which achieved complete or nearly complete remission of neurological symptoms and long-term survival (>2583 days and 1218 days), but with problematic adverse effects. We determined that the dose of nimustine for canine PCNSL or SCNSL with intravenous infusion was 25-30 mg/m2 every 3-4 weeks for a total of four times; however, the data were insufficient to determine the optimal regimen.

Effect of Hot Water Bottles on Body Temperature during Magnetic Resonance Imaging in Dogs under General Anesthesia: A Retrospective Study.

Prevention of hypothermia induced by anesthesia and enhanced by low environmental temperatures is difficult in magnetic resonance imaging (MRI) examinations in dogs as forced warming devices, including magnetic materials, are not acceptable for use in the MRI room. A hot water bottle (HWB) can be carried into an MRI examination room and can contribute to the prevention or attenuation of hypothermia. Here, we retrospectively investigated the effects of HWB on body temperature during MRI examinations in dogs under general anesthesia (GA). From anesthesia records of the Veterinary Medical Teaching Hospital, Okayama University of Science, validated data of 100 dogs that underwent an MRI examination under GA were obtained and divided into the following two groups: one group received HWB, while the other did not. Decrease in rectal temperature 15 min after intubation was significantly smaller in the group using HWB than in the group without HWB. In conclusion, the use of hot water bottles might be one of the methods to attenuate hypothermia in the early period but should not be expected for complete prevention of hypothermia, and it was not recommendable necessarily for body temperature management during MRI examinations in dogs under general anesthesia.

An anatomical study of the skull, the dorsal and ventral nasal conchal bullae and paranasal sinuses in normal Noma horses: Computed tomographic anatomical and morphometric findings.

Noma horses have the smallest body size among native Japanese horses and are classified as pony breeds by their size. Additionally, the Japanese horse breeds are classified into a single lineage, which includes Mongolian horses. Great intraspecific differences reportedly exist in the head shapes of domesticated horses, which have been investigated in various horse breeds. The present study aimed to evaluate the size of the nasal conchal bullae, and the paranasal sinuses of Noma horses in relation to the skull dimensions using computed tomography. Reconstructed images of the heads of five adult Noma horses were used. Skull and paranasal sinus parameters were measured and analysed in relation to each other and were compared with the data in the literature on the skulls of various horse breeds. In comparison with pony breed, Shetland ponies and donkeys had a shorter nasal length than cranial length, while Noma horses had a longer nasal length than cranial length, similar to the larger breeds. In the nasal conchal bullae, Shetland ponies showed a negative correlation between the head and bullae size, while Noma horses, similar to larger breeds, had a positive correlation. In conclusion, our findings suggest that Noma horses, despite having a body size that belongs to the pony breed, had a distinguishing ratio of the skull and paranasal sinuses similar to that of the larger breeds. Our results provide information on the physiological morphology of the head and comparative anatomy based on genetic diversity in horses.

Usefulness of computed tomography for cryptorchidism in bulls.

Cryptorchidism is defined as the failure of the testis to descend into the scrotal position. Bulls with cryptorchidism have problems in both meat quality and husbandry management; thus, it is greatly important to accurately identify the retained testis and remove it during the early stage. Abdominal computed tomography (CT) was performed under general anesthesia in 34 bulls aged 3-9 months with cryptorchidism. All bulls underwent laparoscopic or incision approach for cryptorchidectomy, and 40 testes were dissected. The detection rates of retained testes were 64.5% in the abdominal cavity and 100% in the subcutaneous inguinal region, and the total detection rate was 72.5%. Furthermore, all cases in this study were suspected to have intra-abdominal cryptorchidism in primary care, but CT revealed that 22.5% of cases had cryptorchidism in the subcutaneous inguinal region. The CT value (mean ± standard deviation) of the retained testes was 20.96 ± 7.54 Hounsfield Unit, and the CT value and size of the retained testes showed a positive weak correlation with bovine age. Therefore, there is the demerit that general anesthesia and a huge device are necessary; nevertheless, CT is suggested to be useful in identifying the location of retained testes and selecting an appropriate surgical approach in bulls with cryptorchidism. Moreover, CT findings suggested that the maturation of the retained testes might depend not on the descending process but on age.

A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet.

BACKGROUND: The search for effective treatments of non-alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH. AIMS: To examine if mice treated with gold thioglucose (GTG) - known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity - and then fed a high-fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH. METHODS: C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed. RESULTS: Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory-Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor-ß1 and TIMP-1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR-γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR. CONCLUSIONS: Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities.

Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease.

BACKGROUND: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is incompletely understood. Kupffer cells (KCs), phagocytic liver-resident macrophages, provide a protective barrier against egress of endotoxin from the portal to the systemic circulation. It is not known if KC phagocytic function is impaired in NAFLD. Super-paramagnetic iron oxide (SPIO) magnetic resonance imaging is a comparative technology dependent on KC phagocytic function. OBJECTIVE: To evaluate KC uptake function, in patients and experimental animals with NAFLD, using SPIO. METHODS: Abdominal CT and histological examination of liver biopsy specimens were used to estimate the degree of steatosis in patients with NAFLD and controls with chronic hepatitis C. SPIO-MRI was then performed in all patients. Normal rats fed a methionine-choline-deficient diet to induce non-alcoholic steatohepatitis (NASH), the more severe stage of NAFLD, and obese, insulin resistant, Zucker fa/fa rats with steatohepatitis, were also studied with SPIO-MRI and analysed for hepatic uptake of fluorescent microbeads. Immunohistochemical analysis evaluated the numbers of KCs in patients and rat livers. RESULTS: Relative signal enhancement (RSE), inversely proportional to KC function, was higher in patients with NAFLD than in controls and with the degree of steatosis on CT. RSE also positively correlated with the degree of steatosis on histology and was similarly higher in rats with induced severe NAFLD (NASH). On immunohistochemistry, defective phagocytic function was the result of reduced phagocytic uptake and not due to reduced KC numbers in rats or patients with NAFLD. CONCLUSIONS: KC uptake function is significantly impaired in patients with NAFLD and experimental animals with NASH, worsens with the degree of steatosis and is not due to a reduction of KC numbers.

Noninvasive Thermographic Photographing as an Assessment of the State of Discomfort in a Dog Receiving Radiation Therapy.

In humans, radiation induces dilation of capillaries and inflammatory reactions to raise skin temperature. Thermography is used to detect abnormalities after radiation therapy (RT). However, in veterinary nursing, objective evaluation of the condition of dogs after RT using thermography has not been reported. We investigated the nasal irradiation temperature, behavioral changes, and post-irradiation pain scores in a dog receiving RT for intranasal tumors. The temperature of the nasal planum gradually increased after irradiation, reaching a significantly higher value at 120-240 min. The highest temperature was 42.3 °C and the average temperature increased by 4.4 °C. Behavioral analysis pre- and post-RT did not vary significantly. Post-RT pain levels evaluated by the pain scale ranged from 0 to 1 throughout. No veterinary treatment was provided. In humans, increased skin temperature after radiation causes psychological stress, i.e., pain and discomfort, but no such behavioral changes were observed in this case. Given individual differences in stress-related behaviors, such as pain and discomfort, assessing a dog's painfulness using only subjective methods, such as appearance and behavioral evaluation, is limited. We used thermography to assess changes in conditions not detectable by routine monitoring alone. This method is non-invasive, objective, and indispensable for providing appropriate care.

Local Hemodynamic Changes Immediately after Correction of an Aberrant Right Subclavian Artery in a Dog: A Contrast Computed Tomographic Study.

A 1-year-old female Akita dog was referred for intermittent regurgitation. Computed tomographic angiography (CTA) showed an aberrant right subclavian artery (ARSA), resulting in constriction of the esophagus. After surgical ligation of the ARSA, CTA showed that the ARSA was not enhanced by contrast medium, and that sufficient collateral circulation of the right forelimb was supplied through the vertebral artery. Furthermore, the right and left vertebral arteries merged into the basilar artery at the level of the atlas, and no abnormal expansion of the ventral spinal artery was observed. Overall, we demonstrated the importance of post-surgical CTA for identification of surgical complications, including the formation of abnormal vessel alterations.

Effects of Sedation by Intramuscular Administration of Medetomidine on Canine Abdominal Vascular System and Hepatic Parenchyma Imaging Using Enhancement Dynamic Computed Tomography.

This prospective crossover study compared the effects of intramuscular administration of medetomidine for sedation on parameters of the abdominal vascular system, measured by enhancement computed tomography (CT), to those of propofol-induced sevoflurane maintenance anesthesia, as a control, in five clinically healthy adult male beagle dogs (11.4-12.8 kg). Each animal underwent both protocols at a 1-week interval. The enhancement (HU) and time to peak enhancement on CT were measured for the aorta (AO), caudal vena cava (CVC), portal vein (PV), and hepatic parenchyma (HP). The contrast effects in the AO, PV, and HP were significantly delayed under medetomidine sedation compared to the control anesthesia protocol. Particularly, the contrast effect in the PV and HP was significantly delayed under sedation, appearing approximately 1 min after contrast medium injection. This delay likely reflects the peripheral vasoconstrictive effect of medetomidine. We noted a generally early high contrast enhancement of the CVC under medetomidine sedation, likely contributed by the induced bradycardia. Therefore, findings obtained on contrast enhancement CT under medetomidine sedation may be different from those obtained under propofol-induced sevoflurane maintenance anesthesia. These differences are important to consider when using the findings to inform diagnosis.

Combining non-contrast enhanced magnetic resonance thoracic ductography with vascular contrast-enhanced computed tomography to identify the canine thoracic duct.

Background: In humans, visualization of the thoracic duct by magnetic resonance imaging (MRI) has been attempted, and recent advances have enabled clinicians to visualize the thoracic duct configuration in a less invasive manner. Moreover, MRI does not require contrast media, and it enables visualization of morphological details of the thoracic structures. In veterinary practice, the thoracic duct has not been visualized three dimensionally in MRI. Aim: This study aimed to assess the performance of our magnetic resonance thoracic ductography (MRTD) technique to visualize the thoracic duct and the surrounding 3D anatomical structures by combining MRTD and vascular contrast-enhanced thoracic computed tomography (CT) images in dogs. Methods: Five adult male beagle dogs (11.4-12.8 kg) were included in this study. Sagittal and transverse T2-weighted images were scanned in MRI. Scanning in MRTD used a single-shot fast spin echo sequence with a respiratory gate. CT was performed after the intravenous injection of contrast medium. All MRTD and CT images were merged using a workstation. Results: The thoracic ducts were identified in MRTD images of all dogs, and the surrounding anatomical structures were located with the aid of contrast-enhanced thoracic CT. In all dogs, the thoracic ducts coursed along the right-dorsal side of the aorta, cranially from the L2 level. Thereafter, these bent to the left side at the aortic arch and curved at the left external jugular vein angle. A comparison of the number of thoracic ducts at each vertebra between transverse T2WI and MRTD did not reveal any significant differences for all vertebrae. Conclusion: The results from our study suggest that MRTD using the single-shot fast spin echo sequence could be a useful tool for visualization of the thoracic duct. Furthermore, the image merged from MRTD and vascular-enhanced images provided detailed anatomical annotation of the thorax. The MRTD protocol described in this study is safe and easily adaptable, without the need for contrast medium injection into the lymph system. In addition, the images fused from MRTD and vascular contrast-enhanced CT image of the thorax could provide detailed anatomical annotations for preoperative planning.

High Signal Intensity on Diffusion-Weighted Images Reflects Acute Phase of Deep Vein Thrombus.

The effects of antithrombotic therapy on deep vein thrombosis (DVT) can be affected by thrombus age, which cannot be reliably determined by noninvasive imaging modalities. We investigated whether magnetic resonance (MR) diffusion-weighted imaging (DWI) can localize and determine the age of venous thrombus in patients with DVT, animal models, and human blood in vitro. Signal intensity (SI) on DWI and the apparent diffusion coefficient (ADC) of thrombi were assessed in eight patients with DVT using a 1.5-T MR imaging (MRI) system. We assessed the organizing processes as venous thrombus developed in the rabbit jugular vein using a 3.0-T MRI system over time. We also assessed MRI signals of human blood in vitro using the 1.5-T MRI system. Venous thrombi were detected by DWI as areas of high or mixed high and iso SI in all patients. The ADCs were lower in the proximal, than in the distal portion of the thrombi. The thrombi of rabbit jugular veins histologically organized in a time-dependent manner, with high SI on DWI at 4 hours, mixed high and iso SI at 1 and 2 weeks, and iso SI at 3 weeks. The ADC correlated negatively with erythrocyte content, and positively with smooth muscle cells, macrophages, hemosiderin, and collagen content. MRI signals of human blood in vitro showed that ADCs were affected by erythrocyte content, but not by blood clotting. MR-DWI can detect venous thrombus, and high SI on DWI accompanied by a low ADC might reflect erythrocyte-rich, acute-phase thrombi.

Safety of a Novel Microwave Surgical Instrument for Lung Parenchyma Dissection During Segmentectomy.

BACKGROUND: The choice between electrocautery or automatic suturing instruments for dissection of the lung parenchyma along the intersegmental plane during lung segmentectomy remains controversial. We hypothesized that a novel microwave surgical instrument (MSI) for dissecting the lung parenchyma could have excellent sealing effects. We examined the feasibility and safety of lung parenchymal dissection using a MSI during lung segmentectomy. METHODS: This was a prospective clinical study of lung segmentectomy involving dissection of the entire intersegmental plane using a MSI. Complications related to sealing of the lung parenchyma were evaluated and perioperative outcomes were compared to those of patients who underwent lung segmentectomy using automatic suturing instruments. Propensity score-matched comparisons were used to assess the potential impact of selection bias. RESULTS: Lung segmentectomy using a MSI was successfully performed in 30 patients. According to the propensity score matching analysis, intraoperative blood loss, length of hospital stay, and postoperative complications of the microwave group were significantly lesser (P = .019, .003, and .008, respectively) compared to those of the control group (n = 66). Prolonged air leakage was not observed. There were two cases of subcutaneous emphysema after removal of the chest tube, but no other grade 2 or higher complications were observed. No mortality occurred within 30 or 90 days postoperatively. CONCLUSIONS: The use of a MSI for lung parenchymal dissection was associated with lower blood loss during surgical procedures, reduced air leakage after the operation, and fewer postoperative complications.

The Outcome and CT Findings of Low-Dose Intensity Modulated Radiation Therapy with SQAP in a Cat with Thymoma.

A 9-year-old male intact domestic cat weighing 4.6 kg was referred for tachypnea. A large mass was visible in computed tomography (CT) scans of the thoracic cavity. A histopathological evaluation of the mass was consistent with thymoma. The cat was treated with 2 × 8 Gy intensity modulated radiation therapy and sulfoquinovosyl acyl propanediol (SQAP). Post radiation therapy (RT), the tumor structure appeared cystic in the CT, and the tumor volume decreased by approximately 80% after aspiration than that before aspiration. The tumor was removed surgically. RT treatment with SQAP made it possible to treat the thymoma with a low total radiation dose.

X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL) reduces hypoxic regions of human gastric adenocarcinoma xenografts in SCID mice.

Our previous study showed that X irradiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines under not only normoxia but also hypoxia. X irradiation combined with TNF alpha-related apoptosis-inducing ligand (TRAIL), which is the ligand of DR5, induced apoptosis in vitro (Takahashi et al., (2007) Journal of Radiation Research, 48: 461-468). In this report, we examined the in vivo antitumor efficacy of X irradiation combined with TRAIL treatment in tumor xenograft models derived from human gastric adenocarcinoma MKN45 and MKN28 cells in SCID mice. X irradiation combined with TRAIL synergistically suppressed the tumor growth rates in the xenograft models derived from MKN45 and MKN28 cells, which have wild type Tp53 and mutated Tp53, respectively, indicating that the antitumor effects occurred in a Tp53-independent manner. Histological analysis showed that the combination of X irradiation and TRAIL induced caspase-3-dependent apoptotic cell death. Moreover, the immunohistochemical detection of hypoxic regions using the hypoxic marker pimonidazole revealed that caspase-3-dependent apoptosis occurred in the hypoxic regions in the tumors. These results indicated that X irradiation combined with TRAIL may be a useful treatment to reduce tumor growth in not only normoxic but also hypoxic regions.

A BOLD-fMRI study of cerebral activation induced by injection of algesic chemical substances into the anesthetized rat forepaw.

This study was performed to examine whether the brain activities induced by noxious algesic chemical substances in anesthetized animals could be detected by blood oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI). Multislice gradient echo images of the primary somatosensory cortex were obtained using a 7.05 T superconducting system and a one-turned surface coil centered over the primary somatosensory cortex of the 1.0%-isoflurane-anesthetized rat. The Z-score t-map of BOLD signals and its time-course analysis revealed that subcutaneous injection of formalin into the left forepaw immediately induced an early response in the contralateral primary sensory cortex lasting for a few minutes, followed by a late response until 20 min after stimulation. In contrast, injection of capsaicin into the left forepaw evoked only the early response. Furthermore, pretreatment with morphine completely abolished these responses induced by the chemical algesic substances. Thus BOLD-fMRI is a useful method to analyze the brain activities of painful stimulation in anesthetized animals.

Regulation of cell survival and death signals induced by oxidative stress.

Oxidative stress stimulates two opposite signaling pathways leading to cell death and cell survival. Preferential selection of survival signals leads to the protection of cells against damage induced by reactive oxygen species, whereas preferential acceleration of death signals can be used to advantage in tumor therapy with oxidizing agents such as ionizing radiation and anticancer drugs. In vitro and in vivo experiments using cultured mammalian cells and experimental animals showed that ERK was included in survival signals and SAPK and p38 MAPK in death signals in oxidative stress. The activation of SAPK/JNK and subsequent expression of death receptor Fas on the cell surface caused the induction of cell death. The results mean that the acceleration of the activation of SAPK/JNK might lead to the enhancement of cell death by oxidizing agents like ionizing radiation and anticancer drugs. In fact, when cultured mammalian cells were exposed to ionizing radiation with 2-nitroimidazole derivatives having electrophilicity, the lethal effect of ionizing radiation was found to be enhanced together with the activation of SAPK/JNK and the enhancement of Fas expression. The activation of both survival and death signals was suppressed by the antioxidants N-acetylcystein and Trolox, suggesting that both signaling pathways are redox-regulated.

Treatment combining X-irradiation and a ribonucleoside anticancer drug, TAS106, effectively suppresses the growth of tumor cells transplanted in mice.

PURPOSE: To examine the in vivo antitumor efficacy of X-irradiation combined with administration of a ribonucleoside anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd), to tumor cell-transplanted mice. METHODS AND MATERIALS: Colon26 murine rectum adenocarcinoma cells and MKN45 human gastric adenocarcinoma cells were inoculated into the footpad in BALB/c mice and severe combined immunodeficient mice, respectively. They were treated with a relatively low dose of X-irradiation (2 Gy) and low amounts of TAS106 (0.1 mg/kg and 0.5 mg/kg). The tumor growth was monitored by measuring the tumor volume from Day 5 to Day 16 for Colon26 and from Day 7 to Day 20 for MKN45. Histologic analyses for proliferative and apoptotic cells in the tumors were performed using Ki-67 immunohistochemical and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. The expression of survivin, a key molecule related to tumor survival, was assessed by quantitative polymerase chain reaction and immunohistochemical analysis. RESULTS: When X-irradiation and TAS106 treatment were combined, significant inhibition of tumor growth was observed in both types of tumors compared with mice treated with X-irradiation or TAS106 alone. Marked inhibition of tumor growth was observed in half of the mice that received the combined treatment three times at 2-day intervals. Parallel to these phenomena, the suppression of survivin expression and appearance of Ki-67-negative and apoptotic cells were observed. CONCLUSIONS: X-irradiation and TAS106 effectively suppress tumor growth in mice. The inhibition of survivin expression by TAS106 is thought to mainly contribute to the suppression of the tumor growth.

Modulation of Fas-FasL related apoptosis by PBN in the early phases of choline deficient diet-mediated hepatocarcinogenesis in rats.

This study focused on the detection of apoptosis related events in very early phases of choline-deficient (CD)-induced hepatocarcinogenesis (at 2-5 weeks). Flow cytometry of isolated intact primary hepatocytes from CD diet fed rats indicated increased expression of the apoptosis-associated protein Fas. Increased apoptosis in CD-treated livers was confirmed by Western blot analyses of caspases and cytochrome c. This study was also able to detect differences in apoptotic events following phenyl butyl nitrone (PBN) treatment. Fas expression was inhibited by PBN, indicating that PBN is anti-apoptotic. It is speculated that in the early stages of CD-induced hepatotoxicity, PBN is involved in inhibiting pro-inflammatory factor-driven apoptosis of normal hepatocytes, which protects against the initiation of carcinogenesis. The CD diet model is also considered as a model for non-alcoholic steatohepatitis (NASH) in humans and early expression of Fas could also be a good index of the progression of NASH.