• Development and Reproduction
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• v.13 no.1
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• pp.1-11
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• 2009

Implantation itself is governed by an array of endocrine, paracrine and autocrine modulators, of embryonic and maternal origin. Window of implantation is the unique temporal and spatial expression of factors allows the embryo to implant via signaling, appositioning, attachment, and invasion in a specific time frame of $2{\sim}4$ days. When the embryo has arrived in the uterine cavity, a preprogrammed sequence of events occurs, which involves the production and secretion of a multitude of biochemical factors such as cytokines, growth factors, and adhesion molecules by the endometrium and the embryo, thus leading to the formation of a receptive endometrium. Cytokines such as LIF, CSF-1, and IL-1 have all been shown to play important roles in the cascade of events that leads to implantation. Integrin, L-selectin ligands, glycodelin, mucin-1, HB-EGF and pinopodes are involved in appositioning and attachment. The embryo also produces cytokines and growth factors (ILs, VEGF) and receptors for endometrial signals such as LIF, CSF-1, IGF and HB-EGF. The immune system and angiogenesis play an important role. The usefulness of these factors to assess endometrial receptivity and to estimate the prognosis for pregnancy in natural and artificial cycles remains to be proven. Integrins, pinopodes, glycodelin and LIF (from biopsies) are promising candidates; from uterine flushings, glycodelin and LIF are also candidates. The ideal serum marker is not available, but VEGF, glycodelin and CSF have some clinical implications. Further evaluation that includes larger groups of infertile women and fertile controls are needed to elucidate whether their presence in plasma, flushing fluid, or endometrial samples can be used as some kind of a screening tool to assess endometrial function and prognosis for pregnancy before and after artificial reproductive therapy. A better understanding of their function in human implantation may lead to therapeutic intervention, thereby improving the success rate in reproduction treatment. New molecular techniques are becoming available for measuring both embryonic and endometrial changes prior to and during implantation. The use of predictive sets of markers may prove to be more reliable than a single marker. Ultimately, the aim is to use these tools to increase implantation in artificial cycles and consequently improve live-birth rates.

• Clinical and Experimental Reproductive Medicine
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• v.35 no.4
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• pp.309-317
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• 2008

Objectives: The aim of this study was to evaluate the usefulness of Anti-mullerian hormone (AMH) as a predictive marker for ovarian response and cycle outcome in IVF cycles. Methods: From Jan., to Aug., 2007, 111 patients undergoing IVF/ICSI stimulated by short or antagonist protocol were selected. On cycle day 3, basal serum AMH level and FSH level were measured. The correlation between basal serum AMH or FSH, and COH outcome was analyzed and IVF outcome was compared according to the AMH levels. To determine the threshold value of AMH for poor- and hyper-response, ROC curve was analyzed. Results: Serum AMH showed higher correlation coefficient (r=0.792, p<0.001) with the number of retrieved mature oocyte than serum FSH (r=-0.477, p<0.001). According to ovarian response, FSH and AMH leves showed significant differences among poor, normal, and hyperresponder. For predicting poor (${\leq}2$ oocytes) and hyperresponse (${\geq}17$ oocyets), AMH cut-off values were 0.5 ng/ml (the sensitivity 88.9% and the specificity 89.5%) and 2.5 ng/ml (sensitivity 85.7%, specificity 87.0%), respectively. According to the AMH level, patients were divided into 3 groups: low (${\leq}0.60\;ng/ml$), normal ($0.60{\sim}2.60\;ng/ml$), and high AMH (${\geq}2.60\;ng/ml$). The number of retrieved mature oocytes was significantly higher ($2.7{\pm}2.2$, $8.1{\pm}4.8$, $16.5{\pm}5.7$) and total gonadotropin dose was lower ($3530.5{\pm}1251.0$, $2957.1{\pm}1057.6$, and $2219.2{\pm}751.9\;IU$) in high AMH group (p<0.001). There was no significant difference in fertilization rates and pregnancy rates (23.8%, 34.0%, 37.5%) among the groups. Conclusions: Basal serum AMH level correlated better with the number of retrieved mature oocytes than FSH level, suggesting its usefulness for predicting ovarian response. However, IVF outcome was not significantly different according to the AMH levels. Serum AMH level presented good cut-off value for poor- or hyper-responders, therefore it could be useful in prediction of cycle cancellation, gonadotropin dose, and OHSS risk in IVF cycles.

• Clinical and Experimental Pediatrics
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• v.51 no.3
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• pp.323-328
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• 2008

Purpose : Asthma is defined as chronic inflammation of the lower small airways, and bronchial hyperreactivity (BHR) is a pathophysiologic feature of asthma. It has been proposed that although there is no direct variable capable of assessing the small airways, a forced expiratory flow of between 25 and 75 percent ($FEF_{25-75}$) might be considered a more sensitive early marker of small airway obstruction than the forced expiratory volume in 1 second ($FEV_1$). Thus, we proposed that the presence and degree of positive responses to bronchial methacholine testing were related to the difference (DFF) and ratio (RFF) between $FEV_1$ and $FEF_{25-75}$ in asthmatic children. Methods : The subjects were 583 symptomatic children, including 324 children with BHR and 259 controls. Pulmonary function tests, methacholine challenge tests, and skin prick tests were performed, and the total eosinophil count, total serum IgE, and serum eosinophil cationic protein level were measured in all subjects. From a concentration-response curve, the methacholine concentration required to produce a decrease of 20% from post-saline $FEV_1$ was calculated ($PC_{20}$). Results : The median DFF and RFF values decreased in controls compared to subjects with bronchial hyperresponsiveness, and this trend was found in groups ranked by its severity. $PC_{20}$ had a negative correlation with DFF and RFF. Cutoff values of 0.5 for DFF and 1.042 for RFF were identified, and sensitivity and specificity were calculated. Conclusion : This study revealed that DFF and RFF might be predictive of bronchial hyperresponsiveness in the context of normal $FEV_1$ in children.

• Journal of Life Science
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• v.21 no.11
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• pp.1518-1525
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• 2011

Sorafenib is the only approved systemic, therapeutic agent for hepatocellular carcinoma (HCC). The use of Ginseng Extract (GE) in cancer patients is growing worldwide; however, drug interaction between sorafenib and GE has not been illuminated. Four different human cancer cell lines including HepG2 were used and immunocompetent mice were implanted subcutaneously with a mouse HCC cell line. Treatment with low dose GE stimulated cell growth, while a high dose inhibited growth. pERK (phosphorylation of extracellular signal-regulated kinase) was concomitantly increased and decreased respective of different doses of GE. Antitumoral effect of sorafenib decreased in non-proliferating phase cells but was sensitized after low dose GE (LDG) treatment. PD98059 (ERK phosphorylation inhibitor) efficiently blocked ERK phosphorylation, resulting in loss of sorafenib sensitization even after LDG treatment. In the HCC mouse model, LDG alone slightly increased tumor size while sorafenib alone significantly decreased it. However, a combination of LDG and sorafenib significantly decreased tumor size compared with sorafenib alone. Increase of pERK was observed in some normal mice organs and mild inflammatory change was observed in some of these organs, suggesting pERK activation by LDG may cause unexpected toxicity in normal cells. GE, dose-dependently, induced stimulation or inhibition in some human cancer cell lines. Combinational use of GE and sorafenib possibly potentiated an antitumoral response to sorafenib. pERK level has been provided as a potential predictive marker for sorafenib. Our result may suggest GE's dual effects in relation to pERK level in HCC cancer cell lines, and that certain doses of GE can sensitize sorafenib.

• Radiation Oncology Journal
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• v.22 no.2
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• pp.77-90
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• 2004

Purpose: The purpose of this review Is to provide an update on novel radiation treatments for head and neck cancer Recent Findings: Despite the remarkable advances In chemotherapy and radiotherapy techniques, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor (EGFR) Is an appealing target for novel therapies In head and neck cancer because not only EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Furthermore, EGFR overexpression Is known to be portended for a worse outcome in patients with advanced head and neck cancer. Two categories of compounds designed to abrogate EGFR signaling, such as monoclonal antibodies (Cetuxlmab) and tyrosine kinase inhibitors (ZD1839 and 051-774) have been assessed and have been most extensively studied In preclinical models and clinical trials. Additional TKIs In clinical trials include a reversible agent, Cl-1033, which blocks activation of all erbB receptors. Encouraging preclinical data for head and neck cancers resulted In rapid translation Into the clinic. Results from Initial clinical trials show rather surprisingly that only minority of patients benefited from EGFR inhibition as monotherapy or In combination with chemotherapy. In this review, we begin with a brief summary of erbB- mediated signal transduction. Subsequently, we present data on prognostic-predictive value of erbB receptor expression in HNC followed by preclinlcal and clinical data on the role of EGFR antagonists alone or in combination with radiation In the treatment of HNC. Finally, we discuss the emerging thoughts on resistance to EGFR biockade and efforts In the development of multiple-targeted therapy for combination with chemotherapy or radiation. Current challenges for investigators are to determine (1 ) who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2) how to sequence these agents with radiation and/or cytotoxlc compounds, (3) reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4) mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multi-targeted therapy, Other molecuiar-targeted approaches In head and neck cancer were briefly described, Including angloenesis Inhibitors, farnesyl transferase inhibitors, cell cycle regulators, and gene therapy Summary: Novel targeted theraples are highly appealing in advanced head and neck cancer, and the most premising strategy to use them Is a matter of intense Investigation.

• Radiation Oncology Journal
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• v.23 no.1
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• pp.1-8
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• 2005

Purpose : The objective of this study was to determine whether the expressions of the two components of DNA-dependent protein kinase, Ku70 and DNA-PKcs, influence the response to radiotherapy (RT) and outcome of treatment of non-disseminated nasopharyngeal carcinoma (NPC) in patients who received definitive RT. Materials and Methods : Sixty-six patients with NPC who were treated with radiotherapy alone or with concurrent chemotherapy between June 1995 and December 2001 were divided into groups based on the levels of immunoreactivity for Ku70 and DNA-PKcs in pretreatment biopsy specimens. The over-expression of Ku70 or DNA-PKcs groups Included patients whose biopsy specimens showed at least 50% immunopositive tumor cells; patients in which less than 50% of the tumor cells in the biopsy tissues were immunopositive were placed in the low Ku70 and DNA-PKcs groups. The immunoreactivities for Ku70 and DNA-PKcs were retrospectively compared with the sensitivity of the tumor to radiation and the patterns of therapy failure. Univariate analyses were peformed to determine the prognostic factors that influenced locoregional control of NPC. Results : The five-year locoregional control rate was significantly higher in the low Ku70 group (Ku(-)) (85%) than in the high Ku70 group (Ku(+)) (42%) (p=0.0042). However, there were no differences in the metastases-free survival rates between the two groups (Ku70 (+), 82%; Ku70 (-), 78%; p=0.8672). Univariate analysis indicated that the over-expression of Ku70 surpassed other well-known predictive clinocopathologic parameters as an Independent prognostic factor for locoregionai control. Eighteen of 22 patients who had locoregional recurrences of the tumor displayed an over-expression of Ku70. No significant association was found between the level of DNA-PKcs expression and the clinical outcome. Conclusion : Our data suggest that the level of Ku70 expression can be used as a molecular marker to predict the response to RT and the locoregional control after RT and concurrent chemotherapy in patients with non-disseminated NPC.