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MicroRNAs (miRNAs) are short non-coding RNAs that play an important role in regulating gene expression. Since miRNAs are abnormally expressed in various cancers, they are considered to be promising biomarkers for early cancer diagnosis. However, the short length and strong sequence similarity among miRNAs make their reliable quantification very challenging. We developed a highly selective amplification-free miRNA detection method based on Förster resonance energy transfer (FRET)-aided single-molecule counting. miRNAs were selectively labeled with FRET probes using splinted ligation. When imaged with a single-molecule FRET setup, the miRNA molecules were accurately identified by the probe's FRET. miRNA concentrations were estimated from the count of molecules. The high sensitivity of the method in finding sparse molecules enabled us to achieve a limit of detection of 31-56 amol for miR-125b, miR-100, and miR-99a. Single nucleotide mismatch could be discriminated with a very high target-to-mismatch ratio. The method accurately measured the high expression of miR-125b in gastric cancer cells, which agreed well with previous reports. The high sensitivity and accuracy of this technique demonstrated its clinical potential as a robust miRNA detection method.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis, but how these fatty acids are manipulated in cells is largely unknown. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen identified that darapladib (SB-480848), an inhibitor of Lp-PLA2, synergistically induced ferroptosis with GPX4 inhibitors. Notably, darapladib was able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, Lp-PLA2 was located in the membrane and cytoplasm and suppressed ferroptosis, suggesting the critical role of intracellular Lp-PLA2. Lipidomic analysis showed that phosphatidylethanolamine (PE) species were generally enriched, while lysophosphatidylethanolamine (lysoPE) and free fatty acid levels were reduced, upon darapladib treatment. Finally, combination treatment with darapladib and PACMA31, a GPX4 inhibitor, efficiently inhibited tumor growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Silicon particles have garnered attention as promising biomedical probes for hyperpolarized 29Si magnetic resonance imaging and spectroscopy. However, due to the limited levels of hyperpolarization for nanosized silicon particles, microscale silicon particles have primarily been the focus of dynamic nuclear polarization (DNP) applications, including in vivo magnetic resonance imaging (MRI). To address these current challenges, we developed a facile synthetic method for partially 29Si-enriched porous silicon nanoparticles (NPs) (160 nm) and examined their usability in hyperpolarized 29Si MRI agents with enhanced signals in spectroscopy and imaging. Hyperpolarization characteristics, such as the build-up constant, the depolarization time (T1), and the overall enhancement of the 29Si-enriched silicon NPs (10 and 15%), were thoroughly investigated and compared with those of a naturally abundant NP (4.7%). During optimal DNP conditions, the 15% enriched silicon NPs showed more than 16-fold higher enhancements─far beyond the enrichment ratio─than the naturally abundant sample, further improving the signal-to-noise ratio in in vivo29Si MRI. The 29Si-enriched porous silicon NPs used in this work are potentially capable to serve as drug-delivery vehicles in addition to hyperpolarized 29Si in vivo, further enabling their potential future applicability as a theragnostic platform.

Advancements in photodynamic diagnosis (PDD) and photodynamic therapy (PDT) as a standard care in cancer therapy have been limited. This study is aimed to investigate the clinical availability of 5-aminolevulinic acid (5-ALA)-based PDD and PDT in glioblastoma (GBM) patient-derived tumorspheres (TSs) and mouse orthotopic xenograft model.PDT was performed using a 635 nm light-emitting diode (LED). Transcriptome profiles were obtained from microarray data. For knockdown of C5α, siRNA was transfected into tumor mesenchymal stem-like cells (tMSLCs). The invasiveness of TSs was quantified using collagen-based 3D invasion assays.Treatment with 1 mM 5 ALA induced distinct protoporphyrin IX (PpIX) fluorescence in GBM TSs, but not in non-tumor cells or tissues, including tMSLCs. These observations were negatively correlated with the expression levels of FECH, which catalyzes the conversion of accumulated PpIX to heme. Furthermore, the 5-ALA-treated GBM TSs were sensitive to PDT, thereby significantly decreasing cell viability and invasiveness. Notably, the effects of PDT were abolished by culturing TSs with tMSLC-conditioned media. Transcriptome analysis revealed diverse tMSLC-secreted chemokines, including C5α, and their correlations with the expression of stemness- or mesenchymal transition-associated genes. By adding or inhibiting C5α, we confirmed that acquired resistance to PDT was induced via tMSLC-secreted C5α.Our results show substantial therapeutic effects of 5-ALA-based PDT on GBM TSs, suggesting C5α as a key molecule responsible for PDT resistance. These findings could trigger PDT as a standard clinical modality for the treatment of GBM.

The low therapeutic efficacy of conventional cancer chemotherapy has been associated with an immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), which display an M2-like phenotype, are abundant in many tumors and facilitate tumor growth and resistance to therapy. Here, we show that poly(L-arginine) (PLR), a cationic poly(amino acid) can induce the polarization of macrophages into the tumor-suppressive M1 phenotype

The potential use of alanine as an MRI contrast agent was investigated. The relaxation properties of alanine solutions were measured at 9.4 T. The T

This study used magnetic resonance (MR) thermometry to investigate the temperature increases and thermal diffusion that occur during plasmonic photothermal therapy (PTT) with gold nanorods (GNRs). An artificial tumor phantom made of agarose gel containing GNRs was heated by irradiation with an 808 nm laser. The MR thermometer visualized the conditions: a well-localized temperature distribution with suppressed thermal diffusion that depended on laser power and irradiation time. A tumor phantom model was implanted in mice, and MR thermometry evaluated the temperature change in the presence and absence of GNRs and the thermal diffusion into the surrounding tissues. That experiment showed that MR thermometry can be a useful tool for monitoring PTT. These results suggest that MR temperature measurement could help to establish ideal laser irradiation conditions in GNR-mediated PTT, and that it has great potential for visualizing local photothermal induction and evaluating therapeutic effects.

Objective Benefits of adjuvant treatment in pT1N1 gastric cancer (GC) remain controversial. Additionally, an effective biomarker for early GC is the need of the hour. The prognostic and predictive roles of single patient classifier (SPC) were validated in stage II/III GC. In this study, we aimed to elucidate the role of SPC as a biomarker for pT1N1 GC. Methods The present retrospective biomarker study (NCT03485105) enrolled patients treated for pT1N1 GC between 1996 and 2012 from two large hospitals (the Y cohort and S cohort). For SPC, mRNA expression of four classifier genes (GZMB, WARS, SFRP4 and CDX1) were evaluated by real-time reverse transcription-polymerase chain reaction assay. The SPC was revised targeting pT1 stages and the prognosis was stratified as high- and low-risk group by the expression of SFRP4, a representative epithelial-mesenchymal transition marker. Results SPC was evaluated in 875 patients (n=391 and 484 in the Y and S cohorts, respectively). Among 864 patients whose SPC result was available, 41 (4.7%) patients experience GC recurrence. According to revised SPC, 254 (29.4%) patients were classified as high risk [123 (31.5%) and 131 (27.1%) in the Y and S cohorts, respectively]. The high risk was related to frequent recurrence in both Y and S cohort (log-rank P=0.023, P

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

An increasing number of studies indicate air pollutants infiltrate into the brain. We aimed to find the association of cumulative air pollution exposure in the main body of primary brain tumor: glioblastoma (GBM). In this double‐cohort, retrospective analysis study with a protocol, we compared the health effect of air pollution on the GBM patients from the SEER (Surveillance, Epidemiology, and End Results Program) in 27 U.S. counties from 10 states and GBM patients of Severance cohort of Korea. From 2000 to 2015, 10621 GBM patients of the SEER were individually evaluated for the cumulative average exposure for each pollutant, and 9444 (88.9%) mortality events were reported. From 2011 to 2018, 398 GBM patients of the Severance with the same protocol showed 259 (65.1%) mortality events. The multi‐pollutant models show that the association level of risk with CO is increased in the SEER (HR 1.252; 95% CI 1.141‐1.373) with an increasing linear trend of relative death rate in the spline curve. The Severance GBM data showed such a statistically significant result of the health impact of CO on GBM patients. The overall survival gain of the less exposure group against CO was 2 and 3 months in the two cohorts. Perioperative exposure to CO may increase the risk of shorter survival of GBM patients of the SEER and the Severance cohort., This retrospective observational study found that chronic exposure to ambient level of carbon monoxide is associated with a shorter survival of glioblastoma patients (2‐3 months). Such association was validated in the cohorts of the United states (N=10621, HR 1.252, 95% CI 1.141‐1.373) and Korea (N=398, HR 2.874, 95% CI 1.040‐7.944).

In this study, we uncover a ligation-free DNA extension method in two adjacent fragmented probes, which are hybridized to target RNA, for developing a ligation-free nucleic acid amplification reaction. In this reaction, DNA elongation occurs from a forward probe to a phosphorothioated-hairpin probe in the presence of target RNA regardless of ligation. The second DNA elongation then occurs simultaneously at the nick site of the phosphorothioated probe and the self-priming region. Therefore, the binding site of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) 12a is repeatedly amplified, inducing a fluorescence signal in the presence of CRISPR-Cas12a. This ligation-free isothermal gene amplification method enables the detection of target RNA with 49.2 fM sensitivity. Moreover, two types of mRNA detection are feasible, thus, demonstrating the potential of this method for cancer companion diagnostics. Notably, the proposed method also demonstrates efficacy when applied for the detection of mRNA extracted from human cells and tumor-bearing mouse tissue and urine samples. Hence, this newly developed ligation-free isothermal nucleic acid amplification system is expected to be widely used in a variety of gene detection platforms.

Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

Purpose The potential of L-glutamine as a T2 exchange contrast agent in MRI was investigated. Methods The T2 relaxation rate of L-glutamine solutions prepared in various concentrations was measured at 9.4 T. A series of T2 -weighted images in a mouse cancer model was acquired with an L-glutamine solution infusion. Results The T2 relaxivity caused by the exchange (R2ex ) at 37°C was 0.069 s-1 mM-1 and 0.102 s-1 mM-1 for glutamine and glutamate solutions at pH = 7.2, respectively. The R2ex of glutamine at pH = 6.1-6.7 was in the 0.097-0.1 s-1 mM-1 range. No significant dependence of T1 on the concentration of glutamine was observed. The dynamic measurement of T2 -weighted images in vivo showed that the glutamine uptake was primarily observed at the localized part of the tumor CONCLUSION: L-glutamine can be used as a T2 exchange contrast agent and images of glutamine uptake in vivo can be acquired.

Background Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. Methods To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. Results Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. Conclusion Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. Key Points 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment. 2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.

Breast cancer is one of the most common cancers globally. Because the 5-year survival rate of breast cancer greatly increases when treated in its initial stage, the importance of early detection has been increasing. Herein, one-spot multiple breast cancer circulating microRNA (miRNA) detection via surface-enhanced Raman spectroscopy (SERS) with seed-mediated grown Ag nanopillars (SMGAPs) is described. The electrochemical reduction on the pre-distributed 40 nm gold nanoparticle seeds (sGNP) acted as scaffolds for silver ion growth, and a nanopillar-shaped silver structure was successfully grown on the gold substrate surface. The synthesized structure showed uniform and remarkably increased signal enhancement for malachite green isothiocyanate. Based on this consistency, two circulating miRNA markers for breast cancer (miR-21 and miR-155) were used as the SERS diagnostic target. The limit of detection (LOD) of each labeled target was 451 zmol and 1.65 amol respectively. Moreover, miRNAs in four types of cancer cell extracts (HCC1143, HCC1954, MDA-MB-231, MCF-7) were sorted by miR-21 and miR-155 copies. Finally, quantitative analysis of miRNA in urine was successful compared to that in the healthy group.

Multipotent adult stem cells (MASCs) derived from Pluripotent stem cells (PSCs) have found widespread use in various applications, including regenerative therapy and drug screening. For these applications, highly pluripotent PSCs need to be selectively separated from those that show low pluripotency for reusage of PSCs, and MASCs need to be collected for further application. Herein, we developed immunomagnetic microfluidic integrated system (IM-MIS) for separation of stem cells depending on potency level. In this system, each stem cell was multiple-separated in microfluidics chip by magnetophoretic mobility of magnetic-activated cells based on the combination of two sizes of magnetic nanoparticles and two different antibodies. Magnetic particles had a difference in the degree of magnetization, and antibodies recognized potency-related surface markers. IM-MIS showed superior cell separation performance than FACS with high throughput (49.5%) in a short time (15 min) isolate 1 × 10

Aim: To confirm the biological effects of manganese ferrite magnetic nanoparticles (MFMNPs) and an external magnetic field on glioblastoma cells. Methods: U-87MG glioblastoma cells were prepared, into which the uptake of MFMNPs was high. The cells were then exposed to an external magnetic field using a neodymium magnet in vitro and in vivo. Results: LRP6 and TCF7 mRNA levels involved in the Wnt/β-catenin signaling pathway were elevated by the influence of MFMNPs and the external magnetic field. MFMNPs and the external magnetic field also accelerated tumor growth by approximately 7 days and decreased survival rates in animal experiments. Conclusion: When MFMNPs and an external magnetic field are applied for a long time on glioblastoma cells, mRNA expression related to Wnt/β-catenin signaling is increased and tumor growth is promoted.

MicroRNA (miR), a key molecule involved in endogenous RNA interference, is a promising therapeutic agent. In vivo delivery of miR, however, is a major factor limiting its application because its po...

We investigated the feasibility of using terahertz (THz) reflection imaging to detect keratinizing squamous cell carcinoma (SCC) of the tongue. Four fresh keratinizing SCC tissues were studied, which had been surgically resected. All of the keratinizing SCCs were well distinguished from normal healthy tissues. We showed that the tumor regions exhibited low THz reflection despite having higher water content than normal regions. The refractive indices and absorption coefficients were low in the tumor tissues despite the relatively high water content. Our results showed that there were dominant factors such as keratin pearls, other than the water content affecting the THz reflection signal.

Herein, lipid-coated polyaniline (LiPAni) nanoparticles were fabricated to monitor the redox state of cancer cells. To confirm the characteristics of LiPAni, we firstly analyzed the size and chemical structures of the LiPAni nanoparticles. The absorbance properties of the LiPAni nanoparticles were observed to vary with the pH conditions. Furthermore, cell viability tests conducted with breast cancer cell lines showed that the cell viability of the cells with LiPAni nanoparticles was dramatically increased compared to those with the Tween80-coated polyaniline nanoparticles (TPAni) as a control. Subsequently, the colors of the LiPAni nanoparticles were observed and analyzed using spectroscopic methods. Finally, in order to investigate the more accurate sensing of the redox state using the color changes of the LiPAni nanoparticles with cancer cell lines, dark field microscopic images and scattering spectra were recorded at the single nanoparticle scale. For the TPAni nanoparticles, there was only a change in brightness and no change in color, but for the LiPAni nanoparticles, there was a change of color from yellow to pink in the dark field images.

Background Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. Methods We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. Results We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5. Conclusions GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.

We have successfully fabricated a nanocomposite, which is composed of polyaniline (PAni) and pyrene butyric acid (Pyba) via a solvent shift method, which was self-doped at a neutral pH value. This PAni nanocomposite can act as a fine nanoagent expressing absorbance, fluorescence, and Raman properties according to the surrounding pH values.

As stem cells show great promise in regenerative therapy, stem cell-mediated therapeutic efficacy must be demonstrated through the migration and transplantation of stem cells into target disease areas at the pre-clinical level. In this study, we developed manganese-based magnetic nanoparticles with hollow structures (MnOHo) and modified them with the anti-human integrin β1 antibody (MnOHo-Ab) to enable the minimal-invasive monitoring of transplanted human stem cells at the pre-clinical level. Compared to common magnetic resonance imaging (MRI)-based stem cell monitoring systems that use pre-labeled stem cells with magnetic particles before stem cell injection, the MnOHo-Ab is a new technology that does not require stem cell modification to monitor the therapeutic capability of stem cells. Additionally, MnOHo-Ab provides improved T1 MRI owing to the hollow structure of the MnOHo. Particularly, the anti-integrin β1 antibody (Ab) introduced in the MnOHo targets integrin β1 expressed in the entire stem cell lineage, enabling targeted monitoring regardless of the differentiation stage of the stem cells. Furthermore, we verified that intravenously injected MnOHo-Ab specifically targeted human induced pluripotent stem cells (hiPSCs) that were transferred to mice testes and differentiated into various lineages. The new stem cell monitoring method using MnOHo-Ab demonstrates whether the injected human stem cells have migrated and transplanted themselves in the target area during long-term stem cell regenerative therapy.

Background & aims Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive system for standardizing CEUS at high risk for hepatocellular carcinoma (HCC). We performed a meta-analysis to determine the diagnostic performance of the CEUS LR-5 for HCC and the pooled proportions of HCCs in each CEUS LI-RADS category. Methods We searched multiple databases for studies reporting the diagnostic accuracy of the CEUS LI-RADS. Random-effects model was used to determine summary estimates of the diagnostic performance of CEUS LR-5 and the pooled proportions of HCCs in each CEUS LI-RADS category. Risk of bias and concerns regarding applicability were evaluated with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Results Eleven studies were included in the final analysis, which consisted of 5535 observations with 3983 HCCs. The pooled per-observation sensitivity and specificity of the CEUS LR-5 for diagnosing HCC were 69% (95% confidence interval [CI], 64%-73%) and 92% (95% CI, 83%-96%) respectively. The pooled proportions of HCCs were 0% (95% CI, 0-0%) for LR-1, 1% (95% CI, 0%-4%) for CEUS LR-2, 26% (95% CI, 14%-39%) for CEUS LR-3, 77% (95% CI, 68%-86%) for CEUS LR-4, 97% (95% CI, 95%-98%) for CEUS LR-5, 57% (95% CI, 44%-69%) for CEUS LR-M and 100% (95% CI, 93%-100%) for CEUS LR-5V or TIV. Conclusions The CEUS LR-5 category showed moderate sensitivity and high specificity for diagnosing HCC. The proportion of HCCs was higher in the higher CEUS LI-RADS categories.

We propose that nanogels (HLGs) prepared by simply blending an epidermal growth factor (EGF)-loaded hyaluronan (HA)-based nanoformulation and poloxamers can be efficient transdermal drug carriers. In particular, due to the thermogelling behavior of poloxamer, when the HLGs, which are liquid at room temperature, are applied to the skin's surface, they form a gel at skin temperature. First, lipid-based nanoformulations (EGF-LNs) were fabricated by the lipid thin film method and then chemically conjugated with HA on the surface of the films to prepare EGF-loaded HA-based nanoformulations (EGF-HLNs). Both EGF-LNs and EGF-HLNs exhibited a uniform size and spherical lamellar structure. The EGF-HLN was added to a poloxamer solution to form EGF-HLG, which is a liquid at room temperature and a gel at skin temperature. HLGs have been shown to be able to deliver and permeate EGF well into the skin using both in vitro and in vivo systems, thus serving as an effective transdermal delivery system. In addition, it has been confirmed that this system could be a possible implantable drug carrier. Therefore, HLGs, which are uncomplicated and easily prepared, are expected to be easily used not only in the pharmaceutical field but also in the cosmetic field.

Background Gastric cancer is a considerable burden for worldwide patients. And diffuse gastric cancer is the most insidious subgroup with poor survival. The phenotypic characterization of the diffuse gastric cancer cell line can be useful for gastric cancer researchers. In this article, we aimed to characterize the diffuse gastric cancer cells with MRI and transcriptomic data. We hypothesized that gene expression pattern is associated with the phenotype of the cells and that the heterogeneous enhancement pattern and the high tumorigenicity of SNU484 can be modulated by the perturbation of the highly expressed gene. Methods We evaluated the 9.4 T magnetic resonance imaging and transcriptomic data of the orthotopic mice models from diffuse gastric cancer cells such as SNU484, Hs746T, SNU668, and KATO III. We included MKN74 as an intestinal cancer control cell. After comprehensive analysis integrating MRI and transcriptomic data, we selected CD34 and validated the effect by shRNA in the BALB/c nude mice models. Results SNU484, SNU668, Hs746T, and MKN74 formed orthotopic tumors by the 5 weeks after cell injection. The diffuse phenotype was found in the SNU484 and Hs746T. SNU484 was the only tumor showing the heterogeneous enhancement pattern on T2 images with a high level of CD34 expression. Knockdown of CD34 decreased the round-void shape in the H&E staining (P = 0.028), the heterogeneous T2 enhancement, and orthotopic tumorigenicity (100% vs 66.7%). The RNAseq showed that the suppressed CD34 is associated with the downregulated gene-sets of the extracellular matrix remodeling. Conclusion Suppression of CD34 in the human-originated gastric cancer cell suggests that it is important for the round-void histologic shape, heterogeneous enhancement pattern on MRI, and the growth of gastric cancer cell line.

We report minimal amount of hyaluronic acid (HA) conjugated magnetic nanocrystals (mHMs) for targeted imaging of CD44 abundant breast cancer cells via MRI. These mHMs lead to less induced cancer migration and drug resistance, which is distinct from conventional approaches using nanoplatforms (imaging or therapeutic systems) that are completely covered with HA. To synthesize mHMs, magnetic nanocrystals (MNCs), as MRI contrast agents, were encapsulated mostly with polysorbate 80 (P80, non-reactive to HA) and partially with aminated P80 (reactive to HA). This system enabled conjugation of an immensely diminished amount of HA onto MNCs. While these nanoparticles maintained good CD44 targeted imaging efficacy, they also showed no cytotoxicity and colloidal stability. We varied the HA ratios on an equal amount of MNCs and identified that when more HA was attached on nanoparticles, there was more facilitated cancer migration and drug resistant potentials. We chose the lowest amount of HA conjugated mHMs (mHM1) and demonstrated that mHM1 selectively diagnosed tumor regions in vivo. We believe that the technique described herein can be applied to various applications using HA to detect CD44 abundant cancer cell lines and offer a basis to understand the interaction between the cellular response and surface modification of nanoparticles.