Inhibitory effect of valproic acid on xenografted Kasumi-1 tumor growth in nude mouse and its mechanism / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate in vivo inhibitory effect of histone deacetylase (HDAC) inhibitor valproic acid (VPA) on xenografted Kasumi-1 tumor in nude mice and its mechanism.</p><p><b>METHODS</b>Xenografted Kasumi-1 tumor mouse model was established by subcutaneous inoculation of Kasumi-1 cells. Xenotransplanted nude mice were assigned into control or VPA treatment groups. Volume of the xenografted tumors was measured and compared between the two groups. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) was applied to detection of tumor cell apoptosis. The gene expression of GM-CSF, HDAC1, Ac-H3 and survivin was studied with semi-quantitative RT-PCR and Western blotting. ChIP method was used to assay the effects of VPA on acetylation of histone H3 within GM-CSF promoter region.</p><p><b>RESULTS</b>(1) VAP significantly inhibited xenografted Kasumi-1 tumor growth. The calculated inhibition rate was 57.25%. (2) Morphologic study showed that VPA induced differentiation and apoptosis of Kasumi-1 tumor cells. The apoptosis index of VAP treatment group [(3.661 +/- 0.768)%] was significantly higher than that of control group [(0.267 +/- 0.110)%]. (3) Comparing to those in control group, the level of nuclear HDAC1 protein was significantly decreased, the Ac-H3 protein expression level was increased, the mRNA and protein expression levels of GM-CSF and acetylation of histone H3 were remarkably increased, and the gene expression level of survivin significantly decreased in VPA treatment group.</p><p><b>CONCLUSION</b>VAP significantly inhibits xenografted Kasumi-1 tumor growth and induces tumor cell differentiation and apoptosis. The mechanism may be decrease of survivin gene expression, inhibition of nuclear expression of HDAC, promotion of histone protein acetylation level and acetylation of histone H3 within GM-CSF promoter region, and increase of GM-CSF transcription.</p>

Effects of histone deacetylase inhibitor on the expression of angiogenesis related factors in Kasumi-1 leukemic cell line / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the effects of two histone deacetylase (HDAC) inhibitors, valproic acid (VPA) and TSA, on the expression of vascular endothelial growth factor (VEGF) and its receptor KDR of the leukemia cell line Kasumi-1 cells, and to explore their potential mechanism in leukemia angiogenesis.</p><p><b>METHOD</b>Kasumi-1 cells were treated with VPA and TSA at different concentrations for 3 days. The mRNA and protein expression levels of VEGF and KDR were determined by semi-quantitative RT-PCR and Western blot, and the bFGF mRNA by semi-quantitative RT-PCR.</p><p><b>RESULTS</b>As compared with that of control groups, VPA at 3 mmol/L downregulated the VEGF mRNA expression level for VEGF(121) from 0.632 ± 0.014 to 0.034 ± 0.004 and for VEGF(165) from 0.526 ± 0.021 to 0.015 ± 0.001, for KDR mRNA from 0.258 ± 0.034 to 0.038 ± 0.000, and for bFGF mRNA from 0.228 ± 0.017 to 0.086 ± 0.015. TSA downregulated the VEGF mRNA and KDR mRNA at concentration of 100 nmol/L, but its effect on bFGF mRNA only at higher concentration.</p><p><b>CONCLUSION</b>HDAC inhibitors might inhibit the leukemia angiogenesis by regulating the expression of VEGF and its recptor.</p>

Therapeutic effect of autologous bone marrow stem cell transplantation in the treatment of severe liver damage / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the effect of autologous bone marrow stem cell transplantation in the treatment of severe liver damage.</p><p><b>METHODS</b>Autologous bone marrow (50 ml) was harvested from 6 patients aged 44 to 69 years admitted for severe liver damage. Human bone marrow stem cells (HMSCs) were isolated and transplanted in to the patients' liver. At l, 4, 8, and 12 weeks after the transplantation, the changes in ALT, ALB, Cr, TB, PT and the clinical symptoms of the patients were observed.</p><p><b>RESULTS</b>The transplantation of autologous bone marrow stem cells resulted in obvious improvement of the liver function. At 12 weeks after the transplantation, ALT was reduced from 98.4 IU/L to 41.5 IU/L, TB from 136.5 µmol/L to 78.4 µmol/L, Cr from 112.3 µmol/L to 72.1 µmol/L, and ALB rose from 23.3 g/L to 32.6 g/L. The survival of the patients was 100% at 12 weeks, but one patient died at 7 months after the transplantation. The symptoms of the patients were also alleviated after the transplantation. At 12 weeks after transplantation, 3 patients reported improved appetite, 3 showed recovery of physical strength, and 2 showed lessened abdominal swelling. No serious adverse complications in association with the transplantation were found in the in 4 patients available to the follow-up.</p><p><b>CONCLUSION</b>Autologous bone marrow stem cell transplantation can improve the liver function of patients with severe liver damage without causing serious complications.</p>

Role of Ommaya reservoir in the management of neonates with post-hemorrhagic hydrocephalus / 中华儿科杂志

<p><b>OBJECTIVE</b>Intra-ventricular hemorrhage (IVH) is one of the most serious complications of preterm infants. Significant numbers of the surviving infants with severe IVH go on to develop post-hemorrhagic hydrocephalus (PHH). The management of PHH remains a very challenging problem for both neonatologists and pediatric neurosurgeons. This study aimed to evaluate the efficacy and safety of the use of Ommaya reservoirs and serial cerebrospinal fluid (CSF) drainage in the management of a series of neonates with PHH.</p><p><b>METHOD</b>Between January 1, 2003 and December 30, 2005, 15 consecutive newborn infants with IVH grades III to IV, complicated with progressive ventricular dilatation, underwent placement of an Ommaya reservoir. CSF was intermittently aspirated percutaneously from the reservoir. The amount and frequency of CSF aspiration were based on the clinical presentation and the follow-up results of serial cranial ultrasonograms or CT scans. The changes of CSF cell counts and chemistries were also followed. Patients whose progressive ventricular dilatation persisted despite serial CSF aspiration through Ommaya reservoir eventually had ventriculo-peritoneal shunts (V-P shunt) placed. All the patients were followed up in the outpatient clinic after discharge from the hospital and the neurodevelopmental outcomes were evaluated through 18-36 months of age.</p><p><b>RESULT</b>A total of 15 infants were included in this series. Of them, 11 were preterm infants who were at gestational ages of 29 to 34 weeks and 4 infants were full-term. All of the 4 full term infants presented with progressive ventricular dilatation after suffering from the intra-cranial hemorrhage (3 infants were due to vitamin K deficiency and 1 was due to birth trauma). Thirteen infants had grade III IVH, and 2 had grade IV IVH based on initial cranial ultrasonographic and CT scans. The mean age when IVH was diagnosed was (9 +/- 1) days in preterm infants and (22 +/- 7) days in full-term infants; the mean age when Ommaya reservoir was placed was (18 +/- 11) days in preterm infants and (31 +/- 7) days in full-term infants. All the infants tolerated the surgical procedure well. The Ommaya reservoir was tapped for an average of (21.5 +/- 4.6) times per patient. The mean CSF volume per tap was (10.2 +/- 1.3) ml/kg. The values of CSF protein, glucose and cell counts slowly reached normal levels at approximately 3 - 5 weeks after the placement of the reservoir. The velocity of head circumference increase per week was less than 1 cm in 13 patients in 1 - 4 weeks after the placement of the reservoir and the size of ventricles decreased gradually. By 12 - 18 months, 12 infants had normal size ventricles, and 1 patient still had mild ventricular dilation at 36 months. Two infants developed progressive hydrocephalus after serial CSF aspiration through Ommaya reservoir. One infant had a V-P shunt placed at 2 months of age and another infant died at 3 months of age at home after parents refused further therapy. Complications consisted of reservoir leaking and CSF infection at 16th day of placement in one patient after repeated tapping. By the end of 18 - 36 months of follow-up, 11 of 14 infants were considered normal, two patients had mild impairment in neurodevelopmental outcome (both had spastic bilateral lower limbs paresis, and one of whom also had amblyopia) and the other had seizure disorder.</p><p><b>CONCLUSION</b>The results from this series indicate that the placement of an Ommaya reservoir is relatively safe in newborn infants and is useful in the initial management of neonates with PHH and may be beneficial in improving their neurodevelopmental outcomes. A multicenter randomized trial may be needed to further validate the results of this report.</p>