Time-delay-induced spiral chimeras on a spherical surface of globally coupled oscillators.

We consider globally coupled networks of identical oscillators, located on the surface of a sphere with interaction time delays, and show that the distance-dependent time delays play a key role for the spiral chimeras to occur as a generic state in different systems of coupled oscillators. For the phase oscillator system, we analyze the existence and stability of stationary solutions along the Ott-Antonsen invariant manifold to find the bifurcation structure of the spiral chimera state. We demonstrate via an extensive numerical experiment that the time-delay-induced spiral chimeras are also present for coupled networks of the Stuart-Landau and Van der Pol oscillators in the same parameter regime as that of phase oscillators, with a series of evenly spaced band-type regions. It is found that the spiral chimera state occurs as a consequence of a resonant-type interplay between the intrinsic period of an individual oscillator and the interaction time delay as a topological structure property.

Asymmetric spiral chimeras on a spheric surface of nonlocally coupled phase oscillators.

The spiral chimera state shows a remarkable spatiotemporal pattern in a two-dimensional array of oscillators for which the coherent spiral arms coexist with incoherent cores. In this work, we report on an asymmetric spiral chimera having incoherent cores of different sizes on the spherical surface of identical phase oscillators with nonlocal coupling. This asymmetric spiral chimera exhibits a strongly symmetry-broken state in the sense that not only the coherent and incoherent domains coexist, but also their incoherent cores are nonidentical, although the underlying coupling structure is symmetric. On the basis of analyses along the Ott-Antonsen invariant manifold, the bifurcation conditions of asymmetric spiral chimeras are derived, which reveals that the asymmetric spiral chimera state emerges via a supercritical symmetry-breaking bifurcation from the symmetric spiral chimera. For the coupling function composed of two Legendre modes, rigorous stability analyses are carried out to present a complete stability diagram for different types of spiral chimeras, including the stationary symmetric and asymmetric spiral chimeras as well as breathing asymmetric spiral chimera. For the general coupling scheme the asymmetric spiral chimera occurs as a result of competition between the odd and even Legendre modes of the coupling function. Our theoretical findings are verified by using extensive numerical simulations of the model system.

Spatial distribution, origin and contamination assessment of heavy metals in surface sediments from Jangsong tidal flat, Kangryong river estuary, DPR Korea.

This study aims to investigate spatial distribution, contamination and origin of heavy metals (Pb, Zn, Cu, Ni, Co and Cr) in surface sediments of Jangsong tidal flat (JTF), Kangryong river estuary, DPR Korea, where has been affected by various mining activities. The spatial diverse of heavy metals are due to differences in their sources and sediment properties. Enrichment factor, geoaccumulation index and ecological risk indexes indicate that JTF is not polluted and has low ecological risk, although slight enrichments occur for some metals. Multivariate analyses revealed that Mn, Ni and Cr originated from lithogenic source, whereas other metals were of anthropogenic origin, among which Fe and Co originated from the iron mine settling pond near JTF, while Pb, Zn and Cu originated from AMD effluent by sulfide mining activity in catchment of JTF. The different transport mechanisms of heavy metals from AMD result in diverse distribution of the metals in JTF.

TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis.

PURPOSE: To find biomarkers for disease, there have been constant attempts to investigate the genes that differ from those in the disease groups. However, the values that lie outside the overall pattern of a distribution, the outliers, are frequently excluded in traditional analytical methods as they are considered to be 'some sort of problem.' Such outliers may have a biologic role in the disease group. Thus, this study explored new biomarker using outlier analysis, and verified the suitability of therapeutic potential of two genes (TM4SF4 and LRRK2). MATERIALS AND METHODS: Modified Tukey's fences outlier analysis was carried out to identify new biomarkers using the public gene expression datasets. And we verified the presence of the selected biomarkers in other clinical samples via customized gene expression panels and tissue microarrays. Moreover, a siRNA-based knockdown test was performed to evaluate the impact of the biomarkers on oncogenic phenotypes. RESULTS: TM4SF4 in lung cancer and LRRK2 in breast cancer were chosen as candidates among the genes derived from the analysis. TM4SF4 and LRRK2 were overexpressed in the small number of samples with lung cancer (4.20%) and breast cancer (2.42%), respectively. Knockdown of TM4SF4 and LRRK2 suppressed the growth of lung and breast cancer cell lines. The LRRK2 overexpressing cell lines were more sensitive to LRRK2-IN-1 than the LRRK2 under-expressing cell lines. CONCLUSION: Our modified outlier-based analysis method has proved to rescue biomarkers previously missed or unnoticed by traditional analysis showing TM4SF4 and LRRK2 are novel target candidates for lung and breast cancer, respectively.

Extracellular vesicle-associated miR-135b and -135a regulate stemness in Group 4 medulloblastoma cells by targeting angiomotin-like 2.

BACKGROUND: Extracellular vesicles (EVs) secreted by tumours, including exosomes, are important factors that regulate cell-cell interactions in oncogenesis. Although EV studies are ongoing, the biological understanding of EV-miRNAs derived from brain tumour spheroid-forming cells (BTSCs) of medulloblastoma is poor. PURPOSES: We explored the specific cellular miRNAs and EV-miRNAs in medulloblastoma BTSCs to determine their potential biological function. METHODS: Bulk tumor cells (BTCs) and BTSCs were cultured under different conditions from medulloblastoma tissues (N = 10). RESULTS: Twenty-four miRNAs were simultaneously increased in both cells and EVs derived from BTSCs in comparison to BTCs. After inhibition of miR-135b or miR135a which were the most significantly increased in BTSCs, cell viability, self-renewal and stem cell marker expression decreased remarkably. Through integrated analysis of mRNAs and miRNAs data, we found that angiomotin-like 2 (AMOTL2), which was significantly decreased, was targeted by both miR-135b and miR-135a. STAT6 and GPX8 were targeted only by miR-135a. Importantly, low expression of AMOTL2 was significantly associated with overall poor survival in paediatric Group 3 and Group 4 medulloblastoma patients. CONCLUSION: Our results indicated that inhibition of miR-135b or miR-135a leads to suppress stemness of BTSC through modulation of AMOTL2.

Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome.

BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.

An Immune-Magnetophoretic Device for the Selective and Precise Enrichment of Circulating Tumor Cells from Whole Blood.

Here, we validated the clinical utility of our previously developed microfluidic device, GenoCTC, which is based on bottom magnetophoresis, for the isolation of circulating tumor cells (CTCs) from patient whole blood. GenoCTC allowed 90% purity, 77% separation rate, and 80% recovery of circulating tumor cells at a 90 µL/min flow rate when tested on blood spiked with epithelial cell adhesion molecule (EpCAM)-positive Michigan Cancer Foundation-7 (MCF7) cells. Clinical studies were performed using blood samples from non-small cell lung cancer (NSCLC) patients. Varying numbers (2 to 114) of CTCs were found in each NSCLC patient, and serial assessment of CTCs showed that the CTC count correlated with the clinical progression of the disease. The applicability of GenoCTC to different cell surface biomarkers was also validated in a cholangiocarcinoma patient using anti-EPCAM, anti-vimentin, or anti-tyrosine protein kinase MET (c-MET) antibodies. After EPCAM-, vimentin-, or c-MET-positive cells were isolated, CTCs were identified and enumerated by immunocytochemistry using anti-cytokeratin 18 (CK18) and anti-CD45 antibodies. Furthermore, we checked the protein expression of PDL1 and c-MET in CTCs. A study in a cholangiocarcinoma patient showed that the number of CTCs varied depending on the biomarker used, indicating the importance of using multiple biomarkers for CTC isolation and enumeration.

NAD(P)-dependent steroid dehydrogenase-like is involved in breast cancer cell growth and metastasis.

BACKGROUND: The cholesterol biosynthesis pathway is typically upregulated in breast cancer. The role of NAD(P)-dependent steroid dehydrogenase-like (NSDHL) gene, which is involved in cholesterol biosynthesis, in breast cancer remains unknown. This study aimed to uncover the role of NSDHL in the growth and metastasis of breast cancer. METHODS: After NSDHL knockdown by transfection of short interfering RNA into human breast cancer cell lines (MCF-7, MDA-MB-231 and BT-20) and human breast epithelial cell line (MCF10A), cell proliferation assay, cell cycle analysis, three-dimensional cell culture, clonogenic assay, transwell migration and invasion assays, and wound healing assay were performed. Erlotinib was used as the target drug for epidermal growth factor receptor. Immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1wjl /SzJ) were used as orthotropic breast tumor models by injecting them with NSDHL-knockdown MDA-MB-231 cells using lentivirus-carrying NSDHL short hairpin RNA. Clinical data from 3951 breast cancer patients in Gene Expression Omnibus databases were used to investigate the potential prognostic role of NSDHL by survival analysis. RESULTS: NSDHL knockdown in BT-20, and MDA-MB-231 resulted in a significant decrease in their viability, colony formation, migration, and invasion abilities (p < 0.05). Total cholesterol levels were observed to be significantly decreased in NSDHL-knockdown BT-20 and MDA-MB-231 (p < 0.0001). NSDHL knockdown significantly increased the rate of erlotinib-induced cell death, especially in MDA-MB-231 (p = 0.01). NSDHL knockdown led to significantly decreased tumor growth and lung metastasis in the MDA-MB-231 xenograft model (p < 0.01). Clinically, high NSDHL expression in tumors of patients with breast cancer was associated with significantly reduced recurrence-free survival (p < 0.0001). CONCLUSIONS: NSDHL might have a role in promoting breast cancer progression. The usage of NSDHL as a therapeutic target in breast cancer needs to be clarified in further studies.

Symmetry breakings in two populations of oscillators coupled via diffusive environments: Chimera and heterosynchrony.

We consider two diffusively coupled populations of identical oscillators, where the oscillators in each population are coupled with a common dynamic environment. Existence and stability of a variety of stationary states are analyzed on the basis of the Ott-Antonsen reduction method, which reveals that the chimera state occurs under the diffusive coupling scheme. Furthermore, we find an exotic symmetry-breaking behavior, the so-called the heterosynchronous state, in which each population exhibits in-phase coherence, while the order parameters of two populations rotate at different phase velocities. The chimera and heterosynchronous states emerge from bistabilities of distinct states for decoupled population and occur as a unique continuation for weak diffusive couplings. The heterosynchronous state is caused by an indirect coupling scheme via dynamic environments and could occur for a finite-size system as well, even for the system that consists of one oscillator per population.

Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test.

PURPOSE: Hereditary cancer syndrome means that inherited genetic mutations can increase a person's risk of developing cancer. We assessed the frequency of germline mutations using an next-generation sequencing (NGS)-based multiple-gene panel containing 64 cancer-predisposing genes in Korean breast cancer patients with clinical features of hereditary breast and ovarian cancer syndrome (HBOC). MATERIALS AND METHODS: A total of 64 genes associated with hereditary cancer syndrome were selected for development of an NGS-based multi-gene panel. Targeted sequencing using the multi-gene panel was performed to identify germline mutations in 496 breast cancer patients with clinical features of HBOC who underwent breast cancer surgery between January 2002 and December 2017. RESULTS: Of 496 patients, 95 patients (19.2%) were found to have 48 deleterious germline mutations in 16 cancer susceptibility genes. The deleterious mutations were found in 39 of 250 patients (15.6%) who had breast cancer and another primary cancer, 38 of 169 patients (22.5%) who had a family history of breast cancer (≥ 2 relatives), 16 of 57 patients (28.1%) who had bilateral breast cancer, and 29 of 84 patients (34.5%) who were diagnosed with breast cancer at younger than 40 years of age. Of the 95 patients with deleterious mutations, 60 patients (63.2%) had BRCA1/2 mutations and 38 patients (40.0%) had non-BRCA1/2 mutations. We detected two novel deleterious mutations in BRCA2 and MLH1. CONCLUSION: NGS-based multiple-gene panel testing improved the detection rates of deleterious mutations and provided a cost-effective cancer risk assessment.

Whole Genome Sequencing of Single Circulating Tumor Cells Isolated by Applying a Pulsed Laser to Cell-Capturing Microstructures.

Single cell analysis of heterogeneous circulating tumor cells (CTCs), by which the genomic profiles of rare single CTCs are connected to the clinical status of cancer patients, is crucial for understanding cancer metastasis and the clinical impact on patients. However, the heterogeneity in genotypes and phenotypes and rarity of CTCs have limited extensive single CTC genome research, further hindering clinical investigation. Despite recent efforts to build platforms that separate CTCs, the investigation on CTCs is difficult due to the lack of a retrieval process at the single cell level. In this study, laser-induced isolation of microstructures on an optomechanically-transferrable-chip and sequencing (LIMO-seq) is applied for whole genome sequencing of single CTCs. Also, the whole genome sequences and the molecular profiles of the isolated single cells from the whole blood of a breast cancer patient are analyzed.

Chimera state on a spherical surface of nonlocally coupled oscillators with heterogeneous phase lags.

We consider a network of coupled oscillators embedded in the surface of a sphere with nonlocal coupling strength and heterogeneous phase lags. A nonlocal coupling scheme with heterogeneous phase lags that allows the system to be solved analytically is suggested and the main effects of heterogeneity in the phase lags on the existence and stability of steady states are analyzed. We explore the stability of solutions along the Ott-Antonsen invariant manifold and present a complete bifurcation diagram for stationary patterns including the coherent, incoherent, and modulated drift states as well as chimera state. The stability analysis shows that a continuum of uniform drift states and the modulated drift state could become stable only due to the heterogeneity of the phase lags and that the chimera state is bifurcated from the modulated drift state. Our theoretical results are verified by using the direct numerical simulations of the model system.

Characterization and validation of somatic mutation spectrum to reveal heterogeneity in gastric cancer by single cell sequencing.

Gastric cancer (GC) is a highly heterogeneous disease with multiple cellular types and poor prognosis. However, the cellular evolution and molecular basis of GC at the individual intra-tumor level has not been well demonstrated. We performed single-cell whole exome sequencing to detect somatic single-nucleotide variants (SNVs) and significantly mutated genes (SMGs) among 34 tumor cells and 9 normal cells from a patient with GC. The Complete Prediction for Protein Conformation (CPPC) approach directly predicting the folding conformation of the protein 3D structure with Protein Folding Shape Code, combined with functional experiments were used to confirm the characterization of mutated SMGs in GC cells. We identified 201 somatic SNVs, including 117 non-synonymous mutations in GC cells. Further analysis identified 24 significant mutated genes (SMGs) in single cells, for which a single amino acid change might affect protein conformation. Among them, two genes (CDC27 and FLG) that were mutated only in single cells but not in the corresponding tumor tissue, were recurrently present in another GC tissue cohort, and may play a potential role to promote carcinogenesis, as confirmed by functional characterization. Our findings showed a mutational landscape of GC at intra-tumor level for the first time and provided opportunities for understanding the heterogeneity and individualized target therapy for this disease.

PHLI-seq: constructing and visualizing cancer genomic maps in 3D by phenotype-based high-throughput laser-aided isolation and sequencing.

Spatial mapping of genomic data to tissue context in a high-throughput and high-resolution manner has been challenging due to technical limitations. Here, we describe PHLI-seq, a novel approach that enables high-throughput isolation and genome-wide sequence analysis of single cells or small numbers of cells to construct genomic maps within cancer tissue in relation to the images or phenotypes of the cells. By applying PHLI-seq, we reveal the heterogeneity of breast cancer tissues at a high resolution and map the genomic landscape of the cells to their corresponding spatial locations and phenotypes in the 3D tumor mass.

Symmetry-broken coherent state in a ring of nonlocally coupled identical oscillators.

We report on a modulated coherent state in a ring of nonlocally coupled oscillators. Although the identical oscillators are all synchronized under the symmetric coupling, the phase configuration has an inhomogeneous structure. This symmetry-broken coherent state exists only for a nonlocal coupling with both attracting and repulsive interactions, depending on the distance between oscillators, and emerges via a continuous bifurcation from a uniformly coherent state. We analyze the existence and stability of the modulated coherent states on the basis of Ott-Antonsen equations for the local order parameter. Our theoretical results are verified using the numerical simulations.

Perspective Insight into Future Potential Fusion Gene Transcript Biomarker Candidates in Breast Cancer.

Next generation sequencing has accelerated the discovery of a variety of new fusion gene types in clinical breast cancer samples by analyzing cancer genomes and transcriptomes. Although previous studies have focused on a few clinically validated oncogenic fusion genes as diagnostic and therapeutic targets in breast cancer, a perspective consideration has not been given thus far for a plethora of breast cancer fusion genes, which are being newly identified at an overwhelmingly increasing pace. In this perspective review, we discuss diverse fusion gene types recently identified in a variety of breast cancer subtypes, including breast clinical cancer samples in TCGA (The Cancer Genome Atlas) database. This perspective review will confer fresh and promising guidance onto breast cancer surgeons, clinical oncologists, and tumor biologists in determining research directions for seeking and developing novel fusion gene biomarkers for breast cancer diagnostics and therapeutic treatment in upcoming years.

Genes co-amplified with ERBB2 or MET as novel potential cancer-promoting genes in gastric cancer.

Gastric cancer (GC), one of the most common cancers worldwide, has a high mortality rate due to limited treatment options. Identifying novel and promising molecular targets is a major challenge that must be overcome if treatment of advanced GC is to be successful. Here, we used comparative genomic hybridization and gene expression microarrays to examine genome-wide DNA copy number alterations (CNAs) and global gene expression in 38 GC samples from old and young patients. We identified frequent CNAs, which included copy number gains on chromosomes 3q, 7p, 8q, 20p, and 20q and copy number losses on chromosomes 19p and 21p. The most frequently gained region was 7p21.1 (55%), whereas the most frequently deleted region was 21p11.1 (50%). Recurrent highly amplified regions 17q12 and 7q31.1-7q31.31 harbored two well-known oncogenes: ERBB2 and MET. Correlation analysis of CNAs and gene expression levels identified CAPZA2 (co-amplified with MET) and genes GRB7, MIEN1, PGAP3, and STARD3 (co-amplified with ERBB2) as potential candidate cancer-promoting genes (CPGs). Public dataset analysis confirmed co-amplification of these genes with MET or ERBB2 in GC tissue samples, and revealed that high expression (except for PGAP3) was significantly associated with shorter overall survival. Knockdown of these genes using small interfering RNA led to significant suppression of GC cell proliferation and migration. Reduced GC cell proliferation mediated by CAPZA2 knockdown was attributable to attenuated cell cycle progression and increased apoptosis. This study identified novel candidate CPGs co-amplified with MET or ERBB2, and suggests that they play a functional role in GC.

Targeted exome sequencing of Korean triple-negative breast cancer reveals homozygous deletions associated with poor prognosis of adjuvant chemotherapy-treated patients.

Triple-negative breast cancer is characterized by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is associated with a poorer outcome than other subtypes of breast cancer. Moreover, there are no accurate prognostic genes or effective therapeutic targets, thereby necessitating continued intensive investigation. This study analyzed the genetic mutation landscape in 70 patients with triple-negative breast cancer by targeted exome sequencing of tumor and matched normal samples. Sequencing showed that more than 50% of these patients had deleterious mutations and homozygous deletions of DNA repair genes, such as ATM, BRCA1, BRCA2, WRN, and CHEK2. These findings suggested that a large number of patients with triple-negative breast cancer have impaired DNA repair function and that therefore a poly ADP-ribose polymerase inhibitor may be an effective drug in the treatment of this disease. Notably, homozygous deletion of three genes, EPHA5, MITF, and ACSL3, was significantly associated with an increased risk of recurrence or distant metastasis in adjuvant chemotherapy-treated patients.

Chimera and modulated drift states in a ring of nonlocally coupled oscillators with heterogeneous phase lags.

We consider a ring of phase oscillators with nonlocal coupling strength and heterogeneous phase lags. We analyze the effects of heterogeneity in the phase lags on the existence and stability of a variety of steady states. A nonlocal coupling with heterogeneous phase lags that allows the system to be solved analytically is suggested and the stability of solutions along the Ott-Antonsen invariant manifold is explored. We present a complete bifurcation diagram for stationary patterns including the uniform drift and modulated drift states as well as chimera state, which reveals that the stable modulated drift state and a continuum of metastable drift states could occur due to the heterogeneity of the phase lags. We verify our theoretical results using the direct numerical simulations of the model system.

Incoherent chimera and glassy states in coupled oscillators with frustrated interactions.

We suggest a site disorder model that describes the population of identical oscillators with quenched random interactions for both the coupling strength and coupling phase. We obtain the reduced equations for the suborder parameters, on the basis of Ott-Antonsen ansatz theory, and present a complete bifurcation analysis of the reduced system. New effects include the appearance of the incoherent chimera and glassy state, both of which are caused by heterogeneity of the coupling phases. In the incoherent chimera state, the system displays an exotic symmetry-breaking behavior in spite of the apparent structural symmetry where the oscillators for both of the two subpopulations are in a frustrated state, while the phase distribution for each subpopulation approaches a steady state that differs from each other. When the incoherent chimera undergoes Hopf bifurcation, the system displays a breathing incoherent chimera. The glassy state that occurs on a surface of three-dimensional parameter space exhibits a continuum of metastable states with zero value of the global order parameter. Explicit formulas are derived for the system's Hopf, saddle-node, and transcritical bifurcation curves, as well as the codimension-2 crossing points, including the Takens-Bogdanov point.