Primary cutaneous mucinous carcinoma in a periorbital lesion: two case reports and literature review.

Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy of the sweat glands that most commonly affects the periorbital area. It is characterized by slow growth over a prolonged period, and its morphology can be easily confused with a benign tumor, such as an epidermal cyst. Consequently, many patients experience recurrence after undergoing multiple resections. However, there are few reports concerning the surgical management of PCMC. We present two cases of PCMC originating in the periorbital area. The first case involved a 76-year-old man with a mass measuring 3.0× 1.5 cm that had been increasing in size. The second case was a 61-year-old man with two masses, each measuring 1.0× 1.0 cm, that were also growing. Both patients underwent wide excision with a 5-mm safety margin, which was determined based on the widest view of the cross-section of the mass on the magnetic resonance imaging. Subsequently, based on the intraoperative frozen biopsy results, both patients underwent additional excision with a 5-mm safety margin in only one direction. This report shows that, when determining the surgical margin of PCMC in periorbital area, employing imaging modalities and intraoperative frozen biopsies can be helpful for narrowing the surgical margin.

Congenital Hemihyperplasia in an Infant with Ipsilateral Torticollis: A Case Report.

Hemihyperplasia is a kind of regional body growth asymmetry and can be a symptom of several congenital disorders and tumorous conditions. Torticollis is most commonly caused by asymmetric hypertrophy of the sternocleidomastoid muscle. Herein, we report a case of hemihyperplasia in an infant with ipsilateral torticollis. The baby was evaluated using physical examination and ultrasonography. We observed significant right-side torticollis that was ipsilateral to congenital right-side hemihypertrophy. No abnormal tumorous conditions were found during the evaluation in the pediatrics department. The patient was treated with physical therapy and exhibited mild improvements in torticollis and hemihyperplasia.

Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser.

Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF1R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists-BMK-C203 and BMK-C205-and determined the CRF1R/BMK-C203 and CRF1R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R.

Comparison of clinical and preimplantation genetic testing for aneuploidy outcomes between in vitro fertilization and intracytoplasmic sperm injection in sibling mature oocytes from high-risk patients: A retrospective study.

AIM: To evaluate the influence of insemination methods on clinical outcomes by assessing preimplantation genetic testing for aneuploidy (PGT-A) outcomes in embryos obtained using in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in sibling mature oocytes from high-risk patients. METHODS: This retrospective study involved 108 couples with nonmale or mild male factor infertility who underwent split insemination cycles from January 2018 to December 2021. PGT-A was performed using trophectoderm biopsy, array comparative genome hybridization, or next-generation sequencing with 24-chromosome screening. RESULTS: Mature oocytes were divided into IVF (n = 660) and ICSI (n = 1028) groups. The normal fertilization incidence was similar between the groups (81.1% vs. 84.6%). The total number of blastocysts biopsied was significantly higher in the IVF group than in the ICSI group (59.3% vs. 52.6%; p = 0.018). However, euploidy (34.4% vs. 31.9%) and aneuploidy (63.4% vs. 66.2%) rates per biopsy and clinical pregnancy rates (60.0% vs. 58.8%) were similar between the groups. Implantation (45.6% vs. 50.8%) and live birth or ongoing pregnancy (52.0% vs 58.8%) rates were slightly higher in the ICSI group than in the IVF group and miscarriage rate per transfer was slightly higher in the IVF group than in the ICSI group (12.0% vs 5.9%); however no significant difference was observed. CONCLUSIONS: IVF and ICSI using sibling mature oocytes had similar clinical outcomes, and euploidy and aneuploidy rates in couples with nonmale and mild male factor infertility. These results suggest that IVF is a useful option, along with ICSI, as an insemination method in PGT-A cycles, especially in high-risk patients.

Polystyrene microplastic particles induce autophagic cell death in BEAS-2B human bronchial epithelial cells.

The detection of high levels of microplastics in indoor and outdoor air has increased concerns regarding its toxic effects on the respiratory system. They are not easily degradable and can be deposited deep in the lungs. Although several studies have reported inhalation toxicities of microplastics, they are still controversial due to a lack of evidence. Herein, we evaluated the inhalation toxicities of three differently charged polystyrene microplastics (PS-MPs), the most abundant microplastics in the air. Cytotoxicity and ROS generation were evaluated using WST-1 and DCF-DA assays, respectively. To evaluate the toxic effects on the lung, inflammatory responses were analyzed after repeated exposure to the PS-MPs through intratracheal instillation. To explore the mechanism of toxicity, autophagy and ER stress-associated proteins were analyzed. Only the positively charged PS-MPs (NH2 -PS-MPs) showed cytotoxicity and increased ROS generation in BEAS-2B cells. Similarly, only NH2 -PS-MPs significantly increased the expression and secretion of the pro-inflammatory cytokine IL-ß in the animal experiments. The expression of ER stress proteins indicated that NH2 -PS-MPs increased ER stress via PERK-EIF2α and ATF4-CHOP pathways. Moreover, accumulation of NH2 -PS-MPs in lysosomes and deformity of the nucleus were observed in BEAS-2B cells with autophagy induction. Taken together, our results demonstrated that NH2 -PS-MPs induced autophagic cell death in bronchial epithelial cells, leading to inflammatory responses in the lungs. These results suggest that repeated inhalation of microplastics can result in inflammatory responses in the lung through cellular damage of lung epithelial cells, and that inhalation microplastics should be monitored to reduce inhalation health risks.

Clinical characteristics of pediatric nasal bone fractures by age group.

BACKGROUND: The clinical characteristics of pediatric nasal fractures can vary depending on the child's age, social activities, and environment. Therefore, this study aimed to analyze these characteristics in different age groups. METHODS: We retrospectively reviewed of a series of patients aged under 12 years who received treatment between 2013 and 2021. The initial study design involved dividing the patients into four age groups, corresponding to different developmental ages, but there were no cases in infants aged 0 to 1 year. Therefore, the patients were divided into three groups: group I, between 2 and 5; group II, between 6 and 9; and group III, between 10 and 12 years of age. The following parameters were evaluated: sex, age, etiology, fracture type and severity, and the incidence of septal injuries. RESULTS: In total, 98 patients were included in this study. In group III, the ratio of boys to girls was 3.88:1, exceeding the overall ratio of 1.97:1. The most common cause varied with age: slipping down in group I, bumping accidents in group II, and sports accidents in group III. Concomitant septal injuries were present in 4.17% of patients in group I, 5.71% of patients in group II, and 28.21% of patients in group III. CONCLUSION: Increasing age was accompanied by a greater tendency for male predominance and a higher prevalence of sports-related causes and septal injuries. Violence was infrequent but started to become a contributing factor during school age. These varying environmental factors across age groups can offer valuable insights into the epidemiology and clinical characteristics of pediatric nasal bone fractures.

Comparison of 3D airway models for the assessment of fibrogenic chemicals.

Lung epithelial cells and fibroblasts play key roles in pulmonary fibrosis and are involved in fibrotic signaling and production of the extracellular matrix (ECM), respectively. Recently, 3D airway models consisting of both cell types have been developed to evaluate the fibrotic responses while facilitating cell-cell crosstalk. This study aimed to evaluate the fibrotic responses in these models using different fibrogenic agents, which are known as key events in adverse outcome pathways of pulmonary fibrosis. We quantified cell injury and several sequential steps in fibrogenesis, including inflammation, the epithelial-mesenchymal transition (EMT), fibroblast activation, and ECM accumulation, using two different 3D airway models, the EpiAirway™-full thickness (Epi/FT) and MucilAir™-human fibroblast (Mucil/HF) models. In the Epi/FT model, fibrogenic agents induced the expression of inflammation and EMT-associated markers, while in the Mucil/HF model, they induced fibroblast activation and ECM accumulation. Using this information, we conducted gene ontology term network analysis. In the Epi/FT model, the terms associated with cell migration and response to stimulus made up a large part of the network. In the Mucil/HF model, the terms associated with ECM organization and cell differentiation and proliferation constituted a great part of the network. Collectively, our data suggest that polyhexamethyleneguanidine phosphate and bleomycin induce different responses in the two 3D airway models. While Epi/FT was associated with inflammatory/EMT-associated responses, Mucil/HF was associated with fibroblast-associated responses. This study will provide an important basis for selecting proper 3D airway models and fibrogenic agents to further research or screen chemicals causing inhalation toxicity.

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells.

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/ß-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/ß-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women worldwide, with an overall 5 year survival rate below 30%. The low survival rate is associated with the persistence of cancer stem cells (CSCs) after chemotherapy. Therefore, CSC-targeting strategies are required for successful EOC treatment. Pan-human epidermal growth factor receptor 4 (HER4) and L-type calcium channels are highly expressed in ovarian CSCs, and treatment with the pan-HER inhibitor poziotinib or calcium channel blockers (CCBs) selectively inhibits the growth of ovarian CSCs via distinct molecular mechanisms. In this study, we tested the hypothesis that combination treatment with poziotinib and CCBs can synergistically inhibit the growth of ovarian CSCs. Combined treatment with poziotinib and manidipine (an L-type CCB) synergistically suppressed ovarian CSC sphere formation and viability compared with either drug alone. Moreover, combination treatment synergistically reduced the expression of stemness markers, including CD133, KLF4, and NANOG, and stemness-related signaling molecules, such as phospho-STAT5, phospho-AKT, phospho-ERK, and Wnt/ß-catenin. Moreover, poziotinib with manidipine dramatically induced apoptosis in ovarian CSCs. Our results suggest that the combinatorial use of poziotinib with a CCB can effectively inhibit ovarian CSC survival and function.

Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells.

Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.

Poziotinib suppresses ovarian cancer stem cell growth via inhibition of HER4-mediated STAT5 pathway.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with an overall 5-year survival rate of only 30%. EOC is associated with drug resistance, frequent recurrence, and poor prognosis. A major contributor toward drug resistance might be cancer stem cells (CSCs), which may remain after chemotherapy. Here, we aimed to find therapeutic agents that target ovarian CSCs. We performed a high-throughput screening using the Clinical Compound Library with a sphere culture of A2780 EOCs. Poziotinib, a pan-human epidermal growth factor receptor (HER) inhibitor, decreased sphere formation, viability, and proliferation, and induced G1 cell cycle arrest and apoptosis in ovarian CSCs. In addition, poziotinib suppressed stemness and disrupted downstream signaling of Wnt/ß-catenin, Notch, and Hedgehog pathways, which contribute to many characteristics of CSCs. Interestingly, HER4 was overexpressed in ovarian CSCs and Poziotinib reduced the phosphorylation of STAT5, AKT, and ERK, which are regulated by HER4. Our results suggest that HER4 may be a promising therapeutic target for ovarian CSCs, and that poziotinib may be an effective therapeutic option for the prevention of ovarian cancer recurrence.

Discovery of a novel potent peptide agonist to adiponectin receptor 1.

Activation of adiponectin receptors (AdipoRs) by its natural ligand, adiponectin has been known to be involved in modulating critical metabolic processes such as glucose metabolism and fatty acid oxidation as demonstrated by a number of in vitro and in vivo studies over last two decades. These findings suggest that AdipoRs' agonists could be developed into a potential therapeutic agent for metabolic diseases, such as diabetes mellitus, especially for type II diabetes, a long-term metabolic disorder characterized by high blood sugar, insulin resistance, and relative lack of insulin. Because of limitations in production of biologically active adiponectin, adiponectin-mimetic AdipoRs' agonists have been suggested as alternative ways to expand the opportunity to develop anti-diabetic agents. Based on crystal structure of AdipoR1, we designed AdipoR1's peptide agonists using protein-peptide docking simulation and screened their receptor binding abilities and biological functions via surface plasmon resonance (SPR) and biological analysis. Three candidate peptides, BHD1028, BHD43, and BHD44 were selected and confirmed to activate AdipoR1-mediated signal pathways. In order to enhance the stability and solubility of peptide agonists, candidate peptides were PEGylated. PEGylated BHD1028 exhibited its biological activity at nano-molar concentration and could be a potential therapeutic agent for the treatment of diabetes. Also, SPR and virtual screening techniques utilized in this study may potentially be applied to other peptide-drug screening processes against membrane receptor proteins.

Targeting ligand-receptor interactions for development of cancer therapeutics.

The biological importance and druggable properties of receptors and their cognate ligands have designated them as especially useful clinical targets. This significance continues to expand as new molecular insights underlying disease pathophysiology are uncovered. While both ligands and receptors have been exploited as drug targets, their differing biochemical properties require nuanced considerations for drug development, including where in the body they are located and how they are regulated on a cellular and molecular level. In this review we will discuss ligands and receptors as therapeutics targets, including their biodistribution and biological function. We provide examples of monoclonal antibodies (mAbs) used to modulate the activity of these targets, and discuss approaches for using engineered versions of ligands and receptors themselves for therapeutic intervention in cancer.

Bimetallic Nickel/Ruthenium Catalysts Synthesized by Atomic Layer Deposition for Low-Temperature Direct Methanol Solid Oxide Fuel Cells.

Nickel and ruthenium bimetallic catalysts were heterogeneously synthesized via atomic layer deposition (ALD) for use as the anode of direct methanol solid oxide fuel cells (DMSOFCs) operating in a low-temperature range. The presence of highly dispersed ALD Ru islands over a porous Ni mesh was confirmed, and the Ni/ALD Ru anode microstructure was observed. Fuel cell tests were conducted using Ni-only and Ni/ALD Ru anodes with approximately 350 µm thick gadolinium-doped ceria electrolytes and platinum cathodes. The performance of fuel cells was assessed using pure methanol at operating temperatures of 300-400 °C. Micromorphological changes of the anode after cell operation were investigated, and the content of adsorbed carbon on the anode side of the operated samples was measured. The difference in the maximum power density between samples utilizing Ni/ALD Ru and Pt/ALD Ru, the latter being the best catalyst for direct methanol fuel cells, was observed to be less than 7% at 300 °C and 30% at 350 °C. The improved electrochemical activity of the Ni/ALD Ru anode compared to that of the Ni-only anode, along with the reduction of the number of catalytically active sites due to agglomeration of Ni and carbon formation on the Ni surface as compared to Pt, explains this decent performance.

Minimal systems analysis of mitochondria-dependent apoptosis induced by cisplatin.

Recently, it was reported that the role of mitochondria-reactive oxygen species (ROS) generating pathway in cisplatin-induced apoptosis is remarkable. Since a variety of molecules are involved in the pathway, a comprehensive approach to delineate the biological interactions of the molecules is required. However, quantitative modeling of the mitochondria-ROS generating pathway based on experiment and systemic analysis using the model have not been attempted so far. Thus, we conducted experiments to measure the concentration changes of critical molecules associated with mitochondrial apoptosis in both human mesothelioma H2052 and their ρ(0) cells lacking mitochondrial DNA (mtDNA). Based on the experiments, a novel mathematical model that can represent the essential dynamics of the mitochondrial apoptotic pathway induced by cisplatin was developed. The kinetic parameter values of the mathematical model were estimated from the experimental data. Then, we have investigated the dynamical properties of this model and predicted the apoptosis levels for various concentrations of cisplatin beyond the range of experiments. From parametric perturbation analysis, we further found that apoptosis will reach its saturation level beyond a certain critical cisplatin concentration.

Long-term durability of the CLS femoral prosthesis in patients with osteonecrosis of the femoral head.

Ninety-five hips with cementless wedge-shaped tapered CLS stem were evaluated with a mean duration of 12.7 years (range, 10.7-17.3 years). All patients were young and diagnosed with osteonecrosis of the femoral head. The Harris hip score was 92 at the latest follow-up. A subsidence greater than 3mm was found in 3 hips (3.2%). Focal femoral osteolysis was found in 12 hips (12.6%). Endosteal bone formation and bony pedestal were observed in 94 hips (98.9%) and in 26 hips (27.4%), respectively. With revision for stem loosening as the end point, the survivorship showed 98.9% (95% CI, range 96.9%-100%) at 13 years. Stem alignment and proximal femur morphology did not influence loosening of the stem (p>0.05).

Effect of glucose ingestion in plasma markers of inflammation and oxidative stress: analysis of 16 plasma markers from oral glucose tolerance test samples of normal and diabetic patients.

Sixteen plasma markers of inflammation and oxidative stress were measured during OGTT in 54 subjects. Leptin, RBP4, CRP, OPN, ANG, MDC, and MCSF concentrations significantly decreased during OGTT (P<0.05). IL6, IL8, and MCP3 concentrations significantly increased during OGTT (P<0.05). These results provide evidence that glucose ingestion affects systemic inflammation and oxidative stress.

MicroRNAs in human lymphoblastoid cell lines.

Human lymphoblastoid cell lines (LCLs) are generated by EBV-mediated B-cell transformation to provide unlimited genomic resources for human genetics and immunological studies. The LCL is a good in vitro cell model for assessing population differences in the basal expression of genes and miRNAs as well as in cellular responses to various stimulators. Recently, the utility of LCLs was extended to pharmacogenomic studies to discover genetic factors underlying individual variations in response to chemicals and environmental stresses. Although LCLs represent generally lymphoid tissue-specific biological characteristics, genomic signatures of LCLs can distinguish patients with brain-related diseases and nonlymphoid tumors from normal controls. MicroRNA is known to be an epigenetic transcriptional regulator, and its expression is induced in abnormal conditions such as perturbagen-stimulated, virus-infected, or cancer cells. The epigenetic regulation of gene expression mediated by microRNA and DNA methylation is important for understanding the pathogenesis of cancers and complex diseases as well as discovering for therapeutic targets. For integrative genomic analyses, LCLs can be utilized to generate cellular phenotypes and various genomic data (e.g., SNP, CNV, transcriptome, methylome, etc.), which can be linked to clinical information of donors. Here, we discuss miRNA-mediated gene expression in LCLs and its application to disease genomics and global transcriptional regulatory machinery studies.

Computational modeling of apoptotic signaling pathways induced by cisplatin.

BACKGROUND: Apoptosis is an essential property of all higher organisms that involves extremely complex signaling pathways. Mathematical modeling provides a rigorous integrative approach for analyzing and understanding such intricate biological systems. RESULTS: Here, we constructed a large-scale, literature-based model of apoptosis pathways responding to an external stimulus, cisplatin. Our model includes the key elements of three apoptotic pathways induced by cisplatin: death receptor-mediated, mitochondrial, and endoplasmic reticulum-stress pathways. We showed that cisplatin-induced apoptosis had dose- and time-dependent characteristics, and the level of apoptosis was saturated at higher concentrations of cisplatin. Simulated results demonstrated that the effect of the mitochondrial pathway on apoptosis was the strongest of the three pathways. The cross-talk effect among pathways accounted for approximately 25% of the total apoptosis level. CONCLUSIONS: Using this model, we revealed a novel mechanism by which cisplatin induces dose-dependent cell death. Our finding that the level of apoptosis was affected by not only cisplatin concentration, but also by cross talk among pathways provides in silico evidence for a functional impact of system-level characteristics of signaling pathways on apoptosis.

A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study.

INTRODUCTION: Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent. METHODS: To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls. RESULTS: In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14). CONCLUSIONS: This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.