Enhancing anti-cancer capacity: Novel class I/II HDAC inhibitors modulate EMT, cell cycle, and apoptosis pathways.

Cancer has been a leading cause of death over the last few decades in western countries as well as in Taiwan. However, traditional therapies are limited by the adverse effects of chemotherapy and radiotherapy, and tumor recurrence may occur. Therefore, it is critical to develop novel therapeutic drugs. In the field of HDAC inhibitor development, apart from the hydroxamic acid moiety, 2-aminobenzamide also functions as a zinc-binding domain, which is shown in well-known HDAC inhibitors such as Entinostat and Chidamide. With recent successful experiences in synthesizing 1-(phenylsulfonyl)indole-based compounds, in this study, we further combined two features of the above chemical compounds and generated indolyl benzamides. Compounds were screened in different cancer cell lines, and enzyme activity was examined to demonstrate their potential for anti-HDAC activity. Various biological functional assays evidenced that two of these compounds could suppress cancer growth and migration capacity, through regulating epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis mechanisms. Data from 3D cancer cells and the in vivo zebrafish model suggested the potential of these compounds in cancer therapy in the future.

Environment-friendly organic coordination design of Z-scheme heterojunction N-BOB/BiOIO3 for efficient LED-light-driven photocatalytic and electrochemical performance.

As the climate seriously changes, ecofriendly nanomaterials have attracted tremendous interest in renewable energy as photocatalysis. Herein, we designed a new green bismuth-based Z-scheme Bi2O22+ slabs coordinate with 2-aminoterephthalic acid (N-BOB)/BiOIO3 through a simple anion exchange and postsynthetic hydrothermal reaction. FTIR, XRD, FESEM and TEM were employed to characterize the functional groups, structure, and morphologies. UV-DRS revealed the difference in band energy of the N-BOB and N-BOB/BiOIO3. Toward Rh B, TC and CIP degradation tests, 1-N-BOB/BiOIO3 manifests the best photocatalytic degradation (52.3%, 63.6% and 30.2%) efficiency. Also, 1-N-BOB/BiOIO3 possesses high durability in photocatalytic reactions and can inhibit 32.3% of bacterial growth. The results indicate that the synergistic effect between surface amine groups and Z-scheme heterojunction harvests light absorption to increase solar-to-energy (STE) efficiency, accelerate the charge separation, and increases the active sites with high photoredox potential, thus improving the photocatalytic performance. ROS scavenging tests further elucidated that photogenerated holes and hydroxyl radicals play a critical role. In addition, the surface amine groups and benzene rings can be utilized for supercapacitors and other multidisciplinary applications. 0.5 N-BOB/BiOIO3/GO impressively showed 5 times higher specific capacitance than pure GO electrode. We hope this work provides new sight into designing green nanomaterials to relieve environmental pollution and leave behind a clean future for the next generation.

Mitochondrial Factor C20orf7 Facilitates the EMT-Mediated Cancer Cell Migration and the Proliferation of Colon Cancer In Vitro and In Vivo.

Colon cancer is a major malignant neoplasm with a low survival rate for late-stage patients. Therefore, the investigation of molecules regulating colon cancer progression and the discovery of novel therapeutic targets is critical. Mitochondria play a vital role in maintaining the homeostasis of cells. Abnormal mitochondrial metabolism alterations and the induction of glycolysis can facilitate tumor growth; therefore, targeting mitochondrial molecules is suggested to be a promising strategy for cancer treatment. In this study, we investigated the role of this largely unknown mitochondrial factor, chromosome 20 open reading frame 7 (C20orf7), in colon cancer progression. Clustered regularly interspaced short palindromic repeats (CRISPR) technology was utilized for C20orf7 depletion, and functional assays were performed to examine the regulation of C20orf7 in colon cancer cells. We demonstrated that C20orf7 facilitates epithelial-mesenchymal transition (EMT)-mediated cell migration and promotes the proliferation of colon cancer. The anti-cancer drug 5-fluorouracil (5FU) was also applied, and C20orf7 was targeted with a combination of 5FU treatment, which could further enhance the anti-cancer effect in the colon cancer cell line and the xenograft mice model. In summary, this study demonstrated, for the first time, that C20orf7 plays a promotional role in cancer tumorigenesis and could be a promising therapeutic target in colon cancer treatment.

Preparation of Ni(OH)2/CuO heterostructures for improved photocatalytic degradation of organic pollutants and microorganism.

In this study, the Ni(OH)2/CuO heterostructured photocatalysts have been prepared via microwave (MW) hydrothermal method. The results indicate that the Ni(OH)2/CuO heterostructured composite exhibits a strong absorption in the UV and Vis regions. The construction of the heterojunction also improves the photogenerated carrier transport and inhibits the electron-hole separation due to the enhanced absorbance and the well alignment of the energy band at the Ni(OH)2/CuO interface. The photocatalytic capability of the heterostructured composites with different Ni(OH)2/CuO molar ratios is evaluated by the photodegradation of methylene blue under visible light illumination. The results reveal that the Ni(OH)2/CuO (1:1) heterostructures show the best photocatalytic efficiency, which is 2.18 and 6.13 times higher than that of pure Ni(OH)2 and CuO, respectively. Besides, the Ni(OH)2/CuO composites also reveal remarkable biocompatibility and strong photocatalytic activity in the degradation of antibiotics such as ciprofloxacin (CIP) and tetracycline (TC) and inactivation of Escherichia coli (E. coli).

Bio-Phenolic Resin Derived Porous Carbon Materials for High-Performance Lithium-Ion Capacitor.

In this article, hierarchical porous carbon (HPC) with high surface area of 1604.9 m2/g is prepared by the pyrolysis of rubberwood sawdust using CaCO3 as a hard template. The bio-oil pyrolyzed from the rubber sawdust, followed by the polymerization reaction to form resole phenolic resin, can be used as a carbon source to prepare HPC. The biomass-derived HPC shows a three-dimensionally interconnected morphology which can offer a continuous pathway for ionic transport. The symmetrical supercapacitors based on the as-prepared HPC were tested in 1.0 M tetraethylammonium tetrafluoroborate/propylene carbonate electrolyte. The results of electrochemical analysis show that the HPC-based supercapacitor exhibits a high specific capacitance of 113.3 F/g at 0.5 A/g with superior rate capability and cycling stability up to 5000 cycles. Hybrid lithium-ion capacitors (LICs) based on the HPC and Li4Ti5O12 (LTO) were also fabricated. The LICs have a maximum energy density of 113.3 Wh/kg at a power density of 281 W/kg. Moreover, the LIC also displays a remarkable cycling performance with a retention of 92.8% after 3000 cycles at a large current density of 0.75 A/g, suggesting great potential application in the energy storage of the LIC.

Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors.

Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.

A novel HDAC1/2 inhibitor suppresses colorectal cancer through apoptosis induction and cell cycle regulation.

Colorectal cancer (CRC) is one of the leading causes of death around the world, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as histone deacetylases (HADC) inhibitors, are under intensively studied. The target of HDAC involves in regulating critical cellular mechanisms and underpins the progression of anticancer therapy. However, little is known about the antitumor mechanisms of class I specific HDAC inhibitors in CRC. We structurally designed and synthesized benzamide-based compounds, examined their anticancer activity in several solid tumors, and identified compound 9 with high potential. Results from the in vitro enzyme and cell-based studies demonstrated that compound 9 as a selective HDAC1/2 inhibitor that possessed short-term and long-term suppression capacities against colorectal cancer cells. Investigation of molecular regulatory mechanisms of 9 in colorectal cancer cells by biological functional assays evidenced that treatment of compound 9 could activate apoptosis, induce cell cycle arrest, facilitate DNA damage process, and suppress cancer migration. A non-cancerous cell line and the in vivo zebrafish model were applied for safety evaluation. In summary, our results demonstrate that compound 9 is a promising lead drug worth further investigation for development of future cancer therapeutic agents.

Versatile Functionalization of P25 Conjugated ND Nanocomposites for UV-Mediated Free Radical Scavenging and Facilitates Anti-Inflammation Potential in Human Cells.

In this work, we demonstrated that building different linking groups between nanodiamond (ND) and TiO2 (P25) could provide more effective protection under oxidative stress and ultraviolet (UV) light irradiation compared with the use of TiO2 alone. The establishment of ester (-C-O-O-R), amide (-CONH-), and epoxide-amine adduct (-NHCCO-) groups between ND-TiO2 composites was found to be critical in the generation of reactive oxygen species (ROS) by controlling their charge transfer behaviors. We hypothesized that linking groups between the composites dictate the performance of ROS generation from nano-TiO2 under UV-light irradiation due to the differences in linking groups. The results showed that hydroxyl radicals were attenuated by the incorporation of ND. An MTT cell proliferation assay was performed in human cells under the treatment of ND-TiO2 composites to investigate the impacts of composites on cell viability. The results from the luciferase reporter assay suggested they have anti-inflammatory activity and can reduce cellular DNA damage under ROS stimulation. A zebrafish model was also applied with the ND-TiO2 composite treatment to demonstrate the safety aspects of the composites in vivo and their biomedical application potential. Studies exploring ROS generation behaviors in different linking groups suggested that interactive functionalization between nanoparticles might be an ideal antioxidant and anti-inflammatory strategy.

Multiple myeloma driving factor WHSC1 is a transcription target of oncogene HMGA2 that facilitates colon cancer proliferation and metastasis.

Colon cancer is a common human cancer worldwide. The survival rate of late staged or metastatic colon cancer patients remains low even though the effectiveness of treatment in colon cancer has greatly improved. Research on tumorigenesis mechanisms and discovery of novel molecular target for treating colon cancer is critical. The promotion roles of WHSC1 in multiple myeloma have been demonstrated previously, yet, the regulation of WHSC1 in other cancers is largely unknown, especially in colon cancer. Here, in this study, we analyzed and identified WHSC1 while studying the genetic regulations of HMGA2 in colon cancer cells by microarray analysis, and investigated the HMGA2-WHSC1 interaction. We then applied CRISPR technology to establish stable WHSC1 knockout cells, to address the functional regulation of WHSC1 in colon cancer. In summary, our results for the first time identified the HMGA2-WHSC1 interaction in colon cancer. Moreover, we discovered that WHSC1 promotes cancer proliferation, facilitates resistance of chemotherapy agent, and promotes metastatic capacity of colon cancer.

Ring size changes in the development of class I HDAC inhibitors.

Five pathways involving different ring structures led to generation of fourteen thienylbenzamides (7-20) which display the structure-activity relationships of class I HDAC inhibitors. All the synthesised compounds inhibit HDAC1 and HDAC2 selectively over other isoforms and many inhibit DLD1 and HCT116 cells more effectively than a parent compound. Compounds 8 and 16 inhibit HCT116 cells by activation of the apoptosis pathway.

Co2+-Doped BiOBrxCl1-x hierarchical microspheres display enhanced visible-light photocatalytic performance in the degradation of rhodamine B and antibiotics and the inactivation of E. coli.

In this article, we have synthesized Co2+-doped BiOBrxCl1-x hierarchical nanostructured microspheres, featuring different degrees of Co2+ doping, displaying excellent photocatalytic performance. X-ray diffraction and Raman spectroscopy indicated that the Co2+ ions were successfully doped into the BiOBrxCl1-x nanocrystals. The photodegradation rate of rhodamine B mediated by a doped BiOBrxCl1-x was 150 % greater than that of the non-doped BiOBr. We ascribe the improved photocatalytic capability of the Co2+-doped BiOBrxCl1-x to a combination of its superior degree of light absorption, more efficient carrier separation, and faster interfacial charge migration. The major active species involved in the photodegradation of RhB also has been investigated. Moreover, the doped BiOBrxCl1-x possessed excellent cellular biocompatibility and displayed remarkable performance in the photocatalytic bacterial inactivation.

Simultaneous formation of Bi2O2(OH)(NO3)/BiOBr ultrathin hierarchical microspheres for effectively promoting visible-light-driven photocatalytic activity in environmental remediation.

As a two-dimensional nanomaterial, bismuth oxybromide (BiOBr) have attracted tremendous interest in the area of visible-light photocatalysis since it can provide the internal electric field (IEF) through z-axis through its unique electronic band structure. However, the insufficient active sites and rapid recombination rate of charged carriers hamper the efficiency of the photocatalysis. To address these two major obstacles, an enticing strategy of constructing heterojunction was established by introducing Bi2O2(OH)(NO3) (BiON) in BiOBr with the same precursor. Through a facile one-pot hydrothermal synthesis, two Sillén-type layered photocatalysts, with intimately constructed ultrathin heterostructure, was synthesized by the co-precipitation method. In this work, the formation of Bismuth-based heterojunction for charge separation is established by the excessive bismuth nitrate, which subsequently participates with the in situ growth of ultrathin hierarchical microspheres. By attenuating the thickness of BiOBr from 20 nm to 8 nm with the aid of BiON, the photogenerated charges could migrate to the active sites through shorter charge diffusion pathway. Also, the BiOBr and BiON act as an active bridge to promote the separation of electron-hole pairs, which also brings out more active sites due to its increased specific surface area. BiON/BiOBr ultrathin hierarchical microspheres exhibited enhanced visible-light photocatalytic activity for decontaminating several types of pollutants. Besides, the activity of as-prepared BiON/BiOBr was further evaluated by inhibiting the growth of kanamycin-resistant bacteria strains. This study presents a novel strategy to incorporate the crystalline bismuth hydrate nitrate into BiOBr to form ultrathin hierarchical microspheres with high surface area for environmental remediation.

Intercalating pyrene with polypeptide as a novel self-assembly nano-carrier for colon cancer suppression in vitro and in vivo.

Giving patients right dosage is an essential concept of precision medicine. Most of nanocarriers lack of flexible drug capacity and structural stability to be customized for specific treatment, resulting in low therapeutic efficacy and unexpected side effects. Thus, a growing need emerges for fast and rigorous approaches to develop nanoparticles with properties of adjustable dosage and controllable particle size. Poly-l-Lysine is known for its enhanced bioadhesivity and pH-triggered structural swelling effect, which is utilized as the main agent to activate the multistage drug releasing. Inspired by natural bio-assembly system, we report a simple method to self-assemble Poly-l-Lysine-based nanoparticles via supramolecular recognitions of cross-linked pyrenes, which provides noncovalent force to flexibly encapsulate Doxorubincin and to construct robust nanostructures. Pyrene-modified polypeptide self-assemblies are able to adjust drug payload from 1: 10 to 2:1 (drug: polypeptide) without changing its uniform nano-spherical morphology. This nanostructure remained the as-made morphology even after experiencing the long-term (~ 10 weeks) storage at room temperature. Also, the nanoparticles displayed multi-step drug release behaviours and exhibited great in vitro and in vivo cytotoxicity towards colon cancer cells. The as-mentioned nanoparticles provide a novel perspective to compensate the clinical needs of specific drug feedings and scalable synthesis with advantages of simple-synthesis, size-adaptivity, and morphology reversibility.

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan.

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

Dicoumarol suppresses HMGA2-mediated oncogenic capacities and inhibits cell proliferation by inducing apoptosis in colon cancer.

Colon cancer is one of the leading causes of cancer-related deaths and its five-year survival rate remains low in locally advanced or metastatic stages of colon cancer. Overexpression of high mobility group protein AT-hook2 (HMGA2) is associated with cancer progression, metastasis, and poor prognosis in many malignancies. Oxidative stress regulates cellular mechanisms and provides an environment that favors the cancer cells to survive and progress, yet, at the same time, oxidative stress can also be utilized as a cancer-damaging strategy. The molecular regulatory roles of HMGA2 in oxidative stress and their involvement in cancer progression are largely unknown. In this study, we investigated the involvement of HMGA2 in regulation of oxidative stress responses by luciferase reporter assays. Moreover, we utilized dicoumarol (DIC), a derivative of coumarin which has been suggested to be involved in oxidation regulation with anticancer effects, and demonstrated that DIC could induce apoptosis and inhibit cell migration of HMGA2 overexpressing colon cancer cells. Further investigation also evidenced that DIC can enhance the cancer inhibition effect of 5-FU in colony formation assays. Taken together, our data revealed novel insights into the molecular mechanisms underlying HMGA2 and highlighted the possibility of targeting the cellular antioxidant system for treating patients and preventing from cancer progression in HMGA2 overexpressing colon cancer cells.

GFP Plasmid and Chemoreagent Conjugated with Graphene Quantum Dots as a Novel Gene Delivery Platform for Colon Cancer Inhibition In Vitro and In Vivo.

Scientists have studied intensively the gene delivery carriers for treating genetic diseases. However, there are challenges that impede the application of naked gene-based therapy at the clinical level, such as quick elimination of the circulation, lack of membrane penetrability, and poor endosome trapping. Herein, we develop graphene quantum dots (GQDs)-derivative nanocarriers and introduce polyethylenimine (PEI) to equip the system with enhanced biocompatibility and abundant functional groups for modification. In addition to carrying green fluorescent protein (GFP) as an example of gene delivery, this system covalently binds colon cancer cells targeted antibody and epidermal growth factor receptor (EGFR) to enhance cell membrane penetrability and cell uptake of nanocarriers. To achieve multistrategy cancer therapy, the anticancer drug doxorubicin (Dox) is noncovalently encapsulated to achieve pH-induced drug release at tumor sites and leaves space for further functional gene modification. This nanoparticle serves as a multifunctional gene delivery system, which facilitates improved cytotoxicity and longer-sustained inhibition capacity compared to free Dox treatments in colon cancer cells. Moreover, our GQD composites display compatible tumor suppression ability compared with the free Dox treatment group in xenograft mice experiment with significantly less toxicity. This GQD nanoplatform was demonstrated as a multifunctional gene delivery system that could contribute to treating other genetic diseases in the future.

Doxorubicin conjugated AuNP/biopolymer composites facilitate cell cycle regulation and exhibit superior tumor suppression potential in KRAS mutant colorectal cancer.

Colorectal cancer is a leading cause of death in the world. Despite the progress in therapeutic development, there are still challenges in clinical practice. Nanomedicine has emerged as a solution to enhance traditional therapy. Gold nanoparticles (AuNP) have been demonstrated as potential appliance in treating cancers, yet few studies investigated the capacity of biopolymer-conjugated AuNP in colon cancer as well as examined the system in both cancer cell line and animal models. In this study, we designed the AuNP/biopolymer composite therapeutic system with a chemotherapy agent, doxorubicin (DOX). Two composites with different drug load were applied (referred to as AuPPPyA and AuPPPyB). The composites were characterized by UV spectrum, transmission electron microscope (TEM), zeta potential measurement, and cell cycle analysis. Both therapeutic systems exhibited superior cytotoxic effects compared to DOX alone group. Compatible results were also demonstrated in vivo, as tumor inhibition rate were 46.2% in AuPPPyA and 66.4% in AuPPPyB, which were both higher than that of DOX alone (30%). Cell cycle regulation mediated by our composites was also examined in our study. In conclusion, our data demonstrated that AuNP/biopolymer composites are powerful in treating KRAS gene mutated colorectal cancer, and the system could potentially contribute to other clinical refractory diseases in the future.

NO2 functionalized coumarin derivatives suppress cancer progression and facilitate apoptotic cell death in KRAS mutant colon cancer.

Colon cancer is one of the most lethal cancers worldwide even with the significant progress made in screening techniques and therapeutic agents. Genetic mutations in tumors complicated the treatments, and the survival rate remains low for patients at late or metastatic stages. KRAS gene mutation which leads to failure of the EGFR targeted therapies stands for an example of the challenges in clinical sites. Therefore, development of novel agents for colon cancer treatment is in need. Natural and synthetic coumarin derivatives have been suggested with various biological activities with pharmacologic potential including anti-cancer capacity. Here in this study, five coumarin derivatives, include trifluoromethyl-, dimethoxy-, and/or nitro-substitutions at different positions, were synthesized. Their cancer inhibition potential was investigated in various cancer cell lines. Our data demonstrated that one nitro-coumarin derivate, 5,7-Dimethoxy-4-methyl-6-nitro-chromen-2-one, exhibits cytotoxicity specifically towards colon cancer cells under competitive EC50. Our results showed that this compound can effectively suppress colon cancer cells harboring either wild type or mutant KRAS genes, and that it could inhibit short-term proliferation, long term proliferation, and migration capacities of cancer cells. Finally, we demonstrated that this coumarin derivate facilitates cancer cell death through activation of apoptosis pathway. Our results suggest that this coumarin derivate is a promising lead drug worth further investigation and development for future cancer treatment.

Carboxylated carbon nanomaterials in cell cycle and apoptotic cell death regulation.

Carbon nanomaterials, include carbon nanotubes and graphene nanosheets, have drawn an increasing amount of attention because of their potential applications in daily life or in providing novel therapeutic possibilities for treating diseases. However, the overall biocompatibility, the potential toxic effects of carbon nanomaterials toward human cells, and their modulations in cellular mechanism, are not fully understood. Herein, four types of carbon nanomaterials, include long and short carbon nanotubes and graphene nanosheets, at low and high concentrations, were functionalized and dispersed in the biocompatible buffer for assessment. The surface structure, the morphology, and chemical composition of carbon nanomaterials were characterized. Also, biological assays investigating cellular viability, vitality, cell cycle, and apoptotic cell death were applied on cells co-incubated with nanomaterials, to evaluate the biocompatibility of these nanomaterials in human cells. Our data suggested that even though co-incubation of nanomaterials did not seem to affect the viability of cells notably, high concentrations (50 ug/ml) of SW could lead to unhealthy cells, and we observed dramatic G2 arrest effect mediated by p21 induction in high SW incubated cells. Other nanomaterials at high concentration may also alter cell cycle profile of the cells. In summary, our data demonstrated that these nanomaterials could regulate cell cycle and lead to apoptosis at high concentrations, and the underling molecular mechanisms have been addressed. Caution should be taken on their concentration when nanomaterials are in used in future medical applications.

Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus.

The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of BMD and may be used to predict the risk of osteoporotic fracture. We conducted a genomewide association study (GWAS) for SI using 7742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted a meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci: 7q31.31, 17p13.3, and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank estimated BMD GWAS; these three cytobands were replicated successfully after a meta-analysis with a Korean population cohort as well. However, two SNPs were not replicated. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs and two novel SI-related genes. Overall, these results provide further insight into the genetic architecture of osteoporosis. Further studies in larger East Asian populations are needed. © 2019 American Society for Bone and Mineral Research.