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Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC.Experimental Design: We analyzed gene expression data from Mst1/2−/− and Sav1−/− mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses.Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001).Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256–64. ©2015 AACR.

Recurrence risk score and its clinical significance.

Purpose: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after “curative resection” of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence.Experimental Design: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections.Result: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P = 1.9 × 10−6, log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator–activated receptor-α might have regulatory roles for the early recurrence of HCC.Conclusion: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.

Purpose: Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment.Experimental Design: Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients.Results: We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort.Conclusions: The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy. Clin Cancer Res; 17(7); 1850–7. ©2011 AACR.

Distribution of candidate genes in biological process categories of the Gene Ontology database.

Supplementary Tables 1-4 from Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set

Methods

Primer sequences

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery.Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort.Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence.Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.

Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer. Mol Cancer Ther; 9(2); 257–67

Figure S1: Significant concordance between silence of Hippo signature and YAP1 expression in human hepatocellular carcinoma (HCC); Figure S2: Venn diagram of gene lists from two different gene expression signatures; Table S1: Genes in the SOH signature; Table S2: Functional categories of genes in the SOH signature; Table S3: Canonical Pathways enriched in the SOH signature; Table S4: Significant association between the SOH subtype and YAP1 protein expression in HCC; Table S5: Univariate and multivariate Cox regression analyses of recurrence-free survival with continuous SOH probability; Table S6: Univariate and multivariate Cox regression analyses of overall survival; Table S7: Univariate and multivariate Cox regression analyses of overall survival with continuous SOH probability; Table S8: Drop in concordance index in multivariable analysis; Table S9: Concordance of silence of Hippo signature with other prognostic HCC gene expression signatures in the NCI cohort; Table S10: Characteristics of HCC patients in the MSH cohort, stratified by SOH signature.

Supplementary Figures S1-S6; Supplementary Tables S1-S2.

Purpose: Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSC) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca2+-dependent apoptosis during glucose deprivation.Experimental Design: We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) gene knockdown, and investigated the role of nuclear factor kappa B (NFκB) in CSCs during time-dependent Ca2+-mediated and glucose deprivation–induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-d-glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2α via NFκB activation. Combined treatment with 2-deoxy-d-glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared with that in untreated control animals or those treated with the metabolic inhibitor alone.Conclusions: The current study provides compelling evidence that CaMK2α acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFκB. The latter induces expression of SERCA, allowing survival in glucose-deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment. Clin Cancer Res; 24(7); 1677–90. ©2017 AACR.

Supplementary Data from Gene Expression–Based Recurrence Prediction of Hepatitis B Virus–Related Human Hepatocellular Carcinoma

Supplementary Figure Legends 1-4 from Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set

Supplementary Figures 1-4 from Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set

Genomic copy number aberrations and corresponding transcriptional deregulation in the cancer genome have been suggested to have regulatory roles in cancer development and progression. However, functional evaluation of individual genes from lengthy lists of candidate genes from genomic data sets presents a significant challenge. Here, we report effective gene selection strategies to identify potential driver genes based on systematic integration of genome scale data of DNA copy numbers and gene expression profiles. Using regional pattern recognition approaches, we discovered the most probable copy number–dependent regions and 50 potential driver genes. At each step of the gene selection process, the functional relevance of the selected genes was evaluated by estimating the prognostic significance of the selected genes. Further validation using small interference RNA–mediated knockdown experiments showed proof-of-principle evidence for the potential driver roles of the genes in hepatocellular carcinoma progression (i.e., NCSTN and SCRIB). In addition, systemic prediction of drug responses implicated the association of the 50 genes with specific signaling molecules (mTOR, AMPK, and EGFR). In conclusion, the application of an unbiased and integrative analysis of multidimensional genomic data sets can effectively screen for potential driver genes and provides novel mechanistic and clinical insights into the pathobiology of hepatocellular carcinoma. [Cancer Res 2009;69(9):4059–66]

Supplementary Table 3 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Table 1 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Methods and Materials from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Figures 1-5 from Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma

Supplementary Figure 3 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Figure 2 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Figure Legends 1-4 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Tables 1-5 from Identification of a Cholangiocarcinoma-Like Gene Expression Trait in Hepatocellular Carcinoma

Supplementary Figure 1 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Table 2 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Supplementary Figure 4 from Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening

Purpose: Pedicle screw fixation provides 3-column stabilization, multidimensional control, and a higher rate of interbody fusion. Although computed tomography (CT) is recommended for the postoperative assessment of pedicle screw fixation, its use is limited due to the radiation exposure dose. The purpose of this preliminary retrospective study was to assess the clinical usefulness of low-dose mobile cone-beam CT (CBCT) for the postoperative evaluation of pedicle screw fixation. Methods: The author retrospectively reviewed postoperative mobile CBCT images of 15 patients who underwent posterior pedicle screw fixation for spinal disease from November 2019 to April 2020. Pedicle screw placement was assessed for breaches of the bony structures. The breaches were graded based on the Heary classification. Results: The patients included 11 men and four women, and their mean age was 66±12 years. Of the 122 pedicle screws, 34 (27.9%) were inserted in the thoracic segment (from T7 to T12), 82 (67.2%) in the lumbar segment (from L1 to L5), and six (4.9%) in the first sacral segment. Although there were metal-related artifacts, the image of the screw position (according to Heary classification) after surgery could be assessed using mobile CBCT at all levels (T7–S1). Conclusions: Mobile CBCT was accurate in determining the location and integrity of the pedicle screw and identifying the surrounding bony structures. In the postoperative setting, mobile CBCT can be used as a primary modality for assessing the accuracy of pedicle screw fixation and detecting postoperative complications.

Objective Cerebral vasospasm and delayed cerebral ischemia (DCI) are considered complications after aneurysmal subarachnoid hemorrhage (aSAH). Several hypotheses involving platelet activation have been asserted in the pathophysiology of cerebral vasospasm and DCI. This study aimed to investigate the effect of dual antiplatelet treatment (DAPT) on symptomatic vasospasm and DCI in patients with aSAH. Methods A retrospective study was conducted on patients with aSAH from 2009 to 2018. The patients are divided into 2 groups according to the treatment method such as simple or balloon-assisted coil embolization group (SB coiling), and stent-assisted coil embolization group. Patients treated by SB coiling without DAPT were classified as the control group. Patients who required dual antiplatelet treatment due to stent-assisted coil embolization were classified as DAPT group. The incidence of symptomatic vasospasm and DCI was compared between the two groups. Results Of 743 patients with aSAH, 563 patients were treated with clipping, 115 patients treated with SB coiling, and 65 patients receive stent-assisted coiling. Among 115 patients underwent SB coiling, 14 patients were excluded by the exclusion criteria. Total number of control group (SB coiling) was 101, DAPT group (stent-assisted coiling) was 65. Depending on whether or not taking DAPT, the incidence of symptomatic vasospasm was lower in the DAPT group (p=0.010). DCI incidence was also lower in the DAPT group, which was statistically significant (p=0.029). Conclusions DAPT reduces the frequency of symptomatic vasospasm and DCI in patients with aSAH in our single-center study. To warranting this topic, further, larger prospective and randomized studies should be needed.

Local lymph node assay (LLNA) is a predictive

There has been an influx of school-aged North Korean refugees defecting to South Korea in recent years. Research examining their integration into South Korean schools has shown that these students ...

Purpose: Recent developments in minimally invasive techniques have the potential to reduce surgical morbidity, promote patient recovery, accelerate surgical procedures, and thus improve cost-effectiveness in case management. In this study, we compared the treatment efficacy and results of supraorbital keyhole approach (SOKA) with those of conventional unilateral frontal craniotomy (CUFC) for traumatic intracerebral hemorrhage (TICH) in the frontal lobe. Methods: We analyzed the data of 38 patients who underwent CUFC (n=30) and SOKA (n=8) and retrospectively reviewed their medical records and radiological findings. Furthermore, we tried to identify the best surgical method for such lesions by including patients who underwent burr hole aspiration and drainage (BHAD) (n=9) under local anesthesia due to various circumstances. Results: The difference in the initial Glasgow coma scale score, operative time, and length of hospitalization between the CUFC and SOKA were statistically significant. All radiological features between the two groups including associated skull fracture, amount of pre- and postoperative hematoma, percentage of complete hematoma removal, pre- and postoperative midline shifting of the hematoma, and development of postoperative delayed hematoma were not statistically significant. Our experience of 46 patients with TICH in the frontal lobe with any of the three different surgical methods including BHAD enabled us to obtain valuable findings. Conclusions: Although it is difficult to insist that one particular approach is more useful than the other, we are confident that SOKA will have more advantages over CUFC in carefully selected patients with frontal TICH depending on the surgical experience of a neurosurgeon.

An increasing number of North Koreans have migrated to other countries in the past two decades, with South Korea receiving a significant number of these escapees each year. Research examining young...

Activated leukocyte cell adhesion molecule (ALCAM), a member of type I transmembrane immunoglobulin superfamily of cell adhesion molecule, is expressed in the surface membrane of various cell types including neurons. In the spinal cord dorsal horn (DH), the first gate for the sensory and pain transmission to the brain, the expression and function of ALCAM have not been known yet. Therefore, we here investigate the synaptic function of ALCAM in the substantia gelatinosa (lamina II) of the spinal DH, as well as its expression in the DH. Bath-application of ALCAM/Fc or CD6/Fc, the recombinant human IgG1-Fc chimeric proteins, specifically potentiated C-fiber-mediated excitatory synaptic transmission and predominantly increased spontaneous release of glutamate. In addition, the development of long-term potentiation, a form of synaptic plasticity, at excitatory synapses was significantly inhibited in the presence of the recombinant proteins. The functional roles of ALCAM in the spinal DH were further supported by immunohistochemical analysis; it showed that ALCAM intensely expressed through laminae I/II with the exception of lateral portion of the dorsal part of inner lamina II and distinctly co-localized with molecular markers of C-fibers, such as peptidergic calcitonin gene-related protein and transient receptor potential vanilloid type 1 and non-peptidergic isolectin B4. This study, for the first time, suggests the modulatory roles of ALCAM in the excitatory synaptic transmission and plasticity in the rat spinal DH.

Should teachers spend hours correcting students’ errors, or should they simply underline the errors, leaving it up to the students to self-correct them? The current study examines the utility of indirect feedback on learners’ written output. Journal entries from students enrolled in intact second language (L2) Korean classes ( n = 40) were collected and returned to the students with all of their errors underlined (indirect feedback). The students were then given class time to either identify the target of their errors, or to self-correct them. The results were compared across two proficiency levels (beginning vs. intermediate) and across learners’ prior language exposure/learning experiences (heritage language vs. non-heritage language learners). The results showed that the learners in general were able to self-correct more than a third of their errors, and that the non-heritage language learners were significantly better at perceiving their errors on orthography and particles. It was also found that the higher proficiency and non-heritage language learners were better able to self-correct their errors on particles. The current findings suggest that simply underlining the errors and asking students to self-correct them can be helpful, especially for certain ‘treatable’ errors, including those involving orthography and particles. The findings also highlight the importance of considering individual learner factors, such as the nature and length of their prior L2-learning experience, when providing indirect written feedback.