Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Patient-Derived Organoids Recapitulate Pathological Intrinsic and Phenotypic Features of Fibrous Dysplasia.

Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Initially, transcriptomic profiling of individual cells isolated from patient lesional tissues unveiled intralesional molecular and cellular heterogeneity. Leveraging these insights, we established patient-derived organoids (PDOs) using primary cells obtained from patient FD lesions. Evaluation of PDOs demonstrated preservation of fibrosis-associated constituent cell types and transcriptional signatures observed in FD lesions. Additionally, PDOs retained distinct constellations of genomic and metabolic alterations characteristic of FD. Histological evaluation further corroborated the fidelity of PDOs in recapitulating important phenotypic features of FD that underscore their pathophysiological relevance. Our findings represent meaningful progress in the field, as they open up the possibility for in vitro modeling of rare bone lesions in a three-dimensional context and may signify the first step towards creating a personalized platform for research and therapeutic studies.

High-Performance Memristive Synapse Composed of Ferroelectric ZnVO-Based Schottky Junction.

In pursuit of realizing neuromorphic computing devices, we demonstrated the high-performance synaptic functions on the top-to-bottom Au/ZnVO/Pt two-terminal ferroelectric Schottky junction (FSJ) device architecture. The active layer of ZnVO exhibited the ferroelectric characteristics because of the broken lattice-translational symmetry, arising from the incorporation of smaller V5+ ions into smaller Zn2+ host lattice sites. The fabricated FSJ devices displayed an asymmetric hysteresis behavior attributed to the ferroelectric polarization-dependent Schottky field-emission rate difference in between positive and negative bias voltage regions. Additionally, it was observed that the magnitude of the on-state current could be systematically controlled by changing either the amplitude or the width of the applied voltage pulses. Owing to these voltage pulse-tunable multi-state memory characteristics, the device revealed diverse synaptic functions such as short-term memory, dynamic range-tunable long-term memory, and versatile rules in spike time-dependent synaptic plasticity. For the pattern-recognition simulation, furthermore, more than 95% accuracy was recorded when using the optimized experimental device parameters. These findings suggest the ZnVO-based FSJ device holds significant promise for application in next-generation brain-inspired neuromorphic computing systems.

Comprehensive RNA-sequencing analysis of colorectal cancer in a Korean cohort.

Considering the recent increase in the number of colorectal cancer (CRC) cases in South Korea, we aimed to clarify the molecular characteristics of CRC unique to the Korean population. To gain insights into the complexities of CRC and promote the exchange of critical data, RNA-sequencing analysis was performed to reveal the molecular mechanisms that drive the development and progression of CRC; this analysis is critical for developing effective treatment strategies. We performed RNA-sequencing analysis of CRC and adjacent normal tissue samples from 214 Korean participants (comprising a total of 381 including 169 normal and 212 tumor samples) to investigate differential gene expression between the groups. We identified 19,575 genes expressed in CRC and normal tissues, with 3,830 differentially expressed genes (DEGs) between the groups. Functional annotation analysis revealed that the upregulated DEGs were significantly enriched in pathways related to the cell cycle, DNA replication, and IL-17, whereas the downregulated DEGs were enriched in metabolic pathways. We also analyzed the relationship between clinical information and subtypes using the Consensus Molecular Subtype (CMS) classification. Furthermore, we compared groups clustered within our dataset to CMS groups and performed additional analysis of the methylation data between DEGs and CMS groups to provide comprehensive biological insights from various perspectives. Our study provides valuable insights into the molecular mechanisms underlying CRC in Korean patients and serves as a platform for identifying potential target genes for this disease. The raw data and processed results have been deposited in a public repository for further analysis and exploration.

Exploring the DNA methylome of Korean patients with colorectal cancer consolidates the clinical implications of cancer-associated methylation markers.

Aberrant DNA methylation plays a critical role in the development and progression of colorectal cancer (CRC), which has high incidence and mortality rates in Korea. Various CRC-associated methylation markers for cancer diagnosis and prognosis have been developed; however, they have not been validated for Korean patients owing to the lack of comprehensive clinical and methylome data. Here, we obtained reliable methylation profiles for 228 tumor, 103 adjacent normal, and two unmatched normal colon tissues from Korean patients with CRC using an Illumina Infinium EPIC array; the data were corrected for biological and experiment biases. A comparative methylome analysis confirmed the previous findings that hypermethylated positions in the tumor were highly enriched in CpG island and promoter, 5' untranslated, and first exon regions. However, hypomethylated positions were enriched in the open-sea regions considerably distant from CpG islands. After applying a CpG island methylator phenotype (CIMP) to the methylome data of tumor samples to stratify the CRC patients, we consolidated the previously established clinicopathological findings that the tumors with high CIMP signatures were significantly enriched in the right colon. The results showed a higher prevalence of microsatellite instability status and MLH1 methylation in tumors with high CMP signatures than in those with low or non-CIMP signatures. Therefore, our methylome analysis and dataset provide insights into applying CRC-associated methylation markers for Korean patients regarding cancer diagnosis and prognosis. [BMB Reports 2024; 57(3): 161-166].

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma.

PURPOSE: Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non-small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples. MATERIALS AND METHODS: A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed. RESULTS: TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs. CONCLUSION: Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.

Exploring quantitative traits-associated copy number deletions through reanalysis of UK10K consortium whole genome sequencing cohorts.

OBJECTIVES: We performed comprehensive association analyses of common high-confidence gnomAD-reported copy number deletions (CNDs) with 60 quantitative traits from UK10K consortium WGS data. METHODS: The study made use of data generated by the UK10K Consortium. UK10K consortium WGS data consist of TwinsUK (n = 1754, middle-aged females) and ALSPAC (n = 1867, birth to adolescence) cohorts. UK10K consortium called 18,739 CNDs (hg19) with GenomeSTRiP software. After filtering out variants with minor allele frequency < 0.05 or HWE P < 1.0 × 10- 6, 1222 (TwinsUK) and 1211 (ALSPAC) CNDs remained for association analyses with 60 normalized quantitative traits. RESULTS: We identified 23 genome-wide significant associations at 13 loci, among which 2 associations reached experiment-wide significance. We found that two common deletions in chromosome 4, located between WDR1 and ZNF518B (23.3 kb, dbVar ID:nssv15888957, 4:10211262-10,234,569 and 9.8 kb, dbVar ID:nssv15888975, 4:10392422-10,402,191), were associated with uric acid levels (P = 5.23 × 10- 11 and 2.29 × 10- 8, respectively). We also discovered a novel deletion spanning chromosome 18 (823 bp, dbVar ID: nssv15841628, 8:74347187-74,348,010) associated with low HDL cholesterol levels (P = 4.15 × 10- 7). Additionally, we observed two red blood cell traits-associated loci with genome-wide significance, a 13.2 kb deletion in 7q22.1 (nssv15922542) and a 3.7 kb deletion in 12q24.12 (nssv15813226), both of which were located in regions previously reported to be associated with red blood cell traits. Two deletions in 11q11 (nssv15803200 and nssv15802240), where clusters of multiple olfactory receptor genes exist, and a deletion (nssv15929560) upstream to DOCK5 were associated with childhood obesity. Finally, when defining Trait-Associated copy number Deletions (TADs) as CNDs with phenotype associations at sub-threshold significance (P < 10- 3), we identified 157 (97.5%) out of 161 TADs in non-coding regions, with a mean size of 4 kb (range: 209 - 47,942 bp). CONCLUSION: We conducted a reanalysis of the UK10K Whole Genome Sequencing cohort, which led to the identification of multiple high confidence copy number deletions associated with quantitative traits. These deletions have standard dbVar IDs and replicate previous findings, as well as reveal novel loci that require further replication studies.

Metal-free electrocatalytic nanocomposites of poly azovan blue-decorated graphitic carbon nitride for simultaneously sensing paracetamol and 4-aminophenol.

Excessive consumption of paracetamol (PA) and 4-aminophenol (4-AP) can have harmful effects on the human body. This study developed a novel electroanalytical technique that utilizes the nanocomposites of poly azovan blue (PAB)-decorated graphitic carbon nitride (g-C3N4), deposited onto a screen-printed carbon electrode (SPCE), for the concurrent sensing of PA and 4-AP. The fabricated g-C3N4@PAB/SPCE exhibited exceptional synergistic effects, such as a high active electrochemical surface area and excellent electron transfer properties. The electrochemical behavior of g-C3N4@PAB/SPCE for simultaneous PA and 4-AP sensing was evaluated in the linear dynamic ranges of 0.08-75 and 0.05-90 µM, with the detection limits (S/N = 3) of 0.011 and 0.016 µM and sensitivities of 2.974 and 2.857 µA/µM/cm-2 for PA and 4-AP, respectively. Additionally, g-C3N4@PAB/SPCE showed long-term stability, high reproducibility (RSD = 2.17%, n = 4), and superior anti-interference capabilities. Finally, when g-C3N4@PAB/SPCE was tested for simultaneously sensing both PA and 4-AP in tap water and artificial urine models, it exhibited satisfactory recoveries, demonstrating its potential use for various industrial and clinical applications.

Snoring-related polygenic risk and its relationship with lifestyle factors in a Korean population: KoGES study.

Whereas lifestyle-related factors are recognized as snoring risk factors, the role of genetics in snoring remains uncertain. One way to measure the impact of genetic risk is through the use of a polygenic risk score (PRS). In this study, we aimed to investigate whether genetics plays a role in snoring after adjusting for lifestyle factors. Since the effect of polygenic risks may differ across ethnic groups, we calculated the PRS for snoring from the UK Biobank and applied it to a Korean cohort. We sought to evaluate the reproducibility of the UK Biobank PRS for snoring in the Korean cohort and to investigate the interaction of lifestyle factors and genetic risk on snoring in the Korean population. In this study, we utilized a Korean cohort obtained from the Korean Genome Epidemiology Study (KoGES). We computed the snoring PRS for the Korean cohort based on the UK Biobank PRS. We investigated the relationship between polygenic risks and snoring while controlling for lifestyle factors, including sex, age, body mass index (BMI), alcohol consumption, smoking, physical activity, and sleep time. Additionally, we analyzed the interaction of each lifestyle factor and the genetic odds of snoring. We included 3526 snorers and 1939 nonsnorers from the KoGES cohort and found that the PRS, a polygenic risk factor, was an independent factor for snoring after adjusting for lifestyle factors. In addition, among lifestyle factors, higher BMI, male sex, and older age were the strongest lifestyle factors for snoring. In addition, the highest adjusted odds ratio for snoring was higher BMI (OR 1.98, 95% CI 1.76-2.23), followed by male sex (OR 1.54, 95% CI 1.28-1.86), older age (OR 1.23, 95% CI 1.03-1.35), polygenic risks such as higher PRS (OR 1.18, 95% CI 1.08-1.29), drinking behavior (OR 1.18, 95% CI 1.03-1.35), late sleep mid-time (OR 1.17, 95% CI 1.02-1.33), smoking behavior (OR 0.99, 95% CI 0.82-1.19), and lower physical activity (OR 0.92, 95% CI 0.85-1.00). Our study identified that the UK Biobank PRS for snoring was reproducible in the Korean cohort and that genetic risk served as an independent risk factor for snoring in the Korean population. These findings may help to develop personalized approaches to reduce snoring in individuals with high genetic risk.

Transport Characteristics of Silicon Multi-Quantum-Dot Transistor Analyzed by Means of Experimental Parametrization Based on Single-Hole Tunneling Model.

The transport characteristics of a gate-all-around Si multiple-quantum-dot (QD) transistor were studied by means of experimental parametrization using theoretical models. The device was fabricated by using the e-beam lithographically patterned Si nanowire channel, in which the ultrasmall QDs were self-created along the Si nanowire due to its volumetric undulation. Owing to the large quantum-level spacings of the self-formed ultrasmall QDs, the device clearly exhibited both Coulomb blockade oscillation (CBO) and negative differential conductance (NDC) characteristics at room temperature. Furthermore, it was also observed that both CBO and NDC could evolve along the extended blockade region within wide gate and drain bias voltage ranges. By analyzing the experimental device parameters using the simple theoretical single-hole-tunneling models, the fabricated QD transistor was confirmed as comprising the double-dot system. Consequently, based on the analytical energy-band diagram, we found that the formation of ultrasmall QDs with imbalanced energetic natures (i.e., imbalanced quantum energy states and their imbalanced capacitive-coupling strengths between the two dots) could lead to effective CBO/NDC evolution in wide bias voltage ranges.

Next-generation sequencing analysis of hepatitis C virus resistance-associated substitutions in direct-acting antiviral failure in South Korea.

BACKGROUND/AIMS: We used next-generation sequencing (NGS) to analyze resistance-associated substitutions (RASs) and retreatment outcomes in patients with chronic hepatitis C virus (HCV) infection who failed direct-acting antiviral agent (DAA) treatment in South Korea. METHODS: Using prospectively collected data from the Korean HCV cohort study, we recruited 36 patients who failed DAA treatment in 10 centers between 2007 and 2020; 29 blood samples were available from 24 patients. RASs were analyzed using NGS. RESULTS: RASs were analyzed for 13 patients with genotype 1b, 10 with genotype 2, and one with genotype 3a. The unsuccessful DAA regimens were daclatasvir+asunaprevir (n=11), sofosbuvir+ribavirin (n=9), ledipasvir/sofosbuvir (n=3), and glecaprevir/pibrentasvir (n=1). In the patients with genotype 1b, NS3, NS5A, and NS5B RASs were detected in eight, seven, and seven of 10 patients at baseline and in four, six, and two of six patients after DAA failure, respectively. Among the 10 patients with genotype 2, the only baseline RAS was NS3 Y56F, which was detected in one patient. NS5A F28C was detected after DAA failure in a patient with genotype 2 infection who was erroneously treated with daclatasvir+asunaprevir. After retreatment, 16 patients had a 100% sustained virological response rate. CONCLUSION: NS3 and NS5A RASs were commonly present at baseline, and there was an increasing trend of NS5A RASs after failed DAA treatment in genotype 1b. However, RASs were rarely present in patients with genotype 2 who were treated with sofosbuvir+ribavirin. Despite baseline or treatment-emergent RASs, retreatment with pan-genotypic DAA was highly successful in Korea, so we encourage active retreatment after unsuccessful DAA treatment.

Distinct and overlapping features of nodal peripheral T-cell lymphomas exhibiting a follicular helper T-cell phenotype: a multicenter study emphasizing the clinicopathological significance of follicular helper T-cell marker expression.

Nodal peripheral T-cell lymphoma (PTCL) is a heterogeneous category including angioimmunoblastic T-cell lymphoma (AITL), PTCL of follicular helper T-cell (Tfh) phenotype (PTCL-Tfh), and PTCL, not otherwise specified (PTCL-NOS). We explored Tfh marker profiles in nodal PTCL. Nodal PTCLs (n = 129) were reclassified into AITL (58%; 75/129), PTCL-Tfh (26%; 34/129), and PTCL-NOS (16%; 20/129). Histologically, clear cell clusters, high endothelial venules, follicular dendritic cell proliferation, EBV+ cells, and Hodgkin-Reed-Sternberg (HRS)-like cells were more common in AITL than PTCL-Tfh (HRS-like cells, P = .005; otherwise, P < .001) and PTCL-NOS (HRS-like cells, P = .028; otherwise, P < .001). PTCL-NOS had a higher Ki-67 index than AITL (P = .001) and PTCL-Tfh (P = .002). Clinically, AITL had frequent B symptoms (versus PTCL-Tfh, P = .010), while PTCL-NOS exhibited low stage (versus AITL + PTCL-Tfh, P = .036). Positive Tfh markers were greater in AITL (3.5 ± 1.1) than PTCL-Tfh (2.9 ± 0.9; P = .006) and PTCL-NOS (0.5 ± 0.5; P < .001). Tfh markers showed close correlations among them and AITL-defining histology. By clustering analysis, AITL and PTCL-NOS were relatively exclusively clustered, while PTCL-Tfh overlapped with them. Survival was not different among the PTCL entities. By Cox regression, sex and ECOG performance status (PS) independently predicted shorter progression-free survival in the whole cohort (male, P = .001, HR = 2.5; PS ≥ 2, P = .010, HR = 1.9) and in 'Tfh-lymphomas' (ie, AITL + PTCL-Tfh) (male, P = .001, HR = 2.6; PS ≥ 2, P = .016, HR = 2.1), while only PS predicted shorter overall survival (OS) in the whole cohort (P = .012, HR = 2.7) and in 'Tfh-lymphomas' (P = .001; HR = 3.2). ICOS predicted favorable OS in 'Tfh-lymphomas' (log-rank; P = .016). Despite the overlapping features, nodal PTCL entities could be characterized by Tfh markers revealing clinicopathologic implications.

Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors.

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia [BilIN]), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, six mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

NGS-based targeted gene mutational profiles in Korean patients with pancreatic cancer.

According to molecular profiling studies, a considerable number of patients with pancreatic cancer harbor potentially actionable mutations. However, there are limited relevant data from the Korean population. We assessed the molecular profiles of patients with pancreatic cancer in Korea. This study collected molecular profiling data from patients with pancreatic cancer who visited Seoul National University Bundang Hospital between March 2018 and August 2020. Formalin-fixed, paraffin-embedded tumor specimens were sequenced using a targeted next-generation sequencing (NGS) platform. Cancer-associated mutations were analyzed, and potentially actionable mutations were identified. Potentially actionable mutations were classified into "highly actionable" and "modifies options" based on the Know Your Tumor registry study. In total, 87 patients with NGS tumor panel data were identified. Sixty-one patients (70.1%) had metastatic disease at the time of tissue acquisition. Tissues were obtained from the primary tumors and metastatic sites in 41 (47.1%) and 46 (52.9%) patients, respectively. At least one pathogenic mutation was reported in 86 patients (98.9%). The frequencies of four common mutations in our cohort were similar to those in The Cancer Genome Atlas data. Potentially actionable mutations were identified in 27 patients (31.0%). Of these, mutations categorized as highly actionable and modifies options were identified in 12 (13.8%) and 18 patients (20.7%), respectively. The most frequent highly actionable mutations were located in DNA damage response genes, such as BRCA1, BRCA2, or ATM (n = 6, 6.9%). Two patients with germline BRCA1 mutations received maintenance poly(adenosine diphosphate-ribose) polymerase inhibitor therapy. One patient has been receiving maintenance treatment for 18 months while remaining in radiologically complete remission. Mutational profiles using targeted NGS in Korean patients with pancreatic cancer were similar to those in Western patients. The present study supports the clinical potential and possible expanded clinical use of genetic profiling.

In Situ Facile Synthesis of Low-Cost Biogenic Eggshell-Derived Nanohydroxyapatite/Chitosan Biocomposites for Orthopedic Implant Applications.

In situ facile synthesis and the characterization of nanohydroxyapatite/chitosan (nHAP/CS) biocomposites were investigated for examining their potential applications in orthopedic implant technology. Firstly, the bare nHAP, europium-doped hydroxyapatite (Eu-nHAP), yttrium-doped hydroxyapatite (Y-nHAP), and Eu- and Y-codoped hydroxyapatite (Eu,Y-nHAP) nanoparticles were synthesized by the wet precipitation technique using biowaste-eggshell-derived calcium oxide powders. Then, through ultrasonication using the nanohydroxyapatite/chitosan mixtures (molar ratio = 1:2), the nHAP/CS, Eu-nHAP/CS, Y-nHAP/CS, and Eu,Y-nHAP/CS biocomposites were fabricated. Among them, Eu,Y-nHAP/CS showed higher cell viability (94.9%), higher solubility (pH = 7.6 after 21 days), and greater antibacterial activity than those of the other composites. In addition, Eu,Y-nHAP/CS exhibited improved mechanical properties compared with the other composites. For example, the nanoindentation test displayed the Eu,Y-nHAP/CS-coated 316L stainless steel implant to possess a higher Young's modulus value (9.24 GPa) and greater hardness value (300.71 MPa) than those of the others. The results indicate that the biomass-eggshell-derived Eu,Y-doped nHAP is of good use for orthopedic implant applications.

Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is one of the most deadly and common diseases in the world, accounting for over 881,000 casualties in 2018. The PTPRK-RSPO3 (P:R) fusion is a structural variation in CRC and well known for its ability to activate WNT signaling and tumorigenesis. However, till now, therapeutic targets and actionable drugs are limited in this subtype of cancer. MATERIALS AND METHOD: The purpose of this study is to identify key genes and cancer-related pathways specific for P:R fusion-positive CRC. In addition, we also inferred the actionable drugs in bioinformatics analysis using the Cancer Genome Atlas (TCGA) data. RESULTS: 2,505 genes were altered in RNA expression specific for P:R fusion-positive CRC. By pathway analysis based on the altered genes, ten major cancer-related signaling pathways (Apoptosis, Direct p53, EGFR, ErbB, JAK-STAT, tyrosine kinases, Pathways in Cancer, SCF-KIT, VEGFR, and WNT-related Pathway) were significantly altered in P:R fusion-positive CRC. Among these pathways, the most altered cancer genes (ALK, ACSL3, AXIN, MYC, TP53, GNAQ, ACVR2A, and FAS) specific for P:R fusion and involved in multiple cancer pathways were considered to have a key role in P:R fusion-positive CRC. Based on the drug-target network analysis, crizotinib, alectinib, lorlatinib, brigatinib, ceritinib, erdafitinib, infigratinib and pemigatinib were selected as putative therapeutic candidates, since they were already used in routine clinical practice in other cancer types and target genes of the drugs were involved in multiple cancer-pathways.

Enhanced photocatalytic crystal-violet degradation performances of sonochemically-synthesized AC-CeO2 nanocomposites.

Semiconductor-based photocatalysis is one of the favorable techniques for the wastewater treatment. Herein, we synthesized the activated carbon-decorated cerium dioxide (AC-CeO2) nanocomposites via the facile ultrasonication method by using the biomass-derived AC nanoflakes and the sonochemically-synthesized CeO2 nanoparticles. The AC-CeO2 nanocomposites exhibited the aggregated morphology with the AC nanoflakes-anchored CeO2 nanoparticles. Since the hybridization of conductive AC and semiconductive CeO2 would lead to the increased photocarrier transport and the reduced photocarrier recombination, during the photocatalytic reaction, the AC-CeO2 nanocomposites showed the enhanced crystal violet dye-degradation efficiency up to 97.9 % within 135 min. The results suggest that the AC-CeO2 nanocomposites hold promise as a prominent photocatalyst for future green environmental technology.

Clinical Application of Next-Generation Sequencing in Patients With Breast Cancer: Real-World Data.

PURPOSE: Next-generation sequencing (NGS)-based tumor panel testing has been reimbursed by the Korean government since 2017. We evaluated the use of NGS-based tumor panel testing in real-world clinical practice, focusing on molecular profiling (MP)-guided breast cancer treatment. METHODS: A total of 137 breast cancer patients underwent NGS panel testing between December 2017 and July 2020 at Seoul National University Bundang Hospital (SNUBH). Samples from patients were profiled using an in-house SNUBH pan-cancer panel. Sixty-four patients were profiled on SNUBH Pan_Cancer v1.0, targeting 89 genes, while 73 patients were profiled on SNUBH Pan_Cancer v2.0, targeting 546 genes. RESULTS: Breast cancer subtypes included hormone receptor+/human epidermal growth factor receptor 2 (HER2)- (n = 87), triple-negative (n = 44), and HER2+ (n = 6). Most patients had locally advanced or metastatic cancers (92%). Approximately 92% (126/137) of the patients had significant genomic alterations (tiers I and II), and 62% (85/137) had targetable genomic alterations. The most common targetable genomic alterations were PIK3CA (39%) and ESR1 mutations (9%), followed by ERBB2 (7%), PTEN (7%), BRCA2 (6%), and BRCA1 mutations (4%). Of the 81 patients with locally advanced/metastatic breast cancer with targetable genomic alterations, 6 (7.4%) received MP-guided treatments, including PARP inhibitor (n = 4), ERBB2-directed therapy (n = 1), and PI3K inhibitor (n = 1). Among these 6 patients, 4 participated in clinical trials, 1 underwent treatment at their own expense, and 1 received drugs through an expanded access program. The remaining 66 patients (81%) with targetable genomic alteration did not receive MP-guided treatment due to lack of matched drugs and/or clinical trials, poor performance status, and/or financial burden. CONCLUSION: NGS panel testing allowed MP-guided treatment in only 4.7% (6/127) of patients with advanced breast cancer in a real-world setting. The availability of matched drugs is critical for the realistic implementation of personalized treatment.

rs2671655 single nucleotide polymorphism modulates the risk for gastric cancer in Helicobacter pylori-infected individuals: a genome-wide association study in the Korean population.

OBJECTIVE: To identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection. METHODS: This study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction. RESULTS: In the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori-positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori-negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori-negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori-positive group (P = 0.0112). CONCLUSION: After H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC.