Impact of paraaortic lymphadenectomy for endometrial cancer with positive pelvic lymph nodes: A Korean Radiation Oncology Group study (KROG 13-17).

AIM: We investigated the role of paraaortic lymph node dissection (PALND) in patients with stage IIIC1 endometrial carcinoma after surgery followed by adjuvant radiotherapy (RT) alone or chemoradiotherapy (CTRT). METHODS: We performed a subgroup analysis in 151 patients treated with adjuvant pelvic RT. Paraaortic-recurrence free survival, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: In adjuvant RT alone, PALND was significantly related to reduced risk of paraaortic recurrence (0% vs. 17.1%) and distant metastasis (4.5% vs. 19.5%) compared with the no PALND group. PALND affected 5-year DFS (90.2% vs. 58.9%, p = 0.016) and OS (100% vs. 83.1%, p = 0.022). For the CTRT group, the paraaortic recurrence rate was 19.5% for the no PALND group and 12.8% for the PALND group (p = 0.682). Of patients who underwent PALND in the CTRT group, less extensive PALND was significantly related to increased paraaortic recurrence (≤10 vs. >10 dissected LNs, 17.1% vs. 0%). In the no PALND group (n = 82), 5-year paraaortic-recurrence free survival was 79.4% for the CTRT group and 76.2% for the RT alone group (p = 0.941). In multivariate analysis, PALND was significantly associated with reduced risk of disease-specific death (HR, 0.50; 95% CI, 0.26-0.96; p = 0.037). CONCLUSION: PALND provided excellent paraaortic control and improved outcome in stage IIIC1 endometrial cancer with favorable tumor features treated with adjuvant RT alone. Less extensive PALND was associated with significantly increased paraaortic recurrence in patients with advanced tumor features treated with adjuvant CTRT. Combined CTRT did not affect disease control in the paraaortic region compared with RT alone.

Antiangiogenic activity of 2-formyl-8-hydroxy-quinolinium chloride.

Tumour growth is closely related to the development of new blood vessels to supply oxygen and nutrients to cancer cells. Without the neovascular formation, tumour volumes cannot increase and undergo metastasis. Antiangiogenesis is one of the most promising approaches for antitumour therapy. The exploration of new antiangiogenic agents would be helpful in antitumour therapy. Quinoline is an aromatic nitrogen compound characterized by a double-ring structure which exhibits a benzene ring fused to pyridine at two adjacent carbon atoms. The high stability of quinoline makes it preferable in a variety of therapeutic and pharmaceutical applications, including antitumour treatment. This work is to examine the potential antiangiogenic activity of the synthetic compound 2-Formyl-8-hydroxy-quinolinium chloride. We found that 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of human umbilical vein endothelial cells in vitro. Using the diethylnitrosamine-induced hepatocarcinogenesis model, 2-Formyl-8-hydroxy-quinolinium chloride showed strong antiangiogenic activity. Furthermore, 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of large Hep3B xenografted tumour from the nude mice. We assume that 2-Formyl-8-hydroxy-quinolinium chloride could be a potential antiangiogenic and antitumour agent and it is worthwhile to further study its underlying working mechanism.

Use of hyaluronidase as an adjuvant to ropivacaine to reduce axillary brachial plexus block onset time: a prospective, randomised controlled study.

When considering brachial plexus block as a practical alternative to general anaesthesia for upper limb surgery, the time to achieve complete sensory block is a clinically important variable. In this prospective randomised double-blind controlled trial, we investigated the hypothesis that addition of hyaluronidase to ropivacaine may reduce the time to achieve complete sensory block after axillary brachial plexus block. The patients were randomly assigned into a hyaluronidase group (n = 24) and a control group (n = 24). The hyaluronidase group received ropivacaine 0.5% with 100 IU.ml(-1) of hyaluronidase, and the control group received ropivacaine alone. The primary endpoint was the time to achieve complete sensory block. The hyaluronidase group demonstrated significantly shorter mean (SD) sensory block onset time (13.8 (6.0) min) compared with the control group (22.5 (6.3) min, p < 0.0001). Addition of hyaluronidase to ropivacaine resulted in a reduction in the time needed to achieve complete sensory block.

Microencapsulation-protected l-ascorbic acid for the application of human epithelial HaCaT cell proliferation.

l-ascorbic acid is an abundant water-soluble nutrient found in vegetables and fruits. It enhances the cell proliferation, which is helpful in wound healing process. However, it is relatively unstable and easily degraded under external environments including acidity, alkalinity, evaporation, heat, oxidization, light or moisture. Its storage remains challenged. This study reported the development of l-ascorbic acid microcapsules using the natural protein, gelatin, and the natural polysaccharide, agar, as the wall protection carrier. The physical properties including entrapment efficiency, particle size, surface morphology, chemical compositions and release profile were identified. The cell proliferation of l-ascorbic acid microcapsules was stronger than the free drug. Significant cell growth in microencapsulated l-ascorbic acid-treated human epithelial HaCaT cells was observed when compared with untreated control. Since cell proliferation and wound repair are closely related, it is believed that l-ascorbic acid microcapsules would effectively increase the potential effect of wound healing activity in human skin.

D-Glucose as a modifying agent in gelatin/collagen matrix and reservoir nanoparticles for Calendula officinalis delivery.

Gelatin/Collagen-based matrix and reservoir nanoparticles require crosslinkers to stabilize the formed nanosuspensions, considering that physical instability is the main challenge of nanoparticulate systems. The use of crosslinkers improves the physical integrity of nanoformulations under the-host environment. Aldehyde-based fixatives, such as formaldehyde and glutaraldehyde, have been widely applied to the crosslinking process of polymeric nanoparticles. However, their potential toxicity towards human beings has been demonstrated in many previous studies. In order to tackle this problem, D-glucose was used during nanoparticle formation to stabilize the gelatin/collagen-based matrix wall and reservoir wall for the deliveries of Calendula officinalis powder and oil, respectively. In addition, therapeutic selectivity between malignant and normal cells could be observed. The C. officinalis powder loaded nanoparticles significantly strengthened the anti-cancer effect towards human breast adenocarcinoma MCF7 cells and human hepatoma SKHep1 cells when compared with the free powder. On the contrary, the nanoparticles did not show significant cytotoxicity towards normal esophageal epithelial NE3 cells and human skin keratinocyte HaCaT cells. On the basis of these evidences, D-glucose modified gelatin/collagen matrix nanoparticles containing C. officinalis powder might be proposed as a safer alternative vehicle for anti-cancer treatments.

High glucose level induces cardiovascular dysplasia during early embryo development.

The incidence of gestational diabetes mellitus (GDM) has increased dramatically amongst multiethnic population. However, how gestational diabetes mellitus damages the developing embryo is still unknown. In this study, we used yolk sac membrane (YSM) model to investigate angiogenesis in the developing chick embryo. We determined that in the presence of high glucose, it retarded the growth and extension of the embryonic vascular plexus and it also reduced the density of the vasculature in yolk sac membrane model. Using the same strategy, we used the chorioallantoic membrane (CAM) as a model to investigate the influence of high glucose on the vasculature. We established that high glucose inhibited development of the blood vessel plexus and the blood vessels formed had a narrower diameter than control vessels. Concurrent with the abnormal angiogenesis, we also examined how it impacted cardiogenesis. We determined the myocardium in the right ventricle and left atrium were significantly thicker than the control and also there was a reduction in glycogen content in cardiomyocytes. The high glucose also induced excess reactive oxygen species (ROS) production in the cardiomyocytes. We postulated that it was the excess reactive oxygen species that damaged the cardiomyocytes resulting in cardiac hyperplasia.

Complete reconstitution of a highly reducing iterative polyketide synthase.

Highly reducing iterative polyketide synthases are large, multifunctional enzymes that make important metabolites in fungi, such as lovastatin, a cholesterol-lowering drug from Aspergillus terreus. We report efficient expression of the lovastatin nonaketide synthase (LovB) from an engineered strain of Saccharomyces cerevisiae, as well as complete reconstitution of its catalytic function in the presence and absence of cofactors (the reduced form of nicotinamide adenine dinucleotide phosphate and S-adenosylmethionine) and its partner enzyme, the enoyl reductase LovC. Our results demonstrate that LovB retains correct intermediates until completion of synthesis of dihydromonacolin L, but off-loads incorrectly processed compounds as pyrones or hydrolytic products. Experiments replacing LovC with analogous MlcG from compactin biosynthesis demonstrate a gate-keeping function for this partner enzyme. This study represents a key step in the understanding of the functions and structures of this family of enzymes.

[18F] fluorodeoxyglucose-positron-emission tomography and MR imaging coregistration for presurgical evaluation of medically refractory epilepsy.

Epilepsy is a chronic disorder affecting approximately 1% of the population of the world. Approximately one third of patients with epilepsy remain refractory to medical therapy. For these patients, surgery is a curative option. In order for surgery to be considered, precise localization of the structural abnormality is needed. When MR imaging findings are normal, more sensitive techniques such as positron-emission tomography (PET) can help find the abnormality. Combining MR imaging and PET information increases the sensitivity of the presurgical evaluation. In this review, we discuss the clinical applications of coregistration of [(18)F] fluorodeoxyglucose (FDG)-PET with MR imaging for medically refractory epilepsy. Because FDG-PET/MR imaging coregistration has been a routine component of the presurgical evaluation for patients with epilepsy at our institution since 2004, we also included cases from our data base that exemplify the utility of this technology to obtain better postsurgical outcomes.

A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapy-induced nausea and vomiting in Chinese breast cancer patients receiving moderately emetogenic chemotherapy.

OBJECTIVES: This is a single center, randomized, double-blind placebo-controlled study to evaluate the NK(1)-receptor antagonist, aprepitant, in Chinese breast cancer patients. The primary objective was to compare the efficacy of aprepitant-based antiemetic regimen and standard antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who received moderately emetogenic chemotherapy. The secondary objective was to compare the patient-reported quality of life in these two groups of patients. PATIENTS AND METHODS: Eligible breast cancer patients were chemotherapy-naive and treated with adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2)). Patients were randomly assigned to either an aprepitant-based regimen (day 1, aprepitant 125 mg, ondansetron 8 mg, and dexamethasone 12 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, aprepitant 80 qd) or a control arm which consisted of standard regimen (day 1, ondansetron 8 mg and dexamethasone 20 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, ondansetron 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary, patients quality of life were assessed by self-administered Functional Living Index-Emesis (FLIE). RESULTS: Of 127 patients randomized, 124 were assessable. For CINV in Cycle 1 AC, there was no significant difference in the proportion of patients with reported complete response, complete protection, total control, 'no vomiting', 'no significant nausea' and 'no nausea'. The requirement of rescue medication appears to be lesser in patients treated with the aprepitant-based regimen compared to those with the standard regimen (11% vs. 20%; P = 0.06). Assessment of FLIE revealed that while there was no difference in the nausea domain and the total score between the two groups; however, patients receiving standard antiemetic regimen had significantly worse quality of life in the vomiting domain (mean score [SD] = 23.99 [30.79]) when compared with those who received the aprepitant-based regimen (mean score [SD] = 3.40 [13.18]) (P = 0.0002). Both treatments were generally well tolerated. Patients treated with the aprepitant-based regimen had a significantly lower incidence of neutropenia (53.2% vs. 35.5%, P = 0.0468), grade >or= 3 neutropenia (21.0% vs. 45.2, P = 0.0042) and delay in subsequent cycle of chemotherapy (8.1% vs. 27.4%, P = 0.0048). CONCLUSION: The aprepitant regimen appears to reduce the requirement of rescue medication when compared with the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide, and is associated with a better quality of life during adjuvant AC chemotherapy.

Pancreas: what is the role of minimally invasive surgery?

Advances in minimally invasive surgical technique, technology, and instrumentation have fostered the application of minimally invasive surgery to the management of pancreatic malignancies. Procedures such as laparoscopic staging and laparoscopic distal pancreatectomies that do not require complex reconstructions are feasible, safe, and appear to offer significant benefits in comparison to the comparable open procedures. Moreover, they can be taught to surgical trainees and can be readily disseminated beyond specialized centers. In contrast, more complex procedures such as laparoscopic pancreaticoduodenectomy or central pancreatectomy have been safely performed in specialized centers, but their usefulness in comparison to open procedures remains to be defined. As laparoscopic skills and technology continue to improve, however, it is likely that such complex procedures will be performed with greater frequency. Future trials that confirm the safety and benefits of these advanced laparoscopic procedures in comparison to open procedures are therefore of paramount importance. Additionally, studies that specifically evaluate and compare the oncologic outcomes of laparoscopic and open pancreatic resections are needed.

BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma.

BRE binds to the cytoplasmic domains of tumor necrosis factor receptor-1 and Fas, and in cell lines can attenuate death receptor-initiated apoptosis by inhibiting t-BID-induced activation of the mitochondrial apoptotic pathway. Overexpression of BRE by transfection can also attenuate intrinsic apoptosis and promote growth of the transfected Lewis lung carcinoma line in mice. There is, however, a complete lack of in vivo data about the protein. Here, we report that by using our BRE-specific monoclonal antibody on the immunohistochemistry of 123 specimens of human hepatocellular carcinoma (HCC), significant differences in BRE expression levels between the paired tumoral and non-tumoral regions (P<2.2e-16) were found. Marked overexpression of BRE was detected in majority of the tumors, whereas most non-tumoral regions expressed the same low level of the protein as in normal livers. To investigate whether BRE overexpression could promote cell survival in vivo, liver-specific transgenic BRE mice were generated and found to be significantly resistant to Fas-mediated lethal hepatic apoptosis. The transgenic model also revealed post-transcriptional regulation of Bre level in the liver, which was not observed in HCC and non-HCC cell lines. Indeed, all cell lines analysed express high levels of BRE. In conclusion, BRE is antiapoptotic in vivo, and may promote tumorigenesis when overexpressed.

Exogenous dibutyryl cAMP affects meiotic maturation via protein kinase A activation; it stimulates further embryonic development including blastocyst quality in pigs.

High concentrations of cyclic AMP in germinal vesicle oocytes generally inhibit GVBD. Thus, maintaining the GV stage in growing oocytes is essential for the developmental competence of the eggs. In this study, we traced the effects of dibutyryl cyclic AMP on meiotic maturation and early embryonic development in pigs. We also investigated several blastocyst qualities, including structural integrity, mitochondrial membrane potential, and apoptosis, which are affected by dbcAMP. To determine whether increased concentrations of cAMP inhibit GVBD, we explored the meiotic patterns and during maturation of pig oocytes. When treated with dbcAMP for 22h, 91.1% of the oocytes were arrested in the GV stage compared to only 38.8% of the oocytes in the control group (P<0.05). After completion of IVM, a higher proportion of the dbcAMP-treated oocytes were in metaphase II than the untreated ones (91.3% vs. 72.8%, P<0.05). Western blot analysis showed a reduction (at 22h) and/or increase (at 44h) in MPF and MAP kinase activities in porcine oocytes treated with dbcAMP for the first 22h of IVM compared to the untreated control. We also confirmed that protein kinase A activity increased in dbcAMP-treated oocytes, indicating an elevated intracellular concentration of cAMP. After IVF, the frequency of polyspermy in the dbcAMP-treated group decreased compared to that in the control group (22.4% vs. 47.4%, P<0.05). Furthermore, blastocyst formation, the blastocyst cell number, mitochondrial membrane potential, and apoptosis were enhanced and/or reduced by dbcAMP in both IVF and SCNT embryos. We concluded that synchronizing meiotic resumption by dbcAMP treatment improved the developmental capacity and embryonic qualities of IVF and SCNT embryos by increasing the mitochondrial membrane potential and decreasing the incidence of apoptosis in preimplantation-stage porcine embryos.

Premarital sexual intercourse among adolescents in Malaysia: a cross-sectional Malaysian school survey.

INTRODUCTION: Sexual intercourse among Malaysian adolescents is a major concern, especially with the worry of HIV/AIDS. This study was done to determine the prevalence of sexual intercourse among secondary school students aged 12 to 19 years in Negeri Sembilan, Malaysia. METHODS: This is a cross-sectional school survey conducted on 4,500 adolescent students based on a structured questionnaire. Data were collected using the self-administered questionnaire (translated version of the Youth Risk Behaviour Surveillance in Bahasa Malaysia). RESULTS: The study showed that 5.4 percent of the total sample were reported to have had sexual intercourse. The proportion among male students who had had sex was higher (8.3 percent) compared with female students (2.9 percent). The mean age at first sexual intercourse was 15 years. One percent of students reported that they had been pregnant or had made someone else pregnant. Adolescent sexual intercourse was significantly associated with (1) socio-demographical factors (age, gender); (2) environmental factors (staying with parents); and (3) substance use (alcohol use, cigarette smoking, drug use), even after adjustment for demographical factors. The survey showed that 20.8 percent of respondents had taken alcohol, 14.0 percent had smoked cigarettes, 2.5 percent had tried marijuana, 1.2 percent had tried ecstasy pills, 2.6 percent had tried glue sniffing, 0.7 percent had tried heroin, and 0.7 percent had intravenous drugs. CONCLUSION: Prevalence of sexual intercourse among Malaysian adolescents was relatively low compared to developed countries. However, certain groups of adolescents tend to be at higher risk of engaging in sexual intercourse. This problem should be addressed early by targeting these groups of high-risk adolescents.

Effects of Qi therapy (external Qigong) on symptoms of advanced cancer: a single case study.

The aim of this study was to examine the effectiveness of Qi therapy (external Qigong) in the management of symptoms of advanced cancer in a man. We used a single case study design to evaluate the effectiveness of Qi therapy (external Qigong) in a 35-year-old man with advanced cancer (Stage IV) involving metastases in the stomach, lung and bone (Karnofsky performance scale: KPS, 40: requires special care and assistance, disabled). Treatment involved six days of pre-assessment, eight treatment sessions on alternate days over 16 days, and a two-week follow-up phase. A visual analogue scale (VAS) was used to assess the patient's self-reported symptoms of cancer over the intervention and follow-up periods. Following treatment, VAS scores' analysis revealed beneficial effects on pain, vomiting, dyspnoea, fatigue, anorexia, insomnia, daily activity and psychological calmness. These improvements were maintained over the two-week follow-up phase. After the first Qi therapy session, the patient discontinued medication and could sit by himself; after the fourth session, the patient was able to walk and use the toilet without assistance (improvement in KPS: 70: care for self, unable to perform normal activity or to do active work). Although limited by the single case study approach, our results support previous studies on this topic and provide reasons to conduct controlled clinical trials.

Proteomic analysis of chromatin-modifying complexes in Saccharomyces cerevisiae identifies novel subunits.

Epigenetics is the alteration of phenotype without affecting the genotype. An underlying molecular mechanism of epigenetics is the changes of chromatin structure by covalent histone modifications and nucleosome reorganization. In the yeast, Saccharomyces cerevisiae, two of the most well-studied macromolecular complexes that perform these epigenetic changes are the ATP-dependent Swi/Snf chromatin-remodelling complex and the SAGA histone acetyltransferase complex. To understand fully the mechanism by which these large protein complexes perform their functions in the cell, it is crucial that all the subunits of these complexes are identified. In an attempt to identify new subunits associated with SAGA and Swi/Snf, we used tandem affinity purification, followed by a multidimensional protein identification technology to analyse the subunit composition. Our analysis identified two novel proteins, one associated with SAGA, YPL047W (Sgf11), and another associated with Swi/Snf, Rtt102.

Heart-type fatty acid binding proteins are upregulated during terminal differentiation of mouse cardiomyocytes, as revealed by proteomic analysis.

At birth, the cardiomyocytes in the mouse neonatal heart still retain their ability to proliferate. However, this lasts only a few days and then the cardiomyocytes irreversibly lose their potential to divide. It is still not fully understood what factors are involved in the cessation of cardiomyocyte proliferation. Using proliferating cell nuclear antigen (PCNA) antibodies, we established that cardiomyocytes could divide extensively in 2-day-old mouse neonatal hearts and to a lesser extent in 6-day-old hearts. By 13 days, the cardiomyocytes have mostly stopped dividing. Comparative two-dimensional gel electrophoresis (2-DE) was performed on total proteins extracted from the 2-day- and 13-day-old hearts, in order to identify peptides that might be involved in the inhibition of cardiomyocyte proliferation. Using matrix-assisted laser desorption ionization mass spectroscopy (MALDI-TOF), we identified two protein spots that have the same molecular weight (approximately 14 kDa) but different pIs (5.9 and 6.1). Mass spectra analysis determined the proteins to be isoforms of the heart-type fatty acid binding protein (H-FABP). The pI 6.1 H-FABP is also known as mammary-derived growth inhibitor (MDGI; Specht et al. 1996). MGDI is a breast tumour growth suppressor gene capable of inhibiting tumour cell proliferation (Huynh et al. 1995). Both H-FABP isoforms were expressed in 2-day-old hearts but became strongly upregulated in 13-day-old hearts. We examined whether H-FABPs and PCNA were coexpressed in 2-, 6- and 13-day-old heart histological sections, using MDGI antibodies. The antibody could detect both forms of H-FABPs. It was established that there was a correlation between an increase in H-FABP expression and a decrease in PCNA expression. Hence, we tentatively propose that H-FABP isoforms are involved in regulating cardiomyocyte growth and differentiation in mouse neonatal hearts.

Finite-element analysis for lumbar interbody fusion under axial loading.

A parametric study was conducted to evaluate axial stiffness of the interbody fusion, compressive stress, and bulging in the endplate due to changes in the spacer position with/without fusion bone using an anatomically accurate and validated L2-L3 finite-element model exercised under physiological axial compression. The results show that the spacer plays an important role in initial stability for fusion, and high compressive force is predicted at the ventral endplate for the models with the spacer and fusion bone together. By varying the positioning of the spacer anteriorly along anteroposterior axis, no significant change in terms of axial stiffness, compressive stress, and bulging of the endplate are predicted for the implant model. The findings suggest that varying the spacer position in surgical situations does not affect the mechanical behavior of the lumbar spine after interbody fusion.

Substitution for natural musk in Pien Tze Huang does not affect its hepatoprotective activities.

Previous studies showed that Pien Tze Huang, a Chinese folk medicine well known for its therapeutic activity in treating liver diseases, protected the liver against carbon tetrachloride (CCl4)-induced damage in mice. In the present study, natural musk, one of the important ingredients of Pien Tze Huang, was replaced by a formulated substitute, and the new formulation of Pien Tze Huang was shown to have similar chromatographic patterns to the original Pien Tze Huang in gas chromatography-mass spectrometry and high performance liquid chromatography. When used in treating mice with CCl4- or galactosamine-induced liver damage, both the original and new formulations of Pien Tze Huang were found to be able to suppress to a similar extent both the histopathological changes in the liver and the elevation of serum alanine aminotransferase and aspartate aminotransferase. Necrosis, cellular ballooning, microvesicular steatosis and lymphocytes infiltration were all significantly reduced in the damaged liver. In hepatoma cells, both formulations activated the activator protein 1 (AP1) enhancer sequence, indicating that both of them were able to act through the JNK signal transduction pathway. The results of the present study showed that the substitution for natural musk does not affect the hepatoprotective activities of Pien Tze Huang. It is also postulated that both formulations protect the liver through regulating signal transduction in the cell.