The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.

Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy.

Agents that inhibit bromodomain and extra-terminal domain (BET) proteins have been actively tested in the clinic as potential anticancer drugs. NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy. In this study, we focus on the combination of BET inhibitors (BETis) and NAE inhibitors (NAEis) as a cancer therapeutic strategy and investigate its underlying mechanisms to explore and expand the application scope of both types of drugs. The results showed that this combination synergistically inhibited the proliferative activity of tumor cells from different tissues. Compared to a single drug, combination therapy had a weak effect on cycle arrest but significantly enhanced cell apoptosis. Furthermore, the growth of NCI-H1975 xenografts in nude mice was significantly inhibited by the combination without obvious body weight loss. Research on the synergistic mechanism demonstrated that combination therapy significantly increased the mRNA and protein levels of the proapoptotic gene BIM. The inhibition and knockout of BIM significantly attenuated the apoptosis induced by the combination, whereas the re-expression of BIM restored the synergistic effects, indicating that BIM induction plays a critical role in mediating the enhanced apoptosis induced by the co-inhibition of BET and NAE. Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy.

Tunable High-Sensitivity Four-Frequency Refractive Index Sensor Based on Graphene Metamaterial.

As graphene-related technology advances, the benefits of graphene metamaterials become more apparent. In this study, a surface-isolated exciton-based absorber is built by running relevant simulations on graphene, which can achieve more than 98% perfect absorption at multiple frequencies in the MWIR (MediumWavelength Infra-Red (MWIR) band as compared to the typical absorber. The absorber consists of three layers: the bottom layer is gold, the middle layer is dielectric, and the top layer is patterned with graphene. Tunability was achieved by electrically altering graphene's Fermi energy, hence the position of the absorption peak. The influence of graphene's relaxation time on the sensor is discussed. Due to the symmetry of its structure, different angles of light source incidence have little effect on the absorption rate, leading to polarization insensitivity, especially for TE waves, and this absorber has polarization insensitivity at ultra-wide-angle degrees. The sensor is characterized by its tunability, polarisation insensitivity, and high sensitivity, with a sensitivity of up to 21.60 THz/refractive index unit (RIU). This paper demonstrates the feasibility of the multi-frequency sensor and provides a theoretical basis for the realization of the multi-frequency sensor. This makes it possible to apply it to high-sensitivity sensors.

[Biological Effect of Microplastics with Different Functional Groups on the Bacterial Communities and Metabolic Functions of Zebrafish (Danio rerio) Embryos].

To investigate the influences of functional groups on the biological effects caused by microplastics, the accumulation of three polystyrene microplastics (PS, PS-NH2, and PS-COOH) in zebrafish (Danio rerio) embryos were analyzed, and then the responses of metabolic functions and microbial communities in zebrafish larvae were revealed using the combination of the microbiome and metabolome methods. The results showed that all microplastics could accumulate in zebrafish with concentrations ranging from 143 to 175 µg·g-1, and there were no significant differences in the accumulation potentials among different PS treatments. Exposure to plain PS significantly affected the metabolic capacity of aminoglycosides in zebrafish larvae, whereas the metabolic processes of amino acids were affected by PS-NH2. In the PS-COOH treatment, the metabolic pathways of the tricarboxylic acid cycle, amino acids, and glycolysis in zebrafish were markedly altered. The metabolic functions of zebrafish larvae were changed by all PS microplastics, resulting in toxic effects on zebrafish, and the functional group modification of microplastics may have further enhanced these toxicities. Compared to that in the control, exposure to PS-NH2 significantly reduced the diversity of microbial communities in zebrafish larvae and increased the proportion of Proteobacteria in the composition, leading to an imbalance of the bacterial community in zebrafish and thus disrupting the metabolic functions in the fish. Therefore, the functional modifications of microplastics may significantly alter the related stresses on aquatic organisms, leading to unpredictable ecological risks.

Case report: A lung squamous cell carcinoma patient with a rare EGFR G719X mutation and high PD-L1 expression showed a good response to anti-PD1 therapy.

Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell lung cancer (NSCLC). In this report, we present a case featuring a rare epidermal growth factor receptor (EGFR) mutation accompanied by high programmed death-ligand 1 (PD-L1) expression, demonstrating remarkable therapeutic efficacy through a combination of immunotherapy and chemotherapy. A 77-year-old male with no family history of cancer suffered from upper abdominal pain for more than half months in August 2020 and was diagnosed with stage IV (cT3N3M1c) lung squamous cell carcinoma (LUSC) harboring both a rare EGFR p.G719C mutation and high expression of PD-L1 (tumor proportion score [TPS] = 90%). Treatment with the second-generation targeted therapy drug Afatinib was initiated on September 25, 2020. However, resistance ensued after 1.5 months of treatment. On November 17, 2020, immunotherapy was combined with chemotherapy (Sintilimab + Albumin-bound paclitaxel + Cisplatin), and a CT scan conducted three months later revealed significant tumor regression with a favorable therapeutic effect. Subsequently, the patient received one year of maintenance therapy with Sintilimab, with follow-up CT scans demonstrating subtle tumor shrinkage (stable disease). This case provides evidence for the feasibility and efficacy of immunotherapy combined with chemotherapy in the treatment of EGFR-mutated and PD-L1 highly expressed LUSC.

Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy.

Inhibition of the human ubiquitin-specific protease 7 (USP7), the key deubiquitylating enzyme in regulating p53 protein levels, has been considered an attractive anticancer strategy. In order to enhance the cellular activity of FT671, scaffold hopping strategy was employed. This endeavor resulted in the discovery of YCH2823, a novel and potent USP7 inhibitor.YCH2823 demonstrated remarkable efficacy in inhibiting the growth of a specific subset of TP53 wild-type, -mutant, and MYCN-amplified cell lines, surpassing the potency of FT671 by approximately 5-fold. The mechanism of action of YCH2823 involves direct interaction with the catalytic domain of USP7, thereby impeding the cleavage of ubiquitinated substrates. An increase in the expression of p53 and p21, accompanied by G1 phase arrest and apoptosis, was observed upon treatment with YCH2823. Subsequently, the knockdown of p53 or p21 in CHP-212 cells exhibited a substantial reduction in sensitivity to YCH2823, as evidenced by a considerable increase in IC50 values up to 690-fold. Furthermore, YCH2823 treatment specifically enhanced the transcriptional and protein levels of BCL6 in sensitive cells. Moreover, a synergistic effect between USP7 inhibitors and mTOR inhibitors was observed, suggesting the possibility of novel therapeutic strategies for cancer treatment. In conclusion, YCH2823 exhibits potential as an anticancer agent for the treatment of both TP53 wild-type and -mutant tumors.

Distribution characteristics of reactive silicon in six water bodies in the Yangtze River Basin in China.

Terrestrial silicon (Si) from biogeochemically weathered rocks and soils into oceans must pass through several water bodies, resulting in some Si immobilized. Hence, the knowledge on Si distribution characteristics in different water bodies at a basin scale is helpful to understand Si immobilization. A total of 65 surface sediments and corresponding overlying water samples were sampled from six water bodies (Dianchi Lake, DL; Dadu River, DR; Tuojiang River, TR; Honghu Lake, HL; Donghu Lake, DhL; Taihu Lake, TL) in the Yangtze River Basin of China, total dissolved Si (TDSi) in overlying water and exchangeable Si (Ex-Si), active non-biogenic Si (NBSi), and total acid dissolved Si (TADSi) in sediments were analyzed. Water chemical parameters (pH, EC, and TDP) and sediment components (LOI, TN, TP, and TADFe) showed that the water environment characteristics of six water bodies differed. TDSi differed among regions and between lakes and rivers, significantly higher in water bodies in the upper reaches and rivers than the middle or lower reaches and lakes (p < 0.05), respectively. Ex-Si in sediments in the upper reaches was significantly higher than in the middle or lower reaches (p < 0.05), except for DhL, whose Ex-Si was the highest. Mean TADSi and active NBSi were significantly higher in lakes than rivers (p < 0.05). Oxidation of sediments significantly increased TDSi in overlying water and active NBSi in sediments (p < 0.01). Si forms in six water bodies significantly depended on components of the sediments (e.g. active Ca2+, Mg2+, Fe, and Al3+) and water chemical parameters (p < 0.05). Our results suggest that immobilization of Si in water bodies in the Yangtze River Basin depends on the types of water bodies and sediments, lakes and Fe-Al dominated sediments have a high potential to immobilize Si, but anthropogenic interference should not be ignored.

ARHGAP18 is Upregulated by Transcription Factor GATA1 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma.

Rho GTPase activating protein 18 (ARHGAP18), a member of the RhoGAP gene family that increases GTP hydrolysis and inhibits RhoGTPase, was recently discovered to play a role in the development of breast cancer. However, its exact biological role in hepatocellular carcinoma (HCC) remains unclear. In our present study, we comprehensively assessed ARHGAP18 expression and its correlation with the prognostic value of cancer patients in databases. Cell proliferation and colony formation assays were employed to monitor cell growth. Luciferase reporter assay, Chromatin immunoprecipitation qPCR (ChIP-qPCR), immunofluorescence were performed for mechanism research. The expression of genes and proteins was detected by real-time PCR and western blotting. According to the findings of this research, ARHGAP18 protein levels are increased in HCC tissues compared to adjacent nontumor tissues, and ARHGAP18 overexpression is associated with poor survival. The results of a gain- and loss-of-function experiment with HCC cells in vitro demonstrated that ARHGAP18 stimulated cell proliferation, migration, and invasion. Mechanistically, we found that the transcription factor GATA binding protein 1 (GATA1) could bind to the ARHGAP18 promoter and facilitate ARHGAP18 expression. Further studies revealed that the effects of ARHGAP18 silencing on HCCLM3 and Bel-7402 cells were blocked by GATA1 overexpression. In conclusion, GATA1-mediated ARHGAP18 up-regulation plays an important role in HCC tumorigenesis and might be a potential therapeutic target for HCC.

Stable Operation Induced by Plastic Crystal Electrolyte Used in Ni-Rich NMC811 Cathodes for Li-Ion Batteries.

The LiNi0.8Mn0.1Co0.1O2 (NMC811) cathode material has been of significant consideration owing to its high energy density for Li-ion batteries. However, the poor cycling stability in a carbonate electrolyte limits its further development. In this work, we report the excellent electrochemical performance of the NMC811 cathode using a rational electrolyte based on organic ionic plastic crystal N-ethyl-N-methyl pyrrolidinium bis(fluorosulfonyl)imide C2mpyr[FSI], with the addition of (1:1 mol) LiFSI salt. This plastic crystal electrolyte (PC) is a thick viscous liquid with an ionic conductivity of 2.3 × 10-3 S cm-1 and a high Li+ transference number of 0.4 at ambient temperature. The NMC811@PC cathode delivers a discharge capacity of 188 mA h g-1 at a rate of 0.2 C with a capacity retention of 94.5% after 200 cycles, much higher than that of using a carbonate electrolyte (54.3%). Moreover, the NMC811@PC cathode also exhibits a superior high-rate capability with a discharge capacity of 111.0 mA h g-1 at the 10 C rate. The significantly improved cycle performance of the NMC811@PC cathode can be attributed to the high Li+ conductivity of the PC electrolyte, the stable Li+ conductive CEI film, and the maintaining of particle integrity during long-term cycling. The admirable electrochemical performance of the NMC811|C2mpyr[FSI]:[LiFSI] system exhibits a promising application of the plastic crystal electrolyte for high voltage layered oxide cathode materials in advanced lithium-ion batteries.

Proteasome inhibitors reduce CD73 expression partly via decreasing p-ERK in NSCLC cells.

Ecto-5'-nucleotidase (CD73), encoded by the NT5E gene, mediates tumor immunosuppression and has been targeted for the development of new anticancer drugs. Proteasome inhibitors impair protein degradation by inhibiting proteasome and have been used in the clinic for cancer therapy. Here we report that proteasome inhibitors reduce the protein and mRNA levels of CD73. Among 127 tested small-molecule drugs, proteasome inhibitors were found to consistently decrease the protein and mRNA levels of CD73 in NSCLC NCI-H1299 cells. This effect was further confirmed in different NSCLC cells exposed to different proteasome inhibitors. In those treated cells, the protein levels of ERK and its active form p-ERK, the vital components in the MAPK pathway, were reduced. Consistently, inhibitors of MEK and ERK, another two members of the MAPK pathway, also lowered the protein and mRNA levels of CD73. Correspondingly, treatments with fibroblast growth factor 2 (FGF2), an activator of the MAPK pathway, enhanced the levels of p-ERK and partly rescued the proteasome inhibitor-driven reduction of CD73 mRNA and protein in NSCLC cells. However, exogenous CD73 overexpression in murine Lewis lung carcinoma (LLC) cells was not lowered either in vitro or in vivo, by the treatments with proteasome inhibitors and basically, did not affect their in vitro proliferative inhibition either. In contrast, CD73 overexpression dramatically reduced the in vivo anticancer activity of Bortezomib in immunocompetent mice, with tumor growth inhibition rates from 52.18 % for LLC/vector down to 8.75 % for LLC/NT5E homografts. These findings give new insights into the anticancer mechanisms of proteasome inhibitors.

A fast tomosynthesis method for printed circuit boards based on a multiple multi-resolution reconstruction algorithm.

Digital tomosynthesis (DTS) technology has attracted much attention in the field of nondestructive testing of printed circuit boards (PCB) due to its high resolution and suitability to thin slab objects. However, the traditional DTS iterative algorithm is computationally demanding, and its real-time processing of high-resolution and large volume reconstruction is infeasible. To address this issue, we in this study propose a multiple multi-resolution algorithm, including two multi-resolution strategies: volume domain multi-resolution and projection domain multi-resolution. The first multi-resolution scheme employs a LeNet-based classification network to divide the roughly reconstructed low-resolution volume into two sub-volumes namely, (1) the region of interest (ROI) with welding layers that necessitates high-resolution reconstruction, and (2) the remaining volume with unimportant information which can be reconstructed in low-resolution. When X-rays in adjacent projection angles pass through many identical voxels, information redundancy is prevalent between the adjacent image projections. Therefore, the second multi-resolution scheme divides the projections into non-overlapping subsets, using only one subset for each iteration. The proposed algorithm is evaluated using both the simulated and real image data. The results demonstrate that the proposed algorithm is approximately 6.5 times faster than the full-resolution DTS iterative reconstruction algorithm without compromising image reconstruction quality.

A new dental CBCT metal artifact reduction method based on a dual-domain processing framework.

Objective.Cone beam computed tomography (CBCT) has been wildly used in clinical treatment of dental diseases. However, patients often have metallic implants in mouth, which will lead to severe metal artifacts in the reconstructed images. To reduce metal artifacts in dental CBCT images, which have a larger amount of data and a limited field of view compared to computed tomography images, a new dental CBCT metal artifact reduction method based on a projection correction and a convolutional neural network (CNN) based image post-processing model is proposed in this paper. Approach.The proposed method consists of three stages: (1) volume reconstruction and metal segmentation in the image domain, using the forward projection to get the metal masks in the projection domain; (2) linear interpolation in the projection domain and reconstruction to build a linear interpolation (LI) corrected volume; (3) take the LI corrected volume as prior and perform the prior based beam hardening correction in the projection domain, and (4) combine the constructed projection corrected volume and LI-volume slice-by-slice in the image domain by two concatenated U-Net based models (CNN1 and CNN2). Simulated and clinical dental CBCT cases are used to evaluate the proposed method. The normalized root means square difference (NRMSD) and the structural similarity index (SSIM) are used for the quantitative evaluation of the method.Main results.The proposed method outperforms the frequency domain fusion method (FS-MAR) and a state-of-art CNN based method on the simulated dataset and yields the best NRMSD and SSIM of 4.0196 and 0.9924, respectively. Visual results on both simulated and clinical images also illustrate that the proposed method can effectively reduce metal artifacts.Significance. This study demonstrated that the proposed dual-domain processing framework is suitable for metal artifact reduction in dental CBCT images.

Visible light fingerprint database recovery algorithm based on CP decomposition.

Visible light communication(VLC) is a new method of indoor communication. It can provide an effective solution for indoor positioning. Fingerprint-based visible light positioning(VLP) has been widely studied for its feasibility and high accuracy. The acquisition of 'fingerprint database' is crucial for accurate VLP. However, sparse sensors such as photodiode(PD) can only be arranged because of the space-limited scenario and high costs. Correspondingly, it results in the loss of the fingerprint database. Therefore, it is indispensable to solve the problem of how to effectively and accurately recover the fingerprint database from measurements of sparsely arranged sensors. In this paper, we propose a spatio-temporal constraint tensor completion (SCTC) algorithm based on CANDECOMP/PARAFAC (CP) decomposition to recover the fingerprint database from measurements of sparsely arranged sensors. Specifically, we model the measurements from the spatial and temporal dimensions as a tensor, and formulate the optimization problem based on the low-rank feature of the tensor. To improve the recovery accuracy, spatial and temporal constraint matrices are introduced to effectively constrain the optimization direction when completing the tensor. Spatial constraint matrices are constructed by utilizing the mode-n expansion matrix of the tensor based on the undirected graph theory. Accordingly, the Toeplitz matrix is used as the temporal constraint matrix to excavate the temporal correlation of the tensor. Since the optimization problem is non-convex and difficult to solve, we introduce CP decomposition to decompose the tensor into several factor matrices. By solving the factor matrices, the original tensor is reconstructed. The performance of the proposed SCTC algorithm is confirmed via experimental measured data.

Bioluminescence Contributes to the Adaptation of Deep-Sea Bacterium Photobacterium phosphoreum ANT-2200 to High Hydrostatic Pressure.

Bioluminescence is a common phenomenon in nature, especially in the deep ocean. The physiological role of bacterial bioluminescence involves protection against oxidative and UV stresses. Yet, it remains unclear if bioluminescence contributes to deep-sea bacterial adaptation to high hydrostatic pressure (HHP). In this study, we constructed a non-luminescent mutant of ΔluxA and its complementary strain c-ΔluxA of Photobacterium phosphoreum ANT-2200, a deep-sea piezophilic bioluminescent bacterium. The wild-type strain, mutant and complementary strain were compared from aspects of pressure tolerance, intracellular reactive oxygen species (ROS) level and expression of ROS-scavenging enzymes. The results showed that, despite similar growth profiles, HHP induced the accumulation of intracellular ROS and up-regulated the expression of ROS-scavenging enzymes such as dyp, katE and katG, specifically in the non-luminescent mutant. Collectively, our results suggested that bioluminescence functions as the primary antioxidant system in strain ANT-2200, in addition to the well-known ROS-scavenging enzymes. Bioluminescence contributes to bacterial adaptation to the deep-sea environment by coping with oxidative stress generated from HHP. These results further expanded our understanding of the physiological significance of bioluminescence as well as a novel strategy for microbial adaptation to a deep-sea environment.

Integration of cross-scale milli/microlenses by ion beam etching and femtosecond laser modification.

Integrated cross-scale milli/microlenses offer irreplaceable functions in modern integrated optics with the advantage of reducing the size of the optical system to millimeters or microns. However, the technologies for fabricating millimeter-scale lenses and microlenses are always incompatible, which makes the successful fabrication of cross-scale milli/microlenses with a controlled morphology challenging. Here, ion beam etching is proposed as a means to fabricate smooth millimeter-scale lenses on various hard materials. In addition, by combining femtosecond laser modification and ion beam etching, an integrated cross-scale concave milli/microlens (27,000 microlenses on a lens with a diameter of 2.5 mm) is demonstrated on fused silica, and can be used as the template for a compound eye. The results provide a new, to the best of our knowledge, route for the flexible fabrication of cross-scale optical components for modern integrated optical systems.

Piezophilic Phenotype Is Growth Condition Dependent and Correlated with the Regulation of Two Sets of ATPase in Deep-Sea Piezophilic Bacterium Photobacterium profundum SS9.

Alteration of respiratory components as a function of pressure is a common strategy developed in deep-sea microorganisms, presumably to adapt to high hydrostatic pressure (HHP). While the electron transport chain and terminal reductases have been extensively studied in deep-sea bacteria, little is known about their adaptations for ATP generation. In this study, we showed that the deep-sea bacterium Photobacterium profundum SS9 exhibits a more pronounced piezophilic phenotype when grown in minimal medium supplemented with glucose (MG) than in the routinely used MB2216 complex medium. The intracellular ATP level varied with pressure, but with opposite trends in the two culture media. Between the two ATPase systems encoded in SS9, ATPase-I played a dominant role when cultivated in MB2216, whereas ATPase-II was more abundant in the MG medium, especially at elevated pressure when cells had the lowest ATP level among all conditions tested. Further analyses of the ΔatpI, ΔatpE1 and ΔatpE2 mutants showed that disrupting ATPase-I induced expression of ATPase-II and that the two systems are functionally redundant in MB2216. Collectively, we provide the first examination of the differences and relationships between two ATPase systems in a piezophilic bacterium, and expanded our understanding of the involvement of energy metabolism in pressure adaptation.

Ultrafast Charge-Discharge Capable and Long-Life Na3.9 Mn0.95 Zr0.05 V(PO4 )3 /C Cathode Material for Advanced Sodium-Ion Batteries.

Na4 MnV(PO4 )3 /C (NMVP) has been considered an attractive cathode for sodium-ion batteries with higher working voltage and lower cost than Na3 V2 (PO4 )3 /C. However, the poor intrinsic electronic conductivity and Jahn-Teller distortion caused by Mn3+ inhibit its practical application. In this work, the remarkable effects of Zr-substitution on prompting electronic and Na-ion conductivity and also structural stabilization are reported. The optimized Na3.9 Mn0.95 Zr0.05 V(PO4 )3 /C sample shows ultrafast charge-discharge capability with discharge capacities of 108.8, 103.1, 99.1, and 88.0 mAh g-1 at 0.2, 1, 20, and 50 C, respectively, which is the best result for cation substituted NMVP samples reported so far. This sample also shows excellent cycling stability with a capacity retention of 81.2% at 1 C after 500 cycles. XRD analyses confirm the introduction of Zr into the lattice structure which expands the lattice volume and facilitates the Na+ diffusion. First-principle calculation indicates that Zr modification reduces the band gap energy and leads to increased electronic conductivity. In situ XRD analyses confirm the same structure evolution mechanism of the Zr-modified sample as pristine NMVP, however the strong ZrO bond obviously stabilizes the structure framework that ensures long-term cycling stability.

Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance.

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.

A case of pulmonary aspergillus infection in underground coal mine workers / 中华劳动卫生职业病杂志

The underground environment is dark and humid, and it is easy to breed pathogenic microorganisms. A lump in the right lung of a coal mine underground transport worker was found druing occupational health examination. CT examination showed that the lump was located in the posterior segment of the upper lobe of the right lung, with point strip calcification, liquefaction necrosis, and proximal bronchial stenosis and occlusion. MRI examination FS-T(2)WI and DWI showed "target sign", annular low signal around the central high signal, and low mixed signal around the periphery, and annular high signal in the isosignal lesions on T(1)WI. Then the pulmonary aspergillus infection was confirmed by pathology.

Clinicopathological Features and Prognosis of Patients Newly Diagnosed With Lung Adenocarcinoma With Both EGFR Mutation and C-MET Amplification / 中国医学科学院学报

Objective To explore the clinicopathological features and prognosis of the patients newly diagnosed with lung adenocarcinoma with both EGFR mutation and C-MET amplification.Methods The pathological sections were reviewed.EGFR mutation was detected by amplification refractory mutation system-quantitative real-time polymerase chain reaction,and C-MET amplification by fluorescence in situ hybridization.The clinicopathological features and survival data of the patients newly diagnosed with lung adenocarcinoma with both EGFR mutation and C-MET amplification were analyzed retrospectively.Results In 11 cases of EGFR mutation combined with C-MET amplification,complex glands and solid high-grade components were observed under a microscope in 10 cases except for one case with a cell block,the tissue structure of which was difficult to be evaluated.The incidence of lung adenocarcinoma in the patients with EGFR mutation combined with C-MET amplification at clinical stage Ⅳ was higher than that in the EGFR mutation or C-MET amplification group (all P<0.001),whereas the difference was not statistically significant between the EGFR mutation group and C-MET amplification group at each clinical stage (all P>0.05).There was no significant difference in the trend of survival rate between EGFR gene group and C-MET amplification group (χ2=0.042,P=0.838),while the survival of the patients with EGFR mutation combined with C-MET amplification was worse than that of the patients with EGFR mutation (χ2=246.72,P<0.001) or C-MET amplification (χ2=236.41,P<0.001).Conclusions The patients newly diagnosed with lung adenocarcinoma with EGFR mutation plus C-MET amplification demonstrate poor histological differentiation,rapid progress,and poor prognosis.The patients are often in the advanced stage when being diagnosed with cancer.Attention should be paid to this concurrent adverse driving molecular event in clinical work.With increasing availability,the inhibitors targeting C-MET may serve as an option to benefit these patients in the near future.