Anti‐tumor effects of suberoylanilide hydroxamic acid on Epstein–Barr virus‐associated T cell and natural killer cell lymphoma

The ubiquitous Epstein–Barr virus (EBV) infects not only B cells but also T cells and natural killer (NK) cells and is associated with various lymphoid malignancies. Recent studies have reported that histone deacetylase (HDAC) inhibitors exert anticancer effects against various tumor cells. In the present study, we have evaluated both the in vitro and in vivo effects of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on EBV‐positive and EBV‐negative T and NK lymphoma cells. Several EBV‐positive and EBV‐negative T and NK cell lines were treated with various concentrations of SAHA. SAHA suppressed the proliferation of T and NK cell lines, although no significant difference was observed between EBV‐positive and EBV‐negative cell lines. SAHA induced apoptosis and/or cell cycle arrest in several T and NK cell lines. In addition, SAHA increased the expression of EBV‐lytic genes and decreased the expression of EBV‐latent genes. Next, EBV‐positive NK cell lymphoma cells were subcutaneously inoculated into severely immunodeficient NOD/Shi‐scid/IL‐2Rγnull mice, and then SAHA was administered intraperitoneally. SAHA inhibited tumor progression and metastasis in the murine xenograft model. SAHA displayed a marked suppressive effect against EBV‐associated T and NK cell lymphomas through either induction of apoptosis or cell cycle arrest, and may represent an alternative treatment option.     

Acute aggravation of subdural fluid collection associated with dural metastasis of malignant neoplasms: case report and review of the literature

A 63-year-old woman was admitted to our hospital with serious headache and vomiting. Five months before admission, she had undergone surgery for a primary advanced gastric cancer. Neuroradiological examinations revealed subdural fluid collection. We twice performed evacuation of the subdural fluid collection. However, aggravation of her state of consciousness progressed and she passed away. Histological examinations demonstrated that the dural veins were infiltrated by numerous tumor cells that produced mucus; however, ruptured vessels were not found. Furthermore, the subdural fluid collection increased shortly after the initial operation. We infer that the cause of the collection, which was associated with the dural metastasis of malignant tumors, was not only mucin secretion by tumor cells but also a rapid increase in perfusion pressure in the vessels of the dura mater, resulting in extravasation of plasma components into the subdural space. Our case demonstrates that the pathogenetic mechanism that is specific for subdural fluid collection caused by dural metastasis of malignant tumors differs from the mechanism of production of subdural hematoma associated with dural metastasis.     

Fetal Gyrification in Cynomolgus Monkeys: A Concept of Developmental Stages of Gyrification

Our article summarizes a series of studies about fetal gyrification and its relation to cerebral growth in cynomolgus monkeys. Based on the cerebral growth (i.e., brain weight, cerebral volume, and frontooccipital length of the cerebral hemisphere) and the developmental pattern of gyrification in each sulcus of cynomolgus monkeys, we divided the gyrification process into four stages: Stage 1. Demarcation of cerebral lobes and limbic gyri; Stage 2. Demarcation of neocortical gyri; Stage 3. Emergence of secondary and tertiary sulci; and Stage 4. Growth of sulcal length and depth. Each stage of those gyrification processes was influenced by different developmental events, such as the emergence of corticocortical long‐associative fiber tracts, cortical maturations, and subcortical white‐matter development. This is the first report to systematically propose gyrification processes closely related to the order of phyologenetical development of the cerebral cortex in primates. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Quantitative assessment of central nervous system disorder induced by prenatal X-ray exposure using diffusion and manganese-enhanced MRI

Prenatal radiation exposure induces various central nervous system (CNS) disorders depending on the dose, affected region and gestation period. The goal of this study was to assess noninvasively a CNS development disorder induced by prenatal X-ray exposure using quantitative manganese-enhanced MRI (MEMRI) as well as apparent diffusion coefficient (ADC) and transverse relaxation time (T(2)) maps in comparison with immunohistological staining. The changes in ΔR(1) (increase in the longitudinal relaxation rate (R(1)) from before and after MnCl(2) administration.) induced by the Mn(2+) contrast agent were evaluated in the CNS of normal and prenatally irradiated rats. ADC and T(2) were also compared with the histological results obtained using hematoxylin and eosin (to estimate cell density), activated caspase-3 (apoptotic cells) and glial fibrillary acidic protein (proliferation of astrocytes/astroglia). We found the following: (i) the decreased Mn(2+) uptake (indicated by a smaller ΔR(1)) for radiation-exposed rats was predominantly correlated with a decrease in cell viability (apoptotic cytopathogenicity) and CNS cell density after prenatal radiation exposure; (ii) the longer T(2) and ADC were associated with a decrease in CNS cell density and apoptotic alteration after radiation exposure. In addition to the slight proliferation of astroglia (+58%), there was a substantial decrease in cell density (-78%) and an excessive increase in apoptotic cells (+613%) in our prenatal radiation exposure model. The results suggest that MEMRI in the prenatal X-ray exposure model predominantly reflected the decrease in cell density and viability rather than the proliferation of astroglia. In conclusion, quantitative MEMRI with ADC/T(2) mapping provides objective information for the in vivo assessment of cellular level alterations by prenatal radiation exposure, and has the potential to be used as a standard approach for the evaluation of the cellular damage of radiotherapy.     

Reduced exposure using asymmetric cone beam processing for wide area detector cardiac CT

The purpose of this study was to estimate dose reduction after implementation of asymmetrical cone beam processing using exposure differences measured in a water phantom and a small cohort of clinical coronary CTA patients. Two separate 320?×?0.5?mm detector row scans of a water phantom used identical cardiac acquisition parameters before and after software modifications from symmetric to asymmetric cone beam acquisition and processing. Exposure was measured at the phantom surface with Optically Stimulated Luminescence (OSL) dosimeters at 12 equally spaced angular locations. Mean HU and standard deviation (SD) for both approaches were compared using ROI measurements obtained at the center plus four peripheral locations in the water phantom. To assess image quality, mean HU and standard deviation (SD) for both approaches were compared using ROI measurements obtained at five points within the water phantom. Retrospective evaluation of 64 patients (37 symmetric; 27 asymmetric acquisition) included clinical data, scanning parameters, quantitative plus qualitative image assessment, and estimated radiation dose. In the water phantom, the asymmetric cone beam processing reduces exposure by approximately 20% with no change in image quality. The clinical coronary CTA patient groups had comparable demographics. The estimated dose reduction after implementation of the asymmetric approach was roughly 24% with no significant difference between the symmetric and asymmetric approach with respect to objective measures of image quality or subjective assessment using a four point scale. When compared to a symmetric approach, the decreased exposure, subsequent lower patient radiation dose, and similar image quality from asymmetric cone beam processing supports its routine clinical use.     

Crohn’s disease-specific mortality: a 30-year cohort study at a tertiary referral center in Japan

Background

In this study, survival and cause of death were investigated in patients with Crohn’s disease (CD) at a tertiary referral center.

Methods

A database was created based on the medical records of 1108 CD patients who had a history of visiting our hospital to investigate background characteristics, cumulative survival rates from diagnosis, causes of death, and the standardized mortality ratio (SMR) for each cause of death. A follow-up questionnaire survey of patients followed up inadequately was also conducted. The cumulative survival rate from diagnosis was determined using the life table method and compared with that of a sex- and age-matched population model from the year 2000.

Results

The study included 1108 patients whose mean age at diagnosis was 25.6 ± 10.8 years. The mean duration of follow-up was 14.6 ± 9.4 years, and there were 52 deaths. The cumulative survival rate was significantly lower 25 years after the diagnosis of CD (91.7%) than in the standard population model (95.7%). SMRs for both all causes [3.5; 95% confidence interval (CI): 2.7–4.6] and CD-specific causes (36.7; 95% CI 26.1–51.6) were high. Among the CD-specific causes, SMRs were especially high for small intestine and colorectal cancers, gastrointestinal diseases including intestinal failure (IF), perioperative complications, and amyloidosis.

Conclusion

The SMRs for both all causes and CD-specific causes were high in CD patients. CD-specific causes including intestinal cancer, IF, perioperative complications, and amyloidosis showed especially high SMRs.

     

Entry of CD4 CD8 immature thymocytes into the CD4/CD8 developmental pathway is controlled by tyrosine kinase signals that can be provided through TCR components

Entry of thymus-migrated precursor cells into the CD4/CD8 developmentalpathway was analyzed by using the short-term organ culturesof day 14 fetal mouse thymus lobes. Organ cultures of CD4^–CD8^–day 14 fetal thymocytes for 1-2 days resulted in the generationof CD4^–CD8⁺ cells, which were mostly immediate precursorcells for CD4⁺CD8⁺ thymocytes. This differentiation of CD4^–CD8^–thymocytes into CD4^–CD8⁺ cells was strongly enhanced byanti-CD3 antibodies. The anti-CD3-induced generation of CD4^–CD8⁺cells was even found in the immunodeficient scid fetal thymuscultures, and the cell surface CD3 expression on the scid fetalthymocytes could be directly visualized, indicating that functionalCD3 could be expressed on CD4^–CD8^– immature thymocyteswithout being associated with rearranged TCR components. Theanti-CD3-lnduced generation of CD4^–CD8⁺ cells from scidand normal fetal thymus cultures was inhibited by tyrosine kinaseinhibitors Herblmycin A and Tyrphostin. The generation of CD4^–CD8⁺cells in unstimulated normal fetal thymus cultures was alsomarkedly inhibited by the tyrosine kinase inhibitors but notby Cyclosporin A, suggesting that tyrosine klnase-dependentbut calclneurin-lndependent signals were essential for the differentiationof CD4^–CD8^– thymocytes. Interestingly, the generationof CD4^–CD8⁺ cells from the normal fetal thymus cultureswas modestly but consistently enhanced by anti-TCRßantibody, suggesting that functional TCRß in additionto CD3 was expressed on normal CD4^–CDS⁺ immature thymocytes.On the other hand, anti-TCR antibody did not affect this differentiationin the normal fetal thymus cultures and the generation of CD4^–CD8⁺cells from the normal fetal thymus cultures of TCR-deficientmice was still enhanced by anti-TCRß or anti-CD3 antibodies,indicating that either TCR chains or TCR⁺ cells were not involvedin the control of the differentiation into CD4^–CD8⁺ cells.These results indicate that the entry of CD4^–CD8^–immature thymocytes into the CD4/CD8 developmental pathway iscontrolled by tyrosine kinase signals and that these signalscan be provided through the engagement of TCR-CD3 complexeswith or without TCRß chains expressed on the CD4^–CD8^–immature thymocytes.     

Malignant hemangioendothelioma of the small intestine: Report of a case

(Received for publication on Feb. 18, 1998; accepted on Sept. 11, 1998)