Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting.

Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells-of-origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin-like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new-generation brain-penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma.

The plasma level of mCRP is linked to cardiovascular disease in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: C-reactive protein (CRP) has two natural isomers: C-reactive protein pentamer (pCRP) and C-reactive protein monomer (mCRP). The levels of CRP are significantly elevated in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). mCRP not only activates the endothelial cells, platelets, leukocytes, and complements, but also has a proinflammatory structural subtype that can localize and deposit in inflammatory tissues. Thus, it regulates a variety of clinical diseases, such as ischemia/reperfusion (I/R) injury, Alzheimer's disease, age-related macular degeneration, and cardiovascular disease. We hypothesized that plasma mCRP levels are related to cardiovascular disease in AAV. METHODS: In this cross-sectional study, 37 patients with AAV were assessed. Brain natriuretic peptide (BNP) and mCRP in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). The acute ST-segment elevation myocardial infarction (STEMI) was diagnosed by coronary angiography, and the Gensini score calculated. Echocardiography evaluated the ejection fraction (EF%), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular mass index (LVMI). Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine, age, and gender. RESULTS: The plasma level of mCRP in AAV was significantly higher than that in healthy volunteers (P < 0.001). Then, mCRP and CRP levels were compared with and without STEMI complications in AAV. The plasma level of mCRP was higher, but that of CRP was lower in STEMI. The plasma level of mCRP was correlated with Birmingham vasculitis activity score (BVAS), eGFR, BNP, EF%, LVEDV, LVESV, LVMI, and STEMI complications' Gensini score in AAV; however, CRP did not correlate with BNP, EF%, LVEDV, LVESV, LVMI, and Gensini score. CONCLUSIONS: The plasma level of mCRP was related to cardiovascular diseases in AAV patients.

Sphingosine-1-phosphate in anti-neutrophil cytoplasmic antibody-associated vasculitis: coagulation-related clinical indicators and complications.

BACKGROUND: Sphingosine-1-phosphate (S1P) plays a significant role in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We collected the plasma samples from 40 patients with AAV and 10 healthy volunteers. The plasma levels of S1P were tested by enzyme-linked immunosorbent assay (ELISA). The levels of serum creatinine (Scr) were tested by rate method, and then the estimated glomerular filtration rate (eGFR) of the patients was calculated from the Scr, age, and gender. Prothrombin time (PT), partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), fibrinogen reduction product (FDP), D-dimer and C-reactive protein (CRP) were tested by turbidimetric inhibition immunoassays. Platelets (PLTs) were tested by fluorescently labeled electrical impedance method. RESULTS: The plasma levels of S1P were significantly higher in AAV patients than in healthy volunteers. Correlation analysis showed that plasma levels of S1P were negatively correlated with glomerular filtration (P=0.022, r = -0.306), and positively correlated with circulating levels of Birmingham vasculitis activity score (BVAS), PLT and D-dimer, (P=0.004, r = 0.443; P<0.001, r = 0.654; P=0.006, r = 0.427). The 40 patients with AAV were classified into three groups: the thromboembolism group (with complications of cerebral infarction and myocardial infarction, n=6), cerebral ischemia group (n=4), and cerebral hemorrhage group (n=2). The plasma levels of S1P were highest in the thromboembolism group and lowest in the cerebral hemorrhage group (P=0.003). CONCLUSIONS: Plasma levels of S1P were associated with circulating levels of D-dimer, PLT and BVAS in the patients with AAV. Hence, plasma S1P level can be used as a biomarker to predict coagulation-related complications in AAV.

Copper-Catalyzed Tandem Radical Cyclization of 8-Ethynyl-1-naphthyl-amines for the Synthesis of 2H-Benzo[e][1,2]thiazine 1,1-Dioxides and its Fluorescence Properties.

A copper-catalyzed radical cascade dehydrogenative cyclization of N-tosyl-8-ethynyl-1-naphthylamines under air is described herein for the synthesis of thioazafluoranthenes. The reaction proceeds smoothly with high efficiency and a broad reaction scope. The product is indeed a new fluorophore and its photophysical properties are also investigated. Based on the results, we are pleased to find that the Stokes shift of amino-linked thioazafluoranthenes in dilute tetrahydrofuran is determined to be 143 nm (4830 cm-1).