Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.ope

Disign Study of 2-GeV PAL Pulse Stretcher Ring for Nuclear P레처 가속기 설계

Maste

자가포식작용에 의한 Snail 아세틸화가 KRAS/LKB1 동시변이 폐암세포의 침윤성 및 전이성에 미치는 영향 연구

Autophagy is elevated in metastatic tumors and often associated with active epithelial-to-mesenchymal transition (EMT). However, to what extent EMT is dependent on autophagy and the mechanisms by which autophagy facilitates EMT is largely unknown. To address this challenge, I employed a metabolomic approach in KRAS/LKB1 co-mutant (KL) cells that represent an autophagy/EMT co-activated invasive lung cancer subtype for the identification of molecular mechanisms linked to autophagy-driven EMT activation. I found that acetyl-CoA is the key metabolite increased by autophagy in KL cells and that it facilitates the acetylation and stabilization of an EMT inducing transcription factor, Snail. The autophagy/acetyl-CoA/acetyl-Snail axis was further validated in lung tumor tissues and in autophagy-activated pancreatic cancer cells. I identified TFEB-acetylation in KL cells sustains the pro-metastatic autophagy in mTORC1 independent manner. Pharmacological inhibitions of this axis via CAMKK2 inhibitor or ATP citrate lyase (ACLY) inhibitor consistently reduced the metastatic capacity of KL cells in vivo, indicating that this axis could be a promising therapeutic target to suppress metastasis of KL lung cancer and beyond. 자가포식작용은 전이성 종양에서 상승하며 상피-간엽 이행의 활성과의 연관성에 대해 보고되어 왔다. 그러나 상피-간엽 이행이 자가포식작용에 어느 정도 의존하고 있으며 자가포식이 상피-간엽 이행을 촉진하는 기전에 대해서는 잘 알려져 있지 않다. 이에 본 연구자는 자가포식으로 유도되는 상피-간엽 활성화에 관한 기전을 연구하기 위해 자가포식/상피-간엽 이행 공동 활성화를 보이는 침습적 폐암 유형인 KRAS/LKB1 동시변이 세포에서 대사학적 접근 방식을 사용하였다. 본 연구자는 아세틸 조효소 A가 KRAS/LKB1 동시변이 세포에서 자가포식에 의해 증가된 주요 대사 산물이며 상피-간엽 이행 유도 전사 인자인 Snail의 아세틸화 및 안정화를 촉진한다는 것을 발견하였다. 자가포식작용 / 아세틸 조효소 A / Snail 아세틸화로 이루어지는 축은 폐암 종양 조직과 자가포식작용이 활성화 된 췌장암 세포에서 추가로 검증되었다. 더 나아가 본 연구자는 KRAS/LKB1 동시변이 세포에서 TFEB의 아세틸화가 mTORC1 독립적인 방식으로 암전이를 촉진하는 자가포식작용을 지속적으로 유지한다는 것을 확인하였다. CAMKK2 억제제 또는 ACLY 효소 억제제를 통하여 이 축의 약리학적 억제를 시행할 시 생체 내에서 KRAS/LKB1 동시변이 암 세포의 전이 능력이 감소하였으며, 이는 이 축이 KRAS/LKB1 동시변이 폐암의 전이를 억제하는 유망한 치료 표적이 될 수 있음을 나타낸다.prohibition박

Gold(I)-Catalyzed Intramolecular Hydrothiophenylation of N-Thiophen-3-yl Alkynylamides for Accessing Thieno[3,2-b]pyridine-5(4H)-ones: Development of F-Actin Specific Fluorescent Probes

Herein, we describe an original synthetic method for a series of fluorescent thieno[3,2-b]pyridine-5(4H)-one derivatives prepared via the gold(I)-catalyzed 6-endo-dig intramolecular hydrothiophenylation process involving N-thiophen-3-yl alkynylamides. The brightness was improved; emission could be tuned, and larger Stokes shifts were recorded. We also designed and synthesized the phalloidin-based fluorescent chemical probes KF-P1 and KF-P2 to realize fluorescent F-actin imaging.restrictio

Conservative Management of Segmental Multicystic Dysplastic Kidney in Children

OBJECTIVE: To assess the clinical characteristics and natural course of segmental multicystic dysplastic kidney (MCDK). METHODS: We retrospectively analyzed the medical records of 40 patients (43 renal units) diagnosed as having segmental MCDK between January 2002 and June 2014. Segmental MCDK was classified as typical when it was localized to the upper pole of a duplex collecting system, and otherwise as atypical. We investigated involution, associated anomalies requiring surgery, and complications of segmental MCDK. RESULTS: Of 43 renal units, 23 were typical and 20 were atypical. During 71.5 (interquartile range: 37.5-84.1) months of median follow-up period, complete and partial involution were observed in 48% and 26% of the typical group and 30% and 35% of the atypical group, respectively. In the typical group, involution was complete significantly earlier (P = .048) and ipsilateral anomalies were more frequently observed (P = .002). The initiation point of involution and contralateral anomalies were not different in the two groups. Hypertension developed in 1 case with contralateral MCDK and 1 case with contralateral renal agenesis. CONCLUSION: Segmental MCDK is not a rare disease entity, and conservative treatment appears to be sufficient with thorough follow-up, including regular monitoring of blood pressure and renal function, and with ultrasonography.restrictio

Comparison between prepubertal and postpubertal patients with obstructed hemivagina and ipsilateral renal anomaly syndrome

Background: Obstructive hemivagina with ipsilateral renal anomaly (OHVIRA) syndrome is a rare, complex congenital anomaly with an unknown prevalence. However, case reports and small studies on OHVIRA syndrome have increased rapidly in the last 20 years, which may be related to increased use of imaging, surgical techniques, and prenatal sonography. Objective: This study aimed to analyze and compare patients with OHVIRA syndrome diagnosed in the prepubertal and postpubertal periods to understand the disease characteristics and improve clinical management. Study design: A retrospective cohort study was conducted including 65 patients with OHVIRA syndrome who were diagnosed between January 2004 and September 2018 at a tertiary university hospital. Results: Among the 65 patients, 44 patients were diagnosed with OHVIRA syndrome during the prepubertal period and 21 patients were diagnosed postpubertally. Compared with postpubertally diagnosed patients with OHVIRA syndrome, those diagnosed prepubertally were mostly asymptomatic at initial presentation (82% versus [vs.] 0%, P < 0.001), had a higher incidence of ectopic ureter (68% vs. 24%, P = 0.001), and presented with a higher incidence of multicystic dysplastic kidney (61% vs. 19%, P = 0.01). Approximately half of the patients with prepubertal OHVIRA syndrome (53%) showed spontaneous resolution of hemivaginal fluid within 5 years. Among the patients with postpubertally diagnosed OHVIRA syndrome, those in the pain-dominant group had a larger amount of hemivaginal fluid than those in the painless discharge-dominant group (54% vs. 10%, P = 0.036). Superimposed infection of hemivaginal fluid was markedly present in the discharge-dominant group (9% vs. 75%, P = 0.006). Conclusions: Clinical characteristics of patients with OHVIRA syndrome are altered based on the time of initial diagnosis. Follow-up and timely intervention should be proceeded accordingly.restrictio

Fluorescent probe for F-actin detection and use thereof

KIOST-Fluor 화학 골격의 N-4 위치와 C-7 위치에 천연물 phalloidin-linker를 도입하여 F-actin을 효과적 으로 형광 염색할 수 있는 형광 화학 프로브를 합성하는 방법과 고해상도 형광 이미지를 얻는 방