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Background: Oligodendrocyte precursor cells (OPCs) are myelinated glial cells of the central nervous system (CNS), able to regenerate oligodendrocytes and myelin. This study aimed to elucidate the effect of A2B5-positive (A2B5+) OPC transplantation in rats with spinal cord contusion (SCC) and to investigate changes in expression of various factors involved in the Notch signaling pathway after OPC transplantation. Methods: OPCs were obtained from induced pluripotent stem cells (iPSCs) originating from mouse embryo fibroblasts (MEFs). After identification of iPSCs and iPSC-derived OPCs, A2B5+OPCs were transplanted into the injured site of rats with SCC one week after SCC insult. Behavioral tests evaluated motor and sensory function 7 days after OPC transplantation. Real-time quantitative polymerase chain reaction (RT-qPCR) determined the expression of various cytokines related to the Notch signaling pathway after OPC transplantation. Results: IPSC-derived OPCs were successfully generated from MEFs, as indicated by positive immunostaining of A2B5, PDGFα and NG2. Further differentiation of OPCs was identified by immunostaining of Olig2, Sox10, Nkx2.2, O4, MBP and GFAP. Importantly, myelin formation was significantly enhanced in the SCC+OPC group and SCI-induced motor and sensory dysfunction was largely alleviated by A2B5+OPC transplantation. Expression of factors involved in the Notch signaling pathway (Notch-1, Numb, SHARP1 and NEDD4) was significantly increased after OPC transplantation. Conclusions: A2B5+OPC transplantation attenuates motor and sensory dysfunction in SCC rats by promoting myelin formation, which may be associated with change in expression of factors involved in the Notch signaling pathway.

Purpose: The success of immune checkpoint inhibitors therapy in triple negative breast cancer highlights the potential immunogenic characteristics of breast cancer. Increasing evidence have suggested that conventional chemotherapy can exert anti-cancer activity through various immune-based mechanisms. T cell receptor (TCR) diversity is crucial for immune responses and TCR repertoire has been reported acting as predictive and prognostic markers for cancer outcome. Here, we reported the TCR repertoire profiling in breast cancer and its association with chemotherapy and treatment response in breast cancer patients. Experimental design: This study is part of VGH-TAYLOR study, a comprehensive precision medicine study protocol on the heterogeneity of Taiwanese breast cancer patients (NCT04626440). A total of 856 female patients with luminal A, luminal B1, luminal B2, HER2-enriched, or triple-negative breast cancers were recruited. The enrolled subjects contains patients who receive surgery as the first-line treatment followed by adjuvant therapy and who receive neoadjuvant therapy as the first-line treatment followed by surgery. The blood samples from patients during chemotherapy were collected for TCR sequencing. The Oncomine TCR Beta-LR Assay was applied to determine the dynamic change in TCR repertoire. We examined TCR repertoire in terms of clonality, TCR richness/evenness and convergence. Results: Higher TCR clonality in breast cancer patients was associated with lower clonal richness. TCR clonality was positively correlated with age and stage but not tumor size. Patients with recurrence had higher TCR clonality and lower Shannon diversity. Patients with luminal B2 breast cancer showed lower TCR diversity compared to luminal A and triple-negative breast cancer. However, there were no significant differences in CDR3 length and the usage of variable and joining genes among breast cancer subtypes. Notably, both of adjuvant and neoadjuvant chemotherapies increased convergence and clonality while decreased Shannon diversity of TCR. In neoadjuvant settings, lower post-treatment blood TCR richness was associated with complete pathologic response. Conclusion: These data suggested that TCR repertoire is associated with clinicopathological characteristics including stage and recurrence. TCR clonal richness might provide prognostic value for patients receiving neoadjuvant chemotherapy. Citation Format: Chun-Yu Liu, Chi-Cheng Huang, Ji-Lin Chen, Yi-Fang Tsai, Ta-Chung Chao, Pei-Ju Lien, Yen-Shu Lin, Chin-Jung Feng, Yen-Jen Chen, Jiun-I Lai, Jen-Hwey Chiu, Chih-Yi Hsu, Ling-Ming Tseng. Characteristics of peripheral blood T cell receptor repertoire and correlation with response to chemotherapy in patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2271.

Introduction: Neoadjuvant chemotherapy, one of systemic treatment of breast cancer, is employed for downstaging of inoperable tumor. Pathological complete response (pCR) after neoadjuvant chemotherapy is associated with good prognosis for breast cancer. The critical role of anti-tumor immune responses in conventional chemotherapy and targeted therapy has been reported. However, the pCR-associated immune genes are still ambiguous. Materials and Methods: Thirty-seven primary breast cancer patients receiving neoadjuvant chemotherapy as the first-line treatment for breast cancer were recruited in this VGH-TAYLOR study (NCT04626440). Total RNA of fresh tumor tissues was isolated and then reverse transcribed into cDNA. The Oncomine Immune Response Research Assay was employed for examination of immune-related gene expressions. In silico analyses were performed using the public databases, including Gene Expression Omnibus, Kaplan-Meier plotter, ROC Plotter, Cancer Therapeutics Response Portal, and The Cancer Genome Atlas. Results: Patients achieved a pCR were associated with lower tumor stage and HER2 expression. The next-generation sequencing-based analysis showed that the expression of eight genes were higher in tissues of patients with pCR than non-pCR, including KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4. The 8-gene score was associated with better recurrence-free survival in patients receiving chemotherapy. Data from an ROC Plotter database showed that higher expressions of IGJ, CD69, and MS4A1 in patients respond to neoadjuvant chemotherapy compared to non-responders. In silico analysis revealed that the negative correlation between pCR-associated gene expressions and IC50 values suggesting the gene high expression was sensitive to the drugs. Moreover, the levels of pCR-associated gene were downregulated in breast tumor tissues and positively correlated with immune cell infiltrations. Conclusion: We identified eight immune genes which were associated with better prognosis and drug responses. The 8-gene score may serve as a prognostic marker for breast cancer patients who receiving neoadjuvant chemotherapy. Citation Format: Chun-Yu Liu, Chi-Cheng Huang, Yi-Fang Tsai, Ta-Chung Chao, Yen-Shu Lin, Chin-Jung Feng, Jiun-I Lai, Ji-Lin Chen, Yen-Jen Chen, Jen-Hwey Chiu, Chih-Yi Hsu, Ling-Ming Tseng. Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-45.

Aims. This study sought to report the 10-year clinical outcomes of patients who underwent unprotected left main (LM) percutaneous coronary intervention (PCI) in a large centre. Methods and Results. A total of 913 consecutive patients who underwent unprotected LM PCI from January 2004 to December 2008 at Fu Wai Hospital were retrospectively analysed; the mean age was 60.0 ± 10.9 years, females accounted for 22% of patients, diabetes was present in 27.7% of patients, and an LM bifurcation lesion occurred in 82.9% of patients. During the median follow-up of 9.7 years, major adverse cardiac or cerebrovascular events (MACCEs) occurred in 25.6% (234) of patients, and the rates of all-cause death, myocardial infarction, and stroke were 14.9%, 11.0%, and 7.1%, respectively. Cardiac death occurred in only 7.9% of patients. The estimated event rate was 41.9% for death/myocardial infarction/any revascularization and 45.9% for death/MI/stroke/any revascularization. Definite/probable stent thrombosis occurred in 4.3% (39) of patients. According to the subgroup analysis, IVUS-guided PCI was associated with less long-term MACCEs. Further multivariate analysis identified that age and LVEF

Objective: In order to verify that human urine stem cells can improve the neurological function of rats with cerebral ischemia-reperfusion through animal experiments, and then analyze the changes of gene network of human urine stem cell transplantation on cerebral ischemia-reperfusion through bioinformatics. Methods: Human urine stem cells were cultured, and then the model was established in rats with cerebral ischemia-reperfusion. Human urine stem cells were transplanted through the lateral ventricle. The success of the model was verified by behavioral NSS score. Using the keywords "Cerebral reperfusion" and "human urine stem cells", gene targets were searched and downloaded in Genecards, and the downloaded gene targets were made into The Venny intersection plot, and the resulting intersection genes were used. PubMed and CN.ORG searched literatures by keywords "Cerebral ischemia reperfusion, Stem cell transplantation" and sorted out genes that had been reported and not reported in the intersection genes. GO analysis, KEGG pathway analysis and PPI protein interaction map were used to analyze the interaction between genes. Results: Behavioral NSS score data were obtained on 1 day. Compared with the SHAM group, the neurological function of THE BI rats was significant. After injection of human urine stem cells into the lateral ventricle, the neurological function injury of the BI+USCs=LV group was higher than that of the BI group, P=0.028, which was statistically significant. There were 258 overlapping genes between Cerebral ischemia and human urine stem cells, and the remaining 252 overlapping genes were screened by PubMed and CNKI. GO enrichment analysis mainly involved neutrophil degranulation, neutrophil activation involved in immune response and platelet Positive regulation of degranulation, Hemostasis, blood coagulation, coagulation, etc. KEGG pathway analysis mainly involved Complement and coagulation cascades, ECM-receptor interaction, Glutathione metabolism and Proteoglycans in the correlation between the first 10 genes of cancer, Legionellosis, and Focal adhesion were that ACE: APOB, ACE: C3, APOB: C3, APOB: CD36, C3: CD59, C3: CD55, CD14: CD44, CD14: CD36, CD44: RAC1, CD44: CD55, CD44: CD59, CD55: CD59. Conclusion: Through animal experiments, it has been verified that human urine stem cells can improve the neural function of cerebral ischemia-reperfusion rats, and by studying their interaction relationship, enrichment analysis and pathway analysis, it has been expounded that human urine stem cells can regulate the functional recovery of cerebral ischemia.

Heterogeneity in breast cancer leads to diverse morphological features and different clinical outcomes. There are inherent differences in breast cancer between the populations in Asia and in western countries. The use of immune-based treatment in breast cancer is currently in the developmental stage. The VGH-TAYLOR study is designed to understand the genetic profiling of different subtypes of breast cancer in Taiwan and define the molecular risk factors for breast cancer recurrence. The T-cell receptor repertoire and the potential effects of immunotherapy in breast cancer subjects is evaluated. The favorable biomarkers for early detection of tumor recurrence, diagnosis and prognosis may provide clues for the selection of individualized treatment regimens and improvement in breast cancer therapy.Lay abstract We describe the rationale and design for the VGH-TAYLOR study, which includes Taiwanese patients with breast cancer and with a wide spectrum of clinical scenarios covering different breast cancer subtypes and clinical settings, such as the neoadjuvant, adjuvant and metastatic settings. The gene expression profile and genetic mutations of breast cancer subjects with the primary and recurrent tumors are compared. We also explore whether immune-related gene expression and diversity have any impact on response to treatment and survival. This study aims to discover biomarkers of detection of cancer relapse, diagnosis and prognosis that may enable personalized medicine and improvement in breast cancer treatment.

Purpose To study the effects of Lu-tong Granules (LTG) in ICH etermine the underlying mechanism of molecular network Methods Modern bioinformatics and network pharmacology methods were used to predict molecular network mechanisms between ICH and LTG. Animal experiments were carried out to verify the effect of LTG for the treatment of ICH, combined with behavior test and morphologic detection. Results Forty-three active components in LTG and involved 192 gene targets were identified successfully. Moreoner, they were intersected with 1132 genes of ICH,88 intersection targets were obtained. subsequently, Cytoscape was used to screen Hub genes, in which,6 core molecules, including AKT1, IL6, VEGFA, CASP3, JUN and MMP9 were recognized. Furthermore, we constructed Six core compounds by " disease-drug-active ingredient-target-KEGG " (D-D-A-T-K) network, showed including quercetin, luteolin, β sitosterol, stigmasterol, kaempferol and formononetin, and PPI protein network interaction showed that AKT1:OS3 and CNA2:DKN1A had the highest correlation. Whereas the enrichment of GO and KEGG indicated that LTG was most likely to play a therapeutic role in ICH through AGE-RAGE signaling pathway in diabetic complications. Integrated analysis also showed that the first 10 pathways of KEGG are integrated into 59 genes, among which 6 core genes are closely involved. Lastly, molecular docking showed that there was a good binding activity between the core components and the core genes, and animal experiments confirmed effect of LTG in the treatment of ICH, by using TTC staining and behavior test. Conclusion LTG are effective for the treatment of ICH, the underlying mechanism could be involved in gene network including anti-inflammatory response, nerve repair, analgesia, anti-epilepsy and other aspects.

Glycoprotein non-metastatic B (GPNMB) is a transmembrane protein overexpressed in numerous cancers including triple-negative breast cancers (TNBC). It has been linked to promote cancer aggressiveness and implicated as a novel target for GPNMB-expressing cancers. In current study, we aimed to explore the clinical significance of GPNMB in TNBC. Among 759 specimens, immunohistochemistry (IHC) exhibited GPNMB expressions were variable in different subtypes and significantly higher in TNBC. Kaplan–Meier analysis revealed GPNMB overexpression in TNBC was associated with worse prognosis especially distant metastasis (P = 0.020, HR = 2.515, CI 1.154–5.480). Multivariate analysis showed GPNMB expression was an independent prognostic factor in terms of recurrence and distant metastasis (P = 0.008, HR = 3.22, CI 1.36–7.61; P = 0.017, HR = 3.08, CI 1.22–7.74). In silico analysis showed high mRNA expression of GPNMB was associated with distant metastasis and GPNMB was overexpressed in TNBC. Furthermore, GPNMB positively correlated with epithelial–mesenchymal transition (EMT) regulators, mesenchymal marker vimentin, MMP and integrins. The protein levels of Twist and MMP2 were upregulated by GPNMB overexpression in TNBC cells. GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC.

Background Triple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC. Methods Data from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model. Findings TCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter. Interpretation These findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.

Purpose: The glycoprotein Trop-2 is frequently overexpressed in human malignancies and linked to worse outcome. A Trop2-targeting antibody-drug conjugate, sacituzumab govitecan, has been approved by the FDA for patients with unresectable locally advanced or metastatic triple-negative breast cancer. Trop-2 enhances Akt phosphorylation in numerous cancer cell lines, while the opposite findings are also reported suggesting the cell context-dependent effect of Trop-2. Blockade of PI3K/Akt pathway mediates anti-tumor mechanism of anti-HER2 agents. In this study, we aim to investigate the role of Trop-2 in HER2-positive breast cancer. Experimental design: The archival samples comprising different breast cancer subtypes were analyzed using immunohistochemical staining. The public databases, including, Metabric, KM plotter, ROC plotter, were used to verify the prognostic role and clinical significance of Trop-2 in HER2-positive breast cancer. In vitro tumor models, the transwell migration, invasion and sphere assays, were applied for evaluation of cancer progression. The apoptotic cells were determined by flow cytometry using Annexin V/propidium iodide double staining. Results: We analyzed a cohort of 986 breast cancer patients and found that HER2-positive breast cancer harbored higher Trop-2 protein expression than other breast cancer subtypes. Higher levels of Trop-2 and phospho-Akt in HER2-positive breast cancer tissues compared with normal tissues. Trop-2 expression was correlated with tumor stage and phospho-Akt level. HER2-positive breast cancer patients with high level of Trop-2 protein were linked to worse recurrence-free survival. Consistently, data from the public databases exhibited patients with higher level of Trop-2 transcript had shorter recurrence-free survival and overall survival of HER2-positive breast cancer. Overexpression of Trop-2 increased cell migration, invasion and sphere number in SK-BR-3 and BT-474 cells. In contrast, knockdown of Trop-2 suppressed cell motility and sphere formation. Trop-2-expressing cells had better cell viability compared to control cells in the presence of lapatinib or neratinib treatment. Lapatinib- and neratinib-induced cell apoptosis was rescued by Trop-2 overexpression. Notably, patients responded to anti-HER2 therapy had lower Trop-2 transcript expression than non-responders. Conclusion: These results suggested that the oncogenic role of Trop-2 in HER2-positive breast cancer and Trop-2 expression might confer resistance to anti-HER2 therapy. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Pei-Yi Chu, Chun-Teng Huang, Wan-Lun Wang, Chi-Cheng Huang, Po-Han Lin, Ling-Ming Tseng. Significance of Trop-2 in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5127.

Objective The present study compared 10-year clinical outcomes between transradial access (TRA) and transfemoral access (TFA) for left main (LM) percutaneous coronary intervention (PCI). Background There are limited data regarding the long-term safety and efficacy of TRA for LM PCI. Methods This retrospective study evaluated consecutive patients who underwent unprotected LM PCI between January 2004 and December 2008 at Fu Wai Hospital. The exclusion criteria were age of less than 18 years and presentation with acute myocardial infarction. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), which was defined as a composite of all-cause death, myocardial infarction, stroke, and any revascularization at the 10-year follow-up. Results Among 913 eligible patients, TRA was used for 417 patients (45.7%) and TFA was used for 496 patients (54.3%). The 30-day clinical outcomes were similar between the two groups. Results from the 10-year follow-up revealed that MACCE occurred in 180 patients (46.7%) from the TRA group and in 239 patients (51.2%) from the TFA group (log-rank p = .3). The TRA and TFA groups also had low and comparable cumulative rates of all-cause death (14.6% vs. 17.3%, log-rank p = .56) and cardiac death (7.9% vs. 9.1%, log-rank p = .7). Conclusion The present study revealed no significant differences in long-term clinical outcomes when TRA or TFA were used for LM PCI.

Objectives. To assess the impact of different guidewires on stent coating integrity in jailed wire technique (JWT) for bifurcation treatment. Background. JWT is commonly adopted to protect side branch in provisional one-stent strategy for coronary bifurcation lesions. However, this technique may cause defects in stent coatings. The degree of coating damage caused by different types of jailed wires remains unknown. Methods. A fluid model with a bifurcation was established to mimic the condition in vivo. One-stent strategy was performed with three types of guidewire (nonpolymer-jacketed wire, intermediate polymer-jacketed wire, and full polymer-jacketed wire) tested for JWT. Scanning electron microscopy (SEM) was used to evaluate stent coating integrity and wire structure. The degrees of coating defects were recorded as no, slight, moderate, and severe defects. Results. A total of 27 samples were tested. Analyses of SEM images showed a significant difference in the degree of coating damage among the three types of wire after the procedure of JWT ( P < 0.001 ). Nonpolymer-jacketed wire could inevitably cause a severe defect in stent coatings, while full polymer-jacketed wire caused the least coating damages. Besides, there were varying degrees of coil deformation in nonpolymer-jacketed wires, while no surface damage or jacket shearing was observed in full polymer-jacketed wires. Conclusions. Although nonpolymer-jacketed wire has long been recommended for JWT, our bench-side study suggests that full polymer-jacketed wire may be a better choice. Further clinical studies are needed to confirm our findings.

The standard sample of natural products is an essential standard reference to determine the quality of the product in the quality control of natural products. To develop a certified reference material(CRM) of swertioside according to the Work Guideline for Reference Materials(3): Reference Material-General Principles and Statistical Method for Certification(GB/T 15000.3-2008), swertioside was purified from whole plant of Swertia mussotii by extraction, isolation and Prep-HPLC to obtain certified reference material of swertioside. The structure of swertioside was identified by IR, UV, high-resolution MS, NMR. Thin layer chromatography, optical rotation, elemental analysis and melting point was carried out for the identification. The purity of the prepared sample was tested from different chromatographic elution conditions, thin layer chromatography and HPLC-MS. Swertioside was divided into 140 bottles, with 10 mg per bottle after homogeneity test, stability test and quantitative analysis. This CRM is 7-O-[α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl]; the homogeneity of the 95% confidence interval was good; the certified purity value was 98.66%, with a relative expanded uncertainty of 0.38%; the storage period was 36 months at 0-8 ℃. Therefore, the CRM of sakuranetin reached the technical requirements of CRM, and was accepted by SAC. Swertioside is successfully developed and can be used for determining content, evaluating test methods, detecting relevant products and controlling quality.

Aim. Based on optical coherence tomography (OCT), we aimed to determine the diagnosis, clinical characteristics, and interventions of braid-like coronary arteries, which are rare and tend to be diagnosed as a woven coronary artery (WCA) anomaly. Methods and Results. We identified braid-like lesions on coronary angiography (CAG) in 7 patients (6 men; median age 47 years; age range 26 to 57 years). All patients were heavy smokers. Four patients were diagnosed with an old myocardial infarction and the other 3 with unstable angina. The braid-like lesions were located in the left anterior descending arteries in 2 patients and in the right coronary arteries in the other 5. TIMI grade 2 flow was observed in all involved vessels. OCT findings of all lesions were consistent with recanalization of organized thrombi, which consisted of septa that divided the lumen into multiple small cavities communicating with each other. No separate three-layered structure could be defined. Based on the significance of the stenosis and its related symptoms, drug-eluting stents were implanted in all of the lesions. All patients experienced symptomatic improvement after the intervention and were followed up event-free for 12 months. Conclusions. Braid-like coronary arteries are likely to undergo recanalization of organized thrombi rather than WCA according to our OCT findings. The majority of cases affect men who smoke heavily. Percutaneous stent implantation may be beneficial in selected patients when feasible.

The development of power simulation artificial intelligence technology needs massive open sample data. It is a trend to use the characteristics of online data to construct sample data. In order to solve the problem that the online data of power grid is rich in information, but the utilization rate of features is not high, aiming at the information features of generators, the LTTB dimension reduction and DBSCAN + L2 clustering methods are proposed, which reduce the complexity of feature extraction of time series data. The method is verified by the actual power grid data, and has achieved certain results.

Purpose: Stimulator of interferon genes (STING) is an upstream regulator of interferon and NF-κB, the key mediators of immune and inflammatory responses associated with cancer, triggered by cytosolic DNA. Downregulation of STING in breast tumor tissues has been reported. STING elicits caspase-8-dependent cell apoptosis via NF-κB in breast cancer cells. STING agonists are considered as potent anti-cancer agents. The current study aims to assess the biological functions of STING in breast cancer progression. Experimental design: Data of mRNA expression levels and recurrence-free survival in patients with breast cancer from The Cancer Genome Atlas and Kaplan Meier-plotter databases were analyzed. Transwell assays were used to evaluate cell migrated and invaded abilities. Sphere formation was performed in stem cell-selective medium and ultra-low attachment plates. Two STING agonists, ADU-S100 and diABZI STING agonist-1 trihydrochloride, were used for in vitro studies. The molecular events were examined by Western blot analysis. Results: Data from public database showed that lower transcripts levels of STING in Her2 and luminal B breast cancer tissues than normal breast tissues. Luminal-type breast cancer cell lines harbored low STING transcripts compared with other subtypes. Importantly, breast cancer patients with low expression levels of STING was associated with worse recurrence-free survival. Results of immunoblotting indicated that breast cancer cell lines have lower STING protein expressions than normal MCF10A cells. Knockdown of STING led to aggressive phenotypes of MCF10A and BT474 cells. In contrast, overexpression of STING suppressed the abilities of migration, invasion and sphere formation of MCF7 and BT474 cells. The markers of epithelial were increased while the markers of mesenchymal and stemness were decreased by STING overexpression. STING agonist slightly suppressed cell viability of breast cancer cells but not MCF10A cells. Treatment of STING agonists reduced cell migrated ability with upregulation of E-cadherin and γ-catenin. Conclusion: These findings suggest that STING serves tumor-suppressive effects in breast cancer. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Chun-Teng Huang, Pei-Yi Chu, Mei-Fang Tseng, Yu-Hsuan Lee, Wan-Lun Wang, Ling-Ming Tseng. Pleiotropic anti-cancer effects of STING in estrogen receptor positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2486.

Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients.

Objectives The aim of this study was to assess the impact of operator experience on prognosis after left main coronary artery (LM) percutaneous coronary intervention (PCI). Background LM PCI can be technically challenging and potentially risky considering the amount of supplied myocardium. Methods Consecutive patients who underwent unprotected LM PCI at a single institution were included and compared according to whether the primary operator was an experienced, high-volume LM operator (defined as an operator who performed at least 15 LM PCIs per year for at least 3 consecutive years) or not. Kaplan-Meier estimates and Cox proportional hazards models are presented. Results From January 2004 to December 2011, a total of 1,948 patients underwent unprotected LM PCI by 25 operators. Of these, 7 operators (28%) were considered experienced, and 18 (72%) were considered less experienced, with an overall mean experience of 12.0 ± 11.5 LM PCIs per year. LM PCI was performed in 1,422 patients (73%) by experienced operators and in 526 patients (27%) by less experienced operators. Patients treated by experienced operators had more complex and extensive coronary artery disease. Unadjusted and adjusted risks for cardiac death were lower for patients who were treated by experienced operators, both at 30-day (unadjusted hazard ratio [HR]: 0.23; 95% confidence interval [CI]: 0.09 to 0.60; p = 0.003; adjusted HR: 0.22; 95% CI: 0.09 to 0.59; p = 0.003) and 3-year (unadjusted HR: 0.53; 95% CI: 0.32 to 0.89, p = 0.02; adjusted HR: 0.49; 95% CI: 0.29 to 0.84; p = 0.009) follow-up. Discrimination improved when operator experience was added to Cox proportional hazards models containing the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score (integrated discriminatory index = 0.004, p = 0.03) or SYNTAX score II (integrated discriminatory index = 0.007, p = 0.02). No significant interaction was detected between operator experience and distal bifurcation LM lesion, 2-stent bifurcation stenting, and intravascular ultrasound use (p > 0.10 for all). Conclusions Patients who underwent LM PCI by high-volume and experienced operators had better short- and long-term prognoses. Operator experience is an important factor in a complex intervention such as LM PCI.

A new continuous annealing process which can eliminate the "band" feature of dual phase steels has been designed. The sheets were annealed in MULTIPAS annealing simulator under variation of annealing temperature. The microstructure evolution of dual-phase steel sheets annealed at intercritical temperatures, were analyzed by optical microscopy and scanning electron microscopy. And the properties were compared with the sheets which annealed by the existing annealing process. The results show that: the "band" feature of dual-phase steel can be effectively eliminated by the optimizing continuous annealing process,and the mechanical properties are improved.

The effects of austenite grain size on hardenability and impact toughness were investigated. The results show that: Since the beginning of the two-phase region with quenching temperature, the austenite grain size from the initial 4+6 mixed crystal at 740°C, and gradually increased to 10 at 860°C; Austenite grain size and hardenability was directly proportional to the austenite grain size increased from 8μm to 36μm, the biggest change is the hardness 10HRC; Austenite grain size and impact toughness is linear, with the decrease of grain size, the impact energy increases linearly, and the austenite grain size and impact toughness curve fitting. Comprehensive analysis for ensuring the hardenability of cold heading steels should be considered optimal matching of material strength and plasticity.

Purpose: Luminal type breast cancers account for the most common subtypes of breast cancers, among which luminal B subtype is relatively faster tumor growing and confers substantial risk of recurrence after primary treatment despite adjuvant endocrine therapy. Understanding the molecular alterations underlying the poorer survival outcome for luminal B tumors represents an unmet medical need. Experimental design: The archival samples of 16 recurrences within 5 years, 3 recurrences between 5-10 years and 24 non-recurrence tumor tissues from luminal B breast cancer patients were retrieved. Genomic alterations of these 43 breast cancer samples were detected using deep next-generation sequencing of a 440-gene panel. The mRNA levels of candidate genes in breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA) database. Results: Overall, genomic alterations were found in 340 genes, including single nucleotide variants and copy number variation. Comparing to the non-recurrence tumors, NUP98 (31.3%), MAPK4 (18.8%), PTEN (18.8%), PER1 (18.8%) and TRIP11 (18.8%) showed higher population frequency in the recurrence tumors, and IGF2R (50.0%), PIM1 (45.8%) and ROS1 (37.5%) were dominate in the non-recurrence tumors. After a validation with the public clinical dataset, we identified three potential prognostic biomarkers, including NUP98, PER1, and TRIP11. We observed missense mutation or copy number deletion of NUP98, PER1 and TRIP11 in early recurrence tumors. Data from TCGA database exhibited patients with breast cancer harbored lower NUP98, PER1 and TRIP11 transcripts levels. Notably, lower NUP98, PER1 and TRIP11 expression levels correlated with worse recurrence-free survival in luminal B breast cancer. Interestingly, based on algorithm for visualization of protein interaction network, we found these 3 genes were all involved in androgen receptor signaling network. Conclusion: Our study identified NUP98, PER1, and TRIP11 which potentially served as biomarkers to predict recurrence in luminal B breast cancer. Further research is required to understand the association between genomic alterations and androgen receptor signaling as well as its clinical impact. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Yi-Ting Yang, Yi-Fang Tsai, Ta-Chung Chao, Kien Thiam Tan, Wan-Lun Wang, Pei-Ju Lien, Shu-Jen Chen, Ling-Ming Tseng. Prognostic genomic alterations associated with recurrence after primary therapy for patients with luminal B breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6468.

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners.