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WEE1 has emerged as an attractive target in epithelial ovarian cancer (EOC), but how EOC cells may alter their sensitivity to WEE1 inhibition remains unclear. Here, through a cell cycle machinery- related gene RNAi screen, we found that targeting outer dense fiber of sperm tails 2-like (ODF2L) was a synthetic lethal partner with WEE1 kinase inhibition in EOC cells. Knockdown of ODF2L robustly sensitized cells to treatment with the WEE1 inhibitor AZD1775 in EOC cell lines in vitro as well as in xenografts in vivo. Mechanistically, the increased sensitivity to WEE1 inhibition upon ODF2L loss was accompanied by accumulated DNA damage. ODF2L licensed the recruitment of PKMYT1, a functionally redundant kinase of WEE1, to the CDK1-cyclin B complex and thus restricted the activity of CDK1 when WEE1 was inhibited. Clinically, upregulation of ODF2L correlated with CDK1 activity, DNA damage levels, and sensitivity to WEE1 inhibition in patient-derived EOC cells. Moreover, ODF2L levels predicted the response to WEE1 inhibition in an EOC patient- derived xenograft model. Combination treatment with tumor-targeted lipid nanoparticles that packaged ODF2L siRNA and AZD1775 led to the synergistic attenuation of tumor growth in the ID8 ovarian cancer syngeneic mouse model. These data suggest that WEE1 inhibition is a promising precision therapeutic strategy for EOC cells expressing low levels of ODF2L., Introduction Epithelial ovarian cancer (EOC), the most common subtype of ovarian cancer, ranks fifth in cancer-related deaths among women (1, 2). EOC is more than a single disease, as it [...]

Spin‐orbital angular momentum conversion (SOC) of light has found applications in classical and quantum optics. However, the existing SOC elements suffer severe restrictions on broadband integrated applications at miniature scales, due to bulky configurations, single function, and failing to control the dispersion. Herein, a high‐efficiency broadband achromatic method for independently and elaborately engineering the dispersion and the SOC of light based on a cascaded metasurface device is proposed. The metadevice is capable of efficiently decoupling the SOC from the modulation of dispersion with high‐broadband focusing efficiency up to 75%. For the proof of concept, the generation of high‐efficiency achromatic‐focused and spin‐controlled optical vortices with switchable topological charge (lσ=+1=1$l^{\sigma = + 1} = 1$ and lσ=−1=2$l^{\sigma = - 1} = 2$) is successfully demonstrated. The presence of achromatically and highly concentrated optical vortices with tunable photonic angular momentum using spin as an optical knob makes the proposed ultracompact and multifunctional metadevice a promising platform for optical micromanipulation at nanoscale dimensions. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the initial clinical response of ovarian cancer patients to first-line platinum-based chemotherapy is often excellent, most patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. DNA repair is the best-known effector of resistance to platinum-based agents, which damages DNA and activates DNA damage response. Two major DNA repair pathways exist, including homologous recombination (HR) and nonhomologous end joining (NHEJ). While the role of HR in platinum resistance is well studied, how NHEJ machinery affects platinum resistance in ovarian cancer remains largely unexplored. The goal of the current study is to decipher how NHEJ is involved in platinum resistance in ovarian cancer. Our study demonstrates XRCC4 in the NHEJ pathway specifically contributes to platinum resistance by mitigating the DNA damage caused by platinum drugs and provides preclinical evidence for targeting XRCC4 as a new strategy to battle cisplatin resistance in ovarian cancer treatment. DNA double-strand breaks (DSBs) caused by platinum drugs are dangerous lesions that kill cancer cells in chemotherapy. Repair of DSB by homologous recombination (HR) and nonhomologous end joining (NHEJ) is frequently associated with platinum resistance in ovarian cancer. While the role of the HR pathway and HR-targeting strategy in platinum resistance is well studied, dissecting and targeting NHEJ machinery to overcome platinum resistance in ovarian cancer remain largely unexplored. Here, through an NHEJ pathway-focused gene RNAi screen, we found that the knockdown of XRCC4 significantly sensitized cisplatin treatment in the platinum-resistant ovarian cancer cell lines. Moreover, upregulation of XRCC4 is observed in a panel of platinum-resistant cell lines relative to the parental cell lines, as well as in ovarian cancer patients with poor progression-free survival. Mechanistically, the increased sensitivity to cisplatin upon XRCC4 knockdown was caused by accumulated DNA damage. In cisplatin-resistant ovarian cancer, the JNK-cJUN complex, activated by cisplatin, translocated into the nucleus and promoted the transcription of XRCC4 to confer cisplatin resistance. Knockdown of XRCC4 or treatment of the JNK inhibitor led to the attenuation of cisplatin-resistant tumor growth in the xenograft mouse models. These data suggest targeting XRCC4 is a potential strategy for ovarian cisplatin resistance in ovarian cancer. [ABSTRACT FROM AUTHOR]

In this paper, a marine dual fuel diesel engine fueled with the natural gas (NG: 60%, 70% and 80%) ignited by the biodiesel-diesel blended fuel (25%, 50% and 75% biodiesel by volume) was studied under different conditions. Based on the experiment, a computational fluid dynamics (CFD) model was established, and an improved chemical kinetic mechanism was developed to simulate the fuel spray process and combustion process. The ignition, combustion and emission characteristics of diesel engine fueled with different blended fuels were investigated under different load conditions. In addition, the temperature sensitivity of methane mole fraction with different NG energy fractions was analyzed at the 800 K and 1000 K. The results showed that the additions of NG and biodiesel in the blended fuel had a significant effect on the combustion and emission characteristics of the diesel engine. The starting of combustion (SOC) of the dual fuel engine lagged with the increases of NG and biodiesel content. The maximum enhancement of SOC reached 0.72°CA. The biggest influence on temperature was R122, which was the main reason for the shorter ignition delay during the combustion process. In all cases, NO x , CO and soot emissions decreased with increasing NG energy fraction. The maximum values of NO x , CO and soot emissions reached 1590 ppm, 461 ppm and 1.42 E−07 kg. Considering the combustion and emission characteristics of the engine, the best fuel blending ratio was EF80-B25. • A marine dual fuel diesel engine fueled with the natural gas ignited by the biodiesel-diesel blended fuel is investigated. • An improved 3D model and chemical kinetics mechanism are developed. • The optimum fuel mixture ratio of diesel engine is obtained. • The temperature sensitivity of methane mole fraction with different NG energy fractions is analyzed. [ABSTRACT FROM AUTHOR]