Emodin coupled with high LET neutron beam-a novel approach to treat on glioblastoma.

The primary motivation of this investigative study is trying to find an alternative treatment that can be used to slow down or treat glioblastoma due to the witnessed toxic side effects of the current drugs coupled with limited effectiveness in overall treatment. Consequently, a Chinese plant extract emodin proves to play a critical role in this investigative study since results from the Western blot and the other accompanying assays for anti-cancer effects indicate that it cannot work a lot to suppress cell migration and possible invasion, but rather emodin can be combined with radiation to give desired outcomes. Our result shows that the kind of radiation which acts well with emodin is neutron radiation rather than gamma radiation. Emodin significantly enhanced the radiosensitivity of LN18 and LN428 cells to γ-rays through MTT assay and cell counting. Accordingly, exposure to neutron radiation in the presence of emodin induced apoptotic cell death and autophagic cell death to a significantly higher extent, and suppressed cell migration and invasiveness more robustly. These effects are presumably due to the ability of emodin to amplify the effective dose from neutron radiation more efficiently. Thus, the study below is one such trial towards new interventional discovery and development in relation to glioblastoma treatment.

Aripiprazole sensitizes head and neck cancer cells to ionizing radiation by enhancing the production of reactive oxygen species.

Drug repositioning is an alternative process for drug development in cancer. Specifically, it is a strategy for the discovery of new antitumor drugs by screening previously approved clinical drugs. On the basis of this strategy, aripiprazole, an antipsychotic drug, was found to have anticancer activity. In this study, we investigated the radiosensitizing effects of aripiprazole on head and neck cancer cells at sublethal doses of ionizing radiation (IR) in vitro and in vivo. Treatment with aripiprazole suppressed the growth of head and neck cancer cells in a concentration-dependent manner, as evidenced by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Intriguingly, aripiprazole significantly enhanced the sensitivity of these cells to the IC50 dose of IR. The combination of aripiprazole with IR synergistically increased annexin and propidium iodide double-positive and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cell populations, and induced cleaved poly(ADP-ribose) polymerase and caspase-3 expression, indicating the induction of apoptosis in these cells. Aripiprazole and IR-induced apoptosis were accompanied by an increase in reactive oxygen species and was almost completely suppressed by the addition of the antioxidant, N-acetylcysteine. Finally, aripiprazole greatly sensitized xenograft tumors to IR at doses that did not affect tumor growth. Taken together, these results suggest that aripiprazole could be considered a potent radiosensitizer for head and neck cancer.

Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects.

Glioblastoma is a deadly cancer tumor in the brain and has a survival rate of about 15 months. Despite the high mortality rate, temozolomide has proven to increase the survival rate of patients when combined with radiotherapy. However, its effects may be limited because some patients develop therapeutic resistance. Curcumin has proven to be a cancer treatment due to its broad anticancer spectrum, high efficiency and low toxic level. Additionally, curcumin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, curcumin increased the cell population in the sub-G1 phase and the reactive oxygen species (ROS) level, ultimately increasing GBM cellular apoptosis. The radiosensitizing effects of curcumin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Curcumin plus neutron combination significantly inhibited cell invasion compared with that of single treatment or curcumin combined γ-ray treatment. Curcumin enhances the radiosensitivity of Glioblastoma (GBM), suggesting it may have clinical utility in combination cancer treatment with neutron high-LET radiation.

Fas and FasL genetic polymorphisms in women with recurrent pregnancy loss: a case-control study.

Aberrant apoptosis at the trophoblast-maternal interface and abnormal expression of Fas and Fas ligand (FasL) have been reported in complicated pregnancies with recurrent pregnancy losses (RPL) and preeclampsia. We assessed the prevalence of Fas and FasL genetic polymorphisms in Korean women with RPL and in fertile controls. In total, 306 women with RPL and 298 fertile controls were enrolled. Genotype distributions of Fas and FasL in RPL patients versus fertile controls were examined under the Hardy-Weinberg equilibrium. Fas -670 A/G genotype (AA versus AG versus GG, p = 0.340) and allele frequencies (A versus G, p = 0.412) were not different between the RPL and control groups. There was no difference in each Fas -1377 G/A and FasL -844 C/T genotype, and their allele frequencies. In addition, the unions of two zygosities of each genotype and their combined genotypes did not differ between two groups. No difference in the prevalence of Fas and FasL single-nucleotide polymorphisms (SNPs) was observed between women with RPL and fertile controls among Korean women. To determine the possibility of genetic polymorphisms in Fas and its ligand as risk factors for RPL, further studies in various races and a large study population are needed.

Prolactin receptor gene polymorphism and the risk of recurrent pregnancy loss: a case-control study.

Since the first study was published reporting the candidate association between the prolactin receptor gene intron C/T polymorphism (rs37389) and recurrent miscarriage, no replication study has been performed. In this study, we investigated the role of the prolactin receptor gene C/T polymorphism in 311 Korean women with recurrent pregnancy loss and 314 controls. Genotyping for prolactin receptor gene intron C/T polymorphism was performed using a TaqMan assay. The significance of difference in the genotype distribution was assessed using a chi-square test, and continuous variables were compared using a Student's t-test. The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent pregnancy loss group did not differ from that in the control group (CC/CT/TT rates were 49.8%/41.5%/8.7% and 52.5%/37.6%/9.9% for the recurrent pregnancy loss patient and control groups, respectively, p = .587). When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages or patients without prior live birth, there were also no differences in the genotype distribution between these subgroups and controls. In conclusion, the findings of the current study suggest that the prolactin receptor gene intron C/T polymorphism is not a major determinant of the development of recurrent pregnancy loss. Impact statement What is already known: Many studies have investigated whether there is a genetic component for the risk of recurrent pregnancy loss. Recently, one study investigated whether genetic polymorphisms involved in the regulation of the hypothalamic-pituitary-ovarian axis would be associated with recurrent miscarriage. Among 35 polymorphisms in 20 candidate genes, genotype distribution with regard to the prolactin receptor gene intron C/T polymorphism (rs37389) differed between the recurrent miscarriage and the control groups. Since this study reporting the candidate association between the prolactin receptor gene and recurrent miscarriage, no replication study has been performed. What the results of this study add: The genotype distribution of the prolactin receptor gene C/T polymorphism in the recurrent miscarriage group did not differ from that in the control group. What the implications are of these findings: Our study may be useful in that it is the first replication study since the initial report of the association of prolactin receptor gene polymorphism with recurrent miscarriage. Although no association was found, the potential role of prolactin in pregnancy loss needs to be further investigated because prolactin and its receptor have been postulated to play an important role in the maintenance of normal pregnancy.

Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Recurrent Pregnancy Loss: a Case-Control Study.

The balance between coagulation and fibrinolysis is an essential part in early pregnancy. Mutations in methylenetetrahydrofolate reductase (MTHFR) gene lead to decreased activity of the enzyme and hyperhomocysteinemia, which then induces platelet aggregation by promoting endothelial oxidative damage, possibly resulting in adverse effect on maintenance of pregnancy. We investigated the role of MTHFR single nucleotide polymorphisms (SNPs), C677T and A1298C, in Korean patients with recurrent pregnancy loss (RPL). We conducted a prospective case-control study in the Korean population. Subjects included 302 women with 2 or more consecutive, unexplained, spontaneous miscarriages before 20 weeks of gestation and 315 control women without a history of recurrent miscarriages. The genotyping for C677T and A1298C polymorphisms was performed using the TaqMan assay. Continuous variables were compared using Student's t-test, and χ² test was used to evaluate differences in the genotype distributions between the RPL and the controls. The genotype distribution of both polymorphisms in the RPL group did not differ from those of the controls. For further analysis, if RPL patients were divided according to the numbers of pregnancy losses (≥ 2 and ≥ 3) neither group was significantly different compared with controls. MTHFR gene C677T and A1298C polymorphisms are not associated with idiopathic RPL in Korean women, suggesting that those may not be susceptible allelic variants or be deficient to cause RPL.

Estrogen receptor beta gene polymorphisms and risk of recurrent pregnancy loss: a case-control study.

Estrogen might play a key role in the maintenance of pregnancy. We investigated the role of the ER-ß gene +1730 G/A, +1082 G/A, and CA repeat polymorphisms in Korean patients with recurrent pregnancy loss (RPL). Genotyping was performed using the TaqMan assay in 305 patients with at least two unexplained consecutive spontaneous miscarriages before 20 weeks of gestation and 299 controls. The genotype distributions of the ER-ß gene +1082 G/A and +1730 G/A polymorphisms in the RPL group did not differ from those in the control group. When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages, there were also no differences in the genotype distribution between this subgroup and controls. The number of CA repeats was distributed from 13 to 28 with two large peaks at 18 and 23 in patients with RPL and controls. Using the two major peaks as cut-offs, the allele distributions were compared between patients and controls. However, the distribution of ER-ß gene CA repeats did not differ between women with recurrent miscarriage and controls. Findings of the current study suggest that the ER-ß gene polymorphisms are not major determinants of the development of RPL in Korean women.

The PAI-1 4G/5G and ACE I/D polymorphisms and risk of recurrent pregnancy loss: a case-control study.

PROBLEM: Thrombophilia has been postulated to be a contributor to the pathophysiology of recurrent pregnancy loss (RPL). We investigated the role of the plasminogen activator inhibitor type 1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D polymorphisms in Korean patients with RPL. METHOD OF STUDY: Genotyping was performed using the TaqMan assay in 227 RPL patients and 304 controls. RESULTS: The genotype distributions of both polymorphisms in the RPL group did not differ from those of controls. Because the frequency of being homozygous for ACE D/D and the PAI-I 4G/4G combination has been reported to be significantly higher in RPL patients, this was also analyzed. However, no significant difference was noted; 3.1% of RPL patients had both ACE D/D and PAI-I 4G/4G, as did 4.9% of controls (P = 0.791). CONCLUSION: The current study suggests that both polymorphisms, either alone or in combination, are not major determinants of the development of RPL in Korean women.

Comprehensive chromosome analysis of blastocysts before implantation using array CGH.

BACKGROUND: Chromosomal abnormalities are common in embryos produced in vitro and cause implantation failure, miscarriage, and serious medical problems in infants. Because preimplantation genetic screening (PGS) is increasingly being used to detect aneuploidy in embryos with the purpose of improving implantation rates after IVF (in vitro fertilization), we aimed to validate the usefulness of array CGH for the preimplantation genetic screening (PGS) of embryos at the blastocyst stage of development. RESULTS: A total of 150 blastocysts were biopsied from couples undergoing IVF and analyzed using array CGH. We found that 54.5% (73/134) of the blastocysts were euploid embryos, whereas 45.5% of the embryos (61/134) had chromosomal abnormalities. Multiple chromosome abnormality was most frequently observed (34.4%), and dual aneuploidy was observed in 26.2% of the embryos. Monosomy (21.3%) appeared more frequently than trisomy (18%). CONCLUSION: Chromosomal microarray analysis provided clinically significant cytogenetic information regarding the frequency and variety of chromosomal abnormalities observed in embryos at the blastocyst stage, suggesting that this is a useful tool for comprehensive aneuploidy screening in IVF.

Mitochondrial DNA copy number in peripheral blood in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and various metabolic diseases; and recently, elevated oxidative stress has been detected in PCOS. Mitochondria are highly susceptible to oxidative damage; and disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis, leading to the hypothesis that abnormalities in markers of mitochondrial metabolism are related to PCOS. We compared mitochondrial DNA (mtDNA) copy number in women with and without PCOS and investigated the independent relationship between mtDNA copy number and PCOS after adjustment for metabolic parameters. Fifty women with PCOS and 60 age- and body mass index-matched healthy women were studied. Mitochondrial DNA copy numbers as well as metabolic parameters and indices of insulin resistance were assessed. Mitochondrial DNA copy numbers were significantly lower in women with PCOS (P < .01). In the PCOS group, mtDNA copy number was negatively correlated with indices of insulin resistance, waist circumference, and triglyceride levels and positively correlated with sex hormone-binding globulin levels. In multiple logistic regression, the corresponding odds ratios (95% confidence interval) for PCOS by log-transformed mtDNA copy number and homeostasis model assessment of insulin resistance were 0.15 (0.04-0.56) and 4.26 (1.43-12.68), respectively, after adjustment for age, body mass index, and other metabolic factors. We report decreased mtDNA copy numbers in PCOS patients in relation to controls independently of insulin resistance or other metabolic factors. The pathophysiological and clinical significance of this finding requires further investigation.

Fragmentation of embryos is associated with both necrosis and apoptosis.

OBJECTIVE: To explore the association between embryo fragmentation and necrosis and apoptosis. DESIGN: A prospective study. SETTING: Mizmedi Hospital. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Staining with annexin V (a marker of apoptosis) and propidium iodide (PI, a marker of necrosis), DNA integrity and mitochondrial distribution, and a beneficial effect of fragment removal in human fragmented embryos. RESULT(S): Most of the mouse and human fragmented embryos were stained with PI but not with annexin V. The comet assay revealed severe DNA fragmentation of the fragmented human embryos but not of the unfragmented embryos. Fewer mitochondria were observed in the fragmented compared with the normal blastomeres, indicating a rapid depletion of ATP in the fragmented embryos. Microsurgical fragment removal from the embryos had a beneficial effect on their subsequent development. CONCLUSION(S): Fragments of human embryos exhibited various characteristics of necrosis, such as staining with PI, DNA fragmentation, rapid depletion of ATP, and harmful effects on neighboring blastomeres. We suggest that the fragmentation of embryos is closely associated with both necrosis and apoptosis. Whether this fragmentation is associated with primary or secondary necrosis remains to be elucidated.

Percutaneous transcatheter angiographic embolization in the management of obstetric hemorrhage.

OBJECTIVE: To describe the results of percutaneous arterial embolization in the management of obstetric hemorrhage. STUDY DESIGN: From February 1992 to May 2000, 33 patients with pregnancy-related hemorrhage underwent angiographic embolization to control the hemorrhage. In all cases, hemostatic embolization was performed because of intractable hemorrhage unresponsive to conservative management. All available hospital records were reviewed and detailed, and the clinical data related to complications, clinical status, estimated blood loss and blood replacement requirements, length of time of procedure, emboli used, complications associated with the procedure and results obtained were analyzed. RESULTS: Successful embolization was achieved in 31 of 33 patients. No major complications related to embolization occurred, and 3 women subsequently became pregnant. CONCLUSION: Angiographic embolization is a safe and effective method of controlling pregnancy-related hemorrhagic complications unresponsive to conservative management and maintains reproductive ability.