Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.P30 CA036727 - NCI NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHS; LB506 - Nebraska Department of Health and Human Services (Nebraska DHHS)Accepted manuscriptSupporting documentatio

The K\"ahler-Ricci flow on surfaces of positive Kodaira dimension

The existence of K\"ahler-Einstein metrics on a compact K\"ahler manifold has been the subject of intensive study over the last few decades, following Yau's solution to Calabi's conjecture. The Ricci flow, introduced by Richard Hamilton has become one of the most powerful tools in geometric analysis. We study the K\"ahler-Ricci flow on minimal surfaces of Kodaira dimension one and show that the flow collapses and converges to a unique canonical metric on its canonical model. Such a canonical is a generalized K\"ahler-Einstein metric. Combining the results of Cao, Tsuji, Tian and Zhang, we give a metric classification for K\"aher surfaces with a numerical effective canonical line bundle by the K\"ahler-Ricci flow. In general, we propose a program of finding canonical metrics on canonical models of projective varieties of positive Kodaira dimension

Phenomenological Scaling of Rapidity Dependence for Anisotropic Flows in 25 MeV/nucleon Ca + Ca by Quantum Molecular Dynamics Model

Anisotropic flows ($v_1$, $v_2$, $v_3$ and $v_4$) of light fragments up till the mass number 4 as a function of rapidity have been studied for 25 MeV/nucleon $^{40}$Ca + $^{40}$Ca at large impact parameters by Quantum Molecular Dynamics model. A phenomenological scaling behavior of rapidity dependent flow parameters $v_n$ (n = 1, 2, 3 and 4) has been found as a function of mass number plus a constant term, which may arise from the interplay of collective and random motions. In addition, $v_4/{v_2}^2$ keeps almost independent of rapidity and remains a rough constant of 1/2 for all light fragments.Comment: 4 pages, 5 figure

Proton irradiation effect on SCDs

The Low Energy X-ray Telescope is a main payload on the Hard X-ray Modulation Telescope satellite. The swept charge device is selected for the Low Energy X-ray Telescope. As swept charge devices are sensitive to proton irradiation, irradiation test was carried out on the HI-13 accelerator at the China Institute of Atomic Energy. The beam energy was measured to be 10 MeV at the SCD. The proton fluence delivered to the SCD was $3\times10^{8}\mathrm{protons}/\mathrm{cm}^{2}$ over two hours. It is concluded that the proton irradiation affects both the dark current and the charge transfer inefficiency of the SCD through comparing the performance both before and after the irradiation. The energy resolution of the proton-irradiated SCD is 212 [email protected] keV at $-60\,^{\circ}\mathrm{C}$, while it before irradiated is 134 eV. Moreover, better performance can be reached by lowering the operating temperature of the SCD on orbit

Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity.

Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin\u27s rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critical modulatory role for VDAC2-dependent mitochondrial Ca(2+) uptake in the regulation of cardiac rhythmicity