BLM helicase inhibition synergizes with PARP inhibition to improve the radiosensitivity of olaparib resistant non-small cell lung cancer cells by inhibiting homologous recombination repair

Objective:We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase(PARP)inhibitor,olaparib,and the Bloom syndrome protein(BLM)helicase inhibitor,ML216,in non-small cell lung cancer(NSCLC)cells.Methods:Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays.Mechanistically,the effects of ML216,olaparib,and radiation on cell and tumor proliferation,DNA damage,cell cycle,apoptosis,homologous recombination(HR)repair,and non-homologous end joining(NHEJ)repair activity were determined.Results:Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells,which was seen as decreased surviving fractions and Rad51 foci,increased total DNA damage,andγH2AX and 53BP1 foci(P<0.05).The expressions of HR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation(P<0.05),while olaparib combined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells.In addition to increases of double strand break(DSB)damage and decreases of Rad51 foci,olaparib combined with ML216 also increased pDNA-PKcs(S2056)foci,abrogated G2 cell cycle arrest,and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo(P<0.05).Moreover,Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair,promoted NHEJ repair,and inactivated cell cycle checkpoint signals both in vitro and in vivo(P<0.05).Conclusions:Taken together,these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLC cells,and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization,as well as providing the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitors and radiotherapy.

Robust exponential stability of uncertain discretetime impulsive switching systems with state delay

A new class of hybrid impulsive and switching models are introduced and their robust exponential stability and control synthesis are addressed. The proposed switched system is composed of stable subsystems and unstable subsystems, which not only involves state delay and norm-bounded time-varying parameter uncertainties, but also contains the impulsive switching effects between the subsystems. Based on the extension of the system dimension and the concept of average dwell time, a kind of practically useful switching rule is presented which guarantees the desired robust exponential stability. A switched state feedback controller is also given.

Rapid identification of two-dimensional materials via machine learning assisted optic microscopy

A combination of Fresnel law and machine learning method is proposed to identify the layer counts of 2D materials.Three indexes,which are optical contrast,red-green-blue,total color difference,are presented to illustrate and simulate the visibility of 2D materials on Si/SiO_(2) substrate,and the machine learning algorithms,which are k-mean clustering and k-nearest neighbors,are employed to obtain thickness database of 2D material and test the optical images of 2D materials via red-green-blue index.The results show that this method can provide fast,accurate and large-area property of 2D material.With the combination of artificial intelligence and nanoscience,this machine learning assisted method eases the workload and promotes fundamental research of 2D materials.