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        Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells

        ( Catrin Roolf ),( Jan-niklas Saleweski ),( Arno Stein ),( Anna Richter ),( Claudia Maletzki ),( Anett Sekora ),( Hugo Murua Escobar ),( Xiao-feng Wu ),( Matthias Beller ),( Christian Junghanss ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.5

        Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T- acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with 10 μM up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to 1.94 μM. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer-related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.

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        Degenerative Cervical Myelopathy: A 7-Letter Coding System That Supports Decision-Making for the Surgical Approach

        Luca Papavero,Gregor Schmeiser,Ralph Kothe,Bronek Boszczyk,Oliver Heese,Yoshiharu Kawaguchi,Anna MacDowall,Claes Olerud,Nikolaos Paidakakos,Anastasios Panagiotou,Tobias Pitzen,Marcus Richter,K. Daniel 대한척추신경외과학회 2020 Neurospine Vol.17 No.1

        Objective: To validate with a prospective study a decision-supporting coding system for the surgical approach for multilevel degenerative cervical myelopathy. Methods: Ten cases were presented on an internet platform, including clinical and imaging data. A single-approach (G1), a choice between 2 (G2), or 3 approaches (G3) were options. Senior and junior spine surgeons analyzed 7 parameters: location and extension of the compression of the spinal cord, C-spine alignment and instability, general morbidity and bone diseases, and K-line and multilevel corpectomy. For each parameter, an anterior, posterior, or combined approach was suggested. The most frequent letter or the last letter (if C) of the resulting 7-letter code (7LC) suggested the surgical approach. Each surgeon performed 2 reads per case within 8 weeks. Results: G1: Interrater reliability between junior surgeons improved from the first read (κ=0.40) to the second (κ=0.76, p<0.001) but did not change between senior surgeons (κ=0.85). The intrarater reliability was similar for junior (κ=0.78) and senior (κ=0.71) surgeons. G2: Junior/senior surgeons agreed completely (58%/62%), partially (24%/23%), or did not agree (18%/15%) with the 7LC choice. G3: junior/senior surgeons agreed completely (50%/50%) or partially (50%/50%) with the 7LC choice. Conclusion: The 7LC showed good overall reliability. Junior surgeons went through a learning curve and converged to senior surgeons in the second read. The 7LC helps less experienced surgeons to analyze, in a structured manner, the relevant clinical and imaging parameters influencing the choice of the surgical approach, rather than simply pointing out the only correct one.

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