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LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer.Significance:EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer.This article is highlighted in the In This Issue feature, p. 517

Background/Aims: The study investigated the incidence of thromboembolic events (TEE) in head and neck (H&N) cancer patients who received concurrent chemoradiotherapy (CCRT) with cisplatin, and analyzed the factors affecting TEE occurrenceMethods: Two hundred and fifty-seven patients who started CCRT with cisplatin for H&N cancer from January 2005 to December 2019 were analyzed.Results: TEE occurred in five patients, an incidence rate of 1.9%. The 2-, 4-, and 6-month cumulative incidences of TEE were 0.8%, 1.6%, and 1.9%, respectively. Khorana score was the only factor associated with TEE occurrence (p = 0.010).Conclusions: The incidence of TEE in H&N cancer patients who underwent CCRT with cisplatin was relatively low when compared to other types of cancer. However, patients with a high Khorana score require more careful surveillance for possible TEE occurrence.

EGFR and AXL protein expression in the brain and immunohistochemical characterization of tumors of Lztr1fl/fl;Cdkn2afl/fl;GFAP-Cre+ mice

LZTR1 regulates EGFR and AXL protein stability

Protein expression of LZTR1 substrates and pathway analysis in human schwannoma A

LZTR1 co-localized with EGFR and AXL at the cellular membrane upon ligand stimulation

LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1– and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer.Significance:EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer.This article is highlighted in the In This Issue feature, p. 517

Table S1. List of ubiquitylated peptides from DiGly proteomics assay. Table S2. List of proteins differentially abundant in LZTR1-/- compared toLZTR1+/+ cells quantified by TMT.Table S3. List of top scoring LZTR1 interacting proteins from immunoprecipitation/mass spectrometry.

Phenotype alterations in the liver and brain of Lztr1-deleted mice

Mechanism of LZTR1-mediated degradation of RIT1 and the effect of LZTR1 mutations

Vulnerability of LZTR1 inactive cells to combination treatment of EGFR and AXL inhibitors

The Kelch domain of LZTR1 and carboxyl tail of EGFR are required for their interaction

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973–84. ©2017 AACR.

Supplementary Figure 1 related to Figure 1. TGM2 is highly expressed in the necrotic region of MES GBM. Supplementary Figure 2 related to Figure 2. TGM2 regulates stemness of MES, PN, and CL GSCs. Supplementary Figure 3 related to Figure 4. A negative correlation between C/EBPβ and GADD153.

Background: The optimal treatment (Tx) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients (pts) with brain metastasis (BM) remains to be determined. Methods: A retrospective review was conducted on 77 NSCLC pts with synchronous BM who underwent first-line EGFR-TKI Tx (gefitinib: 46, erlotinib: 11, afatinib: 20). The outcomes of pts were analyzed according to the clinicopathological characteristics including local Tx modalities.Results: Fifty-nine pts underwent local Tx for BM (gamma knife surgery (GKS): 37, whole brain radiotherapy (WBRT): 18, others: 4) concurrently or sequentially with EGFR-TKI. Pts treated with TKI alone showed significantly lower incidence of central nervous system (CNS) symptoms (p=0.006), with a tendency toward a smaller number of BM lesions compared with those who received local treatment. The median progression-free survival (PFS) and overall survival (OS) after the initiation of EGFR-TKI for all pts were 9 and 19 months, respectively. In 60 pts with follow-up brain imaging, the median intracranial PFS was 15 months. Pts with EGFR exon 19 deletion (n=42) had a significantly longer median OS than those with L858R mutation (n=25) or other mutations (n=10) (23 vs. 17 months, p=0.010). Other clinical characteristics, including CNS symptoms (p=0.410), number of BM (p=0.709), and the use of local Tx (p=0.834), were not associated with OS, as well as PFS. In terms of the local optimal treatment modality, no difference was found between GKS and WBRT in the OS and PFS.Conclusions: This study suggests that EGFR-TKI may result in a favorable outcome in NSCLC pts with synchronous BM, especially in deletion 19 mutant, regardless of the extent of BM lesions or local Tx modalities. Pts with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.

Objectives This study aimed to examine the antioxidant activity and antiinflammatory effects of ethanol extract of Polygonum senticosum (EPS) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Methods Antioxidant activity of EPS was assessed by radical-scavenging effects on ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. Proinflammatory markers produced by LPS-induced RAW 264.7 macrophages were quantified to assess the antiinflammatory activity of EPS. Results Our results showed that EPS significantly increased FRAP and DPPH radical-scavenging activity. Additionally, EPS reduced LPS-induced proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), along with proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, without significant cytotoxicity. EPS significantly downregulated the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-1β in LPS-stimulated RAW 264.7 macrophages. Positive correlations were noted between FRAP and DPPH radical-scavenging activity and antiinflammatory capacity. Conclusions Our results indicate that EPS downregulates the expression of pro-inflammatory mediators such as NO, PGE2, and cytokines (IL-1β and TNF-α) in LPS-stimulated RAW 264.7 macrophage cells. Further research is needed for its use as a treatment for inflammation and related diseases.

The purpose of this study was to examine how coaching styles affect athletes’ moral disengagement. To achieve our objectives, we examined the relationships among perceived coaching types, pride, and moral disengagement in the context of elite taekwondo athletes (N = 322). Direct and indirect effects among coaching types, pride, and moral disengagement were assessed through path analysis. The results indicated that the autonomy-support coaching type reduced moral disengagement by decreasing hubristic pride, while the controlled coaching type increased moral disengagement through hubristic pride. Our study found a chain of effects according to the controlled coaching type perceived by taekwondo athletes, hubristic pride, and moral disengagement; therefore, the controlled coaching type and hubristic pride should be closely managed in sport society, as they elicit greater moral disengagement. Managerial strategies to diminish hubristic pride through the autonomy-support coaching type are recommended.

Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options. Using the human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists, we identified the proteins that interact with DRD2. DRD2 signaling promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces DRD2-TRAIL receptor interaction and subsequent cell death. Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy.

Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome. NF1 patients are prone to develop peripheral and central nervous system tumors, with glioma occurring in 15-20% of patients. The molecular profiles of glioma from patients with NF-1 have been previously explored by large scale DNA and RNA bulk analyses, providing the first comprehensive genetic landscape of NF-1 glioma. However, the intra-tumoral architecture and the microenvironment organization remained largely concealed within the global bulk profile. Here, to characterize the complexity of molecular states of both malignant and non-malignant cells, we profiled NF-1 glioma gene expression at individual cell resolution. We performed single-nuclei RNA sequencing (Nucseq) on frozen NF-1 glioma specimens, including high-grade and low-grade tumors. The functional classification of the transcriptional programs activated in the individual tumor cells identified three main molecular states that partially overlapped with the cellular subtypes of sporadic glioblastoma. Tumor cells of low-grade NF-1 glioma exhibited marked enrichment of neuronal functions, suggesting that the gliomagenesis process in the context of NF1 inactivation might be supported by specialized neuronal activities. Conversely, the proliferative state characterized high-grade NF-1 glioma, indicating that cell cycle-associated pathways are drivers of tumor progression. The single-cell deconvolution of immune microenvironment in NF-1 low grade glioma revealed infiltration of CD8+ T lymphocytes and the active crosstalk of these cells with pro-inflammatory macrophages and mature dendritic cells, supporting a possible anti-tumor cell-mediated response. The identification of divergent tumor cell states as well as the characterization of the immune infiltrates provide new insights for accurate stratification of NF-1 glioma patients and to inform personalized therapeutics.

Plants produce chemicals of immense diversity that provide great opportunities for development of new antifungal compounds. In search for environment-friendly alternatives to the fungicide of current use, we screened plant extracts obtained from more than eight hundred plant materials collected in Korea for their antifungal activity against the model plant pathogenic fungus, Magnaporthe oryzae. This initial screening identified antifungal activities from the eleven plant extract samples, among which nine showed reproducibility in the follow-up screening. These nine samples were able to suppress not only M. oryzae but also other fungal pathogens. Interestingly, the plant extracts obtained from Actinostemma lobatum comprised five out of eight samples, and were the most effective in their antifungal activity. We found that butanol fraction of the A. lobatum extract is the most potent. Identification and characterization of antifungal substances in the A. lobatum extracts would provide the promising lead compounds for new fungicide.

This study aimed to investigate the melanogenesis inhibitory activity of epicatechin-3-O-gallate (ECG) isolated from Polygonum amphibium L. ECG was isolated from the ethanol extract of P. amphibium L, and its chemical structure was determined using spectroscopic methods such as LC-ESI-MS, 1D-NMR, and UV spectroscopy. ECG inhibited the melanogenesis of B16F10 cells in a dose-dependent manner. Particularly, it decreased the melanin content by 27.4% at 200 μM concentration, compared with the control, in B16F10 cells, without causing cytotoxicity. It is noteworthy that the expression of three key proteins, including tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), involved in melanogenesis, is significantly inhibited by ECG. The ECG isolated in this study caused the inhibition of body pigmentation and tyrosinase activity in vivo in the zebrafish model. These results suggest that the ECG isolated from P. amphibium L. is an effective anti-melanogenesis agent.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Interplay between histone acetylation and deacetylation is one of the key components in epigenetic regulation of transcription. Here we report the requirement of Mo- HDA1-mediated histone deacetylation during asexual development and pathogenesis for the rice blast fungus, Magnaporthe oryzae. Structural similarity and phylogenetic analysis suggested that MoHDA1 is an ortholog of Saccharomyces cerevisiae Hda1, which is a representative member of class II histone deacetylases. Targeted deletion of MoHDA1 caused a little decrease in radial growth and large reduction in asexual sporulation. Comparison of acetylation levels for H3K9 and H3K14 showed that lack of MoHDA1 gene led to significant in- crease in H3K9 and H3K14 acetylation level, compared to the wild-type and complementation strain, confirm- ing that it is a bona fide histone deacetylase. Expression analysis on some of the key genes involved in asexual reproduction under sporulation-promoting condition showed almost no differences among strains, except for MoCON6 gene, which was up-regulated more than 6-fold in the mutant than wild-type. Although the deletion mutant displayed little defects in germination and subsequent appressorium formation, the mutant was compromised in its ability to cause disease. Wound- inoculation showed that the mutant is impaired in invasive growth as well. We found that the mutant was defective in appressorium-mediated penetration of host, but did not lose the ability to grow on the media containing H2O2. Taken together, our data suggest that MoHDA1-dependent histone deacetylation is important for efficient asexual development and infection of host plants in M. oryzae.

Microalgae-derived docosahexaenoic acid (DHA) production has been considered an alternative technology to overcome several disadvantages of fish oil-based DHA production. Despite its potential, efficient production methods for DHA have been rarely reported. Accordingly, in this study we investigated the potential application of Jerusalem artichoke and lipid-extracted algae (LEA) hydrolysates as inexpensive sources of carbon and other nutrients for DHA production using Aurantiochytrium sp. KRS101. Response surface methodology (RSM) with central composite design (CCD) was used to determine the maximum point of DHA productivity in the presence of 51.9 g L−1 fructose and 4.9 g L−1 yeast extract. Hydrolysis of 76.6 g L−1 Jerusalem artichoke powder with 0.25 N sulfuric acid at 70 °C yielded the desired concentration of fructose for use as the medium. Cultivation of the microalgae using the Jerusalem artichoke hydrolysate (JAH) and JAH + LEA (JLH-1) resulted in 27.8% and 31.3% improvements in biomass productivity, respectively, compared with the basal medium control. In addition, simultaneous one-step hydrolysis of Jerusalem artichoke and LEA (JLH-2) resulted in 7.2% higher biomass and 47% higher DHA yields than that obtained from hydrolyzing the two components separately (JLH-1). These results suggested that a strategy using JAH combined with LEA could replace expensive nutrient sources and produce efficient and eco-friendly DHA from Aurantiochytrium sp. KRS101.

Background/Aims We investigated metabolic comorbidity status and patterns of medical institution utilization among breast cancer survivors using medical claims data from the Health Insurance Review and Assessment Service (HIRA). Methods Using claims data obtained from the HIRA, we selected breast cancer survivors between 2010 and 2015. Descriptive statistics were calculated to determine the frequency of metabolic comorbidities, as well as to analyze patterns of medical institution utilization in accordance with disease status. Results A total of 89,953 breast cancer survivors were identified. Among these, 12,364 (13.7%) had hypercholesterolemia, 20,754 (23.1%) had hypertension (HTN), and 11,102 (12.3%) had diabetes mellitus (DM). In particular, more than half of breast cancer survivors older than 60 years had HTN, and other diseases sharply increased beginning at age 50 years. For HTN, a total of 531,292 claims were submitted; more than 80% (n = 473,737) were from primary medical institutions, whereas only 2.4% (n = 12,551) were from tertiary medical institutions. The number of claims submitted for DM was 231,526; those from primary medical institutions accounted for 68.5% (n = 158,566), whereas claims from tertiary medical institutions accounted for 12.0% (n = 27,693). In subgroup analyses, the utilization of secondary and tertiary medical institutions was higher among patients with severe diseases and those diagnosed following their breast cancer diagnosis. Conclusions More than 10% of breast cancer survivors were diagnosed with a metabolic comorbidity. Through analysis of medical institution utilization patterns, we ascertained that a communication system linking secondary and tertiary medical institutions with primary medical institutions is needed.

Tumor heterogeneity and broad therapeutic resistance are major challenges when treating patients with glioblastoma (GBM). Moreover, different from other cancer types, the absence of clinically useful classifiers for glioblastoma has hampered the translation of genomic and proteomic information to improve diagnosis and design precision therapeutics for patients. We analyzed a large dataset of human GBM to determine the multi-omics features characterizing the four GBM subtypes that we have recently identified through single-cell RNA sequencing and validated in bulk tumor analysis. Each subtype exhibits activation of unique functional traits that confer distinct therapeutic vulnerabilities. The examination of proteomics, phosphoproteomics, metabolomics, lipidomics and acetylomics data revealed that each GBM subtype has a coherent molecular structure driving the dominant function traceable in each analytical platform. Functional classes are not a specific attribute of GBM as we identified the same subtypes in breast and lung cancer. To test the translational impact of proteomic data in GBM, we developed an unbiased protein kinase signaling network approach for the selection of master kinases (MKs) aberrantly activated in each GBM subtype. We identified therapeutically actionable MKs and novel phosphorylation substrates that we experimentally validated. To provide rapid translation of the functional classifier for precision medicine in GBM, we developed a probabilistic classification tool which determines the probability that a patient’s GBM belongs to one of the four subtypes, exhibiting optimal performance when using RNA extracted from either frozen and paraffin-embedded tissues. The algorithm is publicly accessible and can be used to evaluate the association of therapeutic response with GBM subtypes and as tool for selection criteria in prospective clinical trials.

LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among the most frequently mutated ubiquitin ligase coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, in which approximately 27% of cases harbor inactivating mutations and copy number loss. However, both the identity of the protein substrates targeted by LZTR1-mediated ubiquitylation and the biological contexts regulated by specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations and in a new conditional Lztr1 knockout mouse. Multiple screens converged on the receptor tyrosine kinases EGFR and AXL as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome by LZTR1-CUL3 complexes. Pathogenic mutations affecting LZTR1 failed to promote degradation of EGFR and AXL in human tumors. Mice harboring conditional deletion of the LZTR1 gene combined with loss of CDKN2A in the neural progenitor compartment generated peripheral nervous system tumors including schwannoma like and malignant peripheral nervous system tumors (MPNST). Tumors from the LZTR1-mutant mouse model accumulated very high levels of EGFR and AXL and exhibited potent and specific vulnerability to the combinatorial inhibition of EGFR and AXL kinases. These findings explain the mechanism of tumorigenesis associated with LZTR1 inactivation and offer a therapeutic strategy to patients affected by tumors carrying mutations of LZTR1.

Purpose: Studies on de-escalation in radiation therapy (RT) for human papillomavirus-related (HPV(+)) oropharyngeal cancer (OPC) are currently ongoing. This study investigated the current practice regarding the radiation dose and field in the treatment of HPV(+) OPC.Materials and Methods: The Korean Society for Head and Neck Oncology conducted a questionnaire on the primary treatment policy. Among them, for HPV(+) OPC scenarios, radiation oncologists were questioned regarding the field and dose of RT.Results: Forty-two radiation oncologists responded to the survey. In definitive concurrent chemoradiotherapy (CCRT) treatment for stage T2N1M0 OPC, most respondents prescribed a dose of >60 Gy to the primary tonsil and involved ipsilateral lymph nodes. However, eight of the respondents prescribed a relatively low dose of ≤54 Gy. For stage T2N1M0 OPC, postoperative adjuvant RT was prescribed by eight and nine respondents with a lower dose of ≤50 Gy for the ipsilateral tonsil and involved neck, respectively. In definitive CCRT in complete remission after induction chemotherapy for initial stage T2N3M0 OPC, de-escalation of the tonsil and involved neck were performed by eight and seven respondents, respectively. Regarding whether de-escalation is applied in radiotherapy for HPV(+) OPC, 27 (64.3%) did not do it at present, and 15 (35.7%) were doing or considering it.Conclusion: The field and dose of prescribed treatment varied between institutions in Korea. Among them, dose de-escalation of RT in HPV(+) OPC was observed in approximately 20% of the respondents. Consensus guidelines will be set in the near future after the completion of ongoing prospective trials.

본 연구의 목적은 한국판 운동의존성 척도(EDS-K)가 우리나라 태권도선수들에게도 타당하고 신뢰롭게 적용될 수 있는지 여부를 검증하였다. 연구 1에서는 태권도 선수 231명을 대상으로, 연구 2에서는 태권도 선수 355명을 대상으로 이루어졌다. 탐색적, 확인적 요인분석을 통해 구인 타당도를 검증하고 준거변인들과의 상관관계 분석을 통하여 준거타당도 검증과 신뢰도분석을 실시하여 다음과 같은 주요 결과를 추출하였다. 첫째, 탐색적 요인분석을 통하여 21문항 7개의 요인을 추출하였다. 21문항 7요인 척도는 양호한 신뢰도 값을 얻었으며, 확인적 요인분석을 통해 7요인 구조를 확증하였다. 또한 본 척도의 수렴타당성과 판별타당성도 양호한 것으로 나타났다. 열정, 의도적 연습 변인들과 본 연구에서 개발된 7요인들 간의 상관관계분석을 통하여 적절한 준거타당도를 확보하였다. 둘째, 연구 2의 분석결과 연구 1의 요인구조를 재확인하였고, 적절한 수준의 타당도와 신뢰도를 확보하였다. 또한 열정, 완벽주의, 의도적 연습, 수치심과 EDS-R간의 상관분석을 통하여 구인타당도를 재확인하였다. 셋째, 구인타당도 분석 결과, 성별과 학교급간에 따라서 유의한 차이를 보였다. 결론적으로 EDS-K는 한국 태권도선수들의 운동의존성을 신뢰롭고 타당하게 측정할 수 있는 다차원의 도구임을 확인하였다.

The effects of the external stress on memory device characteristics are numerically discussed, and experimental observations are made, based on the wafer curvature method for extraction of stress. An analysis of the interface state is then performed. The external force applied to the device was controlled by depositing a metal film on the wafer backside; then, the residual stress induced on the substrate was extracted. We observed that the dangling bond generated by the residual stress increases the trap site and deteriorates the interface properties. A resulting degradation of cell characteristics occurred, including an increase in the leakage current and degradation of the memory window, featuring a reduction in the oxide/nitride/oxide trap density, which worsens as the magnitude of stress increases. From these results, we concluded that minimizing the stress is essential for retaining the cell characteristics. Especially, our results are expected to be of great help in determining the effect of external force on the memory characteristics during the back-end-of-line processing.

The proteogenomic characterization of human tumors has begun to uncover molecular attributes enriched in different tumor subtypes and proposed a panoply of subtype-specific targets. As these studies lacked experimental testing of potential targets in high-quality cell models accurately reflecting individual tumor subtypes, it remains unclear whether any of the proposed targets retained value for precision medicine. The absence of clinically useful classifiers further hampered translation of proteogenomic information to better diagnose and treat cancer patients. In the case of the brain tumor glioblastoma (GBM), such challenges are exacerbated by tumor heterogeneity and broad therapeutic resistance. Here, we analyzed a large dataset of human GBM to determine the multi-omics features that characterize four GBM subtypes we recently identified through single cell RNAseq analysis. Each subtype exhibits activation of unique hallmark functional traits including distinct sensitivity to inhibitors of mitochondrial respiration for the mitochondrial subtype. The inspection of proteomics, phosphoproteomics, metabolomics, lipidomics and acetylomics data revealed that each GBM subtype has a coherent molecular structure that drives the dominant function and can be extracted by each analytical platform. Stratification of tumors in four functional classes is not a specific attribute of GBM as we were able to unbiasedly identify the same subtypes in breast and lung cancer. To identify actionable targets in GBM we developed an unbiased protein kinase signaling network approach for the selection of master kinases aberrantly activated in each GBM subtype. The experimental follow-up using a library of annotated GBM patient derived organoids (PDOs) established that inhibition of DNA-PK with the clinically tested compound nedisertib radiosensitizes proliferative/progenitor PDOs by exacerbating replication stress-induced DNA damage in this GBM subtype. Furthermore, genetic and pharmacological tools qualified PKCδ as vulnerable target for the broadly resistant glycolytic/plurimetabolic GBM subtype. Thus, together with the targeting of mitochondrial GBM with OXPHOS inhibitors, the functional classification delivers experimentally validated actionable targets for three GBM subtypes. To provide rapid translation of the classifier for precision medicine in GBM, we developed a probabilistic classification tool which determines the probability that a patient’s GBM belongs to one of the four subtypes based on transcriptomic features and exhibits optimal performance when using RNA extracted from either frozen and paraffin embedded tissues. The algorithm is publicly accessible. It can be used in retrospective studies to evaluate the association of therapeutic response with GBM subtypes and as tool for selection criteria in prospective clinical trials. Citation Format: Simona Migliozzi, Young Taek Oh, Luciano Garofano, Hasanain Mohammad, Fulvio D'Angelo, Ryan D. Najac, Franck Bielle, Karima Mokhtari, Jann N. Sarkaria, Michele Ceccarelli, Marc Sanson, Anna Lasorella, Antonio Iavarone. Pathway based analysis of glioblastoma by multi-omics with applications in targeted therapy, prognosis and probabilistic classification [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 4014.

Background: Studies on de-escalation in radiation therapy (RT) for human papillomavirus-related [HPV(+)] oropharyngeal cancer (OPC) are currently ongoing. This study investigated the current practice regarding the radiation dose and field in the treatment of HPV(+) OPC.Methods: The subcommittee on Oropharyngeal Cancer Treatment Guidelines of the Korean Society for Head and Neck Oncology (KSHNO) conducted a questionnaire on the primary treatment policy in five scenarios. Among them, for HPV(+) OPC scenarios, radiation oncologists were questioned regarding the field and dose of RT.Results: Forty-two radiation oncologists responded to the survey. In definitive concurrent chemoradiotherapy (CCRT) treatment for stage T2N1M0 OPC, most respondents prescribed a dose of >60 Gy to the primary tonsil and involved ipsilateral lymph nodes (LNs). However, eight of the respondents prescribed a relatively low dose of ≤54 Gy. Various doses were prescribed for the non-involved chain, and 50 and 54 Gy were the most commonly selected doses. For stage T2N1M0 OPC, postoperative adjuvant RT was prescribed by eight and nine respondents with a lower dose of ≤50 Gy for the ipsilateral tonsil and involved neck, respectively. In definitive CCRT in complete remission after induction chemotherapy for initial stage T2N3M0 OPC, most respondents included the contralateral LNs with less de-escalated radiation fields. De-escalation of the tonsil and involved neck were performed by eight and seven respondents, respectively. Regarding whether de-escalation is applied in radiotherapy for HPV(+) OPC, 27 (64.3%) did not do it at present, and 15 (35.7%) were doing or considering it.Conclusions: The field and dose of prescribed treatment varied between institutions in Korea. Among them, dose de-escalation of RT in HPV(+) OPC was observed in approximately 20% of the respondents. Consensus guidelines will be set in the near future after the completion of ongoing prospective trials.

Purpose: We investigated the prognostic impact of body mass index (BMI) on local recurrence (LR) according to intrinsic subtype in Korean women with early stage, invasive breast cancer. Materials and methods: We included 907 patients with pathological stage T1-2 and N0-1 breast cancer who underwent curative surgery between 2007 and 2012. Systemic treatments were administered in 876 patients (96.6%). In total, 701 patients (77.3%) received radiotherapy. Intrinsic subtypes were determined using immunohistochemical staining results. Results: During the median follow-up period of 72 months, LR as the first failure occurred in 29 patients, including 24 patients with isolated LR. The 5-year cumulative incidence rate of LR was 3.2% among all patients. In the luminal A subtype, a BMI of 30 kg/m2) with the triple negative subtype had an increased risk of LR (relative risk, 3.81; p = 0.048). Conclusion: The present study identified traditionally underestimated risk groups for LR. BMI may diversely influence the rate of LR across intrinsic subtypes in Korean patients with breast cancer.

The name of author Do Hoon Lim was incorrect in the initial online publication. The original article has been corrected.