In the financial field, texts such as news and commentaries, as carriers of public opinion, have the function of reflecting investor sentiment, influencing investment decisions and market trends, and ...extracting positive or negative sentiment from them in a timely manner is very important to the investment decisions of fintech companies and investors. However, financial sentiment analysis is challenging due to issues such as unclear sentiment polarity of financial texts, high context-dependency, and highly specialised and specific expressions of the linguistic features of financial texts. In order to overcome these challenges, we design a hybrid topic feature and pre-trained model financial text sentiment analysis model, and we design the method of improved attention mechanism to optimise the model iteratively, the improved attention mechanism reduces the noise caused by the improper allocation of attention to a single word through adaptive attention threshold, attention weight masking mechanism, so as to capture more contextual information and avoid the loss of information, thus improving the stability of the model. This improves the stability of the model. The introduction of thematic features enables the model to capture potential semantic structures and long-distance word associations in the text to enhance the understanding of text context. The experimental results show that the method has an improvement of 2.05%-7.27% in F1 value compared with the baseline method, which is suitable for financial text sentiment analysis.
Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor ...of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ...ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC.
Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC.
We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo.
Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.
Overall survival for patients with ovarian cancer (OC) has shown little improvement for decades meaning new therapeutic options are critical. OC comprises multiple histological subtypes, of which the ...most common and aggressive subtype is high-grade serous ovarian cancer (HGSOC). HGSOC is characterized by genomic structural variations with relatively few recurrent somatic mutations or dominantly acting oncogenes that can be targeted for the development of novel therapies. However, deregulation of pathways controlling homologous recombination (HR) and ribosome biogenesis has been observed in a high proportion of HGSOC, raising the possibility that targeting these basic cellular processes may provide improved patient outcomes. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has been approved to treat women with defects in HR due to germline
mutations. Recent evidence demonstrated the efficacy of targeting ribosome biogenesis with the specific inhibitor of ribosomal RNA synthesis, CX-5461 in v-myc avian myelocytomatosis viral oncogene homolog (MYC)-driven haematological and prostate cancers. CX-5461 has now progressed to a phase I clinical trial in patients with haematological malignancies and phase I/II trial in breast cancer. Here we review the currently available targeted therapies for HGSOC and discuss the potential of targeting ribosome biogenesis as a novel therapeutic approach against HGSOC.
Intracellular vesicle transport pathways are critical for neuronal survival and central nervous system development. The Vps-C complex regulates multiple vesicle transport pathways to the lysosome in ...lower organisms. However, little is known regarding its physiological function in mammals. We deleted Vps18, a central member of Vps-C core complex, in neural cells by generating Vps18F/F; Nestin-Cre mice (Vps18 conditional knock-out mice). These mice displayed severe neurodegeneration and neuronal migration defects. Mechanistic studies revealed that Vps18 deficiency caused neurodegeneration by blocking multiple vesicle transport pathways to the lysosome, including autophagy, endocytosis, and biosynthetic pathways. Our study also showed that ablation of Vps18 resulted in up-regulation of β1 integrin in mouse brain probably due to lysosome dysfunction but had no effects on the reelin pathway, expression of N-cadherin, or activation of JNK, which are implicated in the regulation of neuronal migration. Finally, we demonstrated that knocking down β1 integrin partially rescued the migration defects, suggesting that Vps18 deficiency-mediated up-regulation of β1 integrin may contribute to the defect of neuronal migration in the Vps18-deficient brain. Our results demonstrate important roles of Vps18 in neuron survival and migration, which are disrupted in multiple neural disorders.
Background: The physiological function of Vps18 in mammals is unknown.
Results: Deleting Vps18 in mice leads to neurodegeneration by disrupting multiple vesicle transport pathways to lysosomes and impairs neuron migration via accumulation of β1 integrin.
Conclusion:Vps18 contributes to neuron survival and migration.
Significance: This study demonstrates the critical functions of Vps18-mediated vesicle transport pathways in mammalian brain development.
► We examine neuron dendrite development in Vps18 conditional knockout mice. ► Lysosome degradative function is required for Purkinje cell dendrite development. ► Lox is degraded by lysosome. ► ...Lysosome regulates Purkinje cell dendrite development through degrading Lox.
Dendrite development occupies a central position in the formation of nervous system. However, whether lysosomal degradative function is required for dendritogenesis of neurons remains unknown. We have recently demonstrated the critical role of Vps18 in the lysosomal degradation pathway in mice. Here, we report that Vps18 deficiency severely blocks the dendrite development of Pukinje cells but not cerebral cortical neurons. Furthermore, we also demonstrate that the lysyl oxidase (Lox) protein is degraded through lysosome and accumulated in the Vps18 deficient cerebellum but not in cerebral cortices. Our results suggest that lysosome regulates dendritogenesis of Purkinje cells though degrading Lox.
The traditional oriented FAST and rotated BRIEF（ORB） algorithm has problems of instability and repetition of keypoints and it does not possess scale invariance. In order to deal with these drawbacks, ...a modified ORB（MORB） algorithm is proposed. In order to improve the precision of matching and tracking, this paper puts forward an MOK algorithm that fuses MORB and Kanade-Lucas-Tomasi（KLT）. By using Kalman, the object＇s state in the next frame is predicted in order to reduce the size of search window and improve the real-time performance of object tracking. The experimental results show that the MOK algorithm can accurately track objects with deformation or with background clutters, exhibiting higher robustness and accuracy on diverse datasets. Also, the MOK algorithm has a good real-time performance with the average frame rate reaching 90.8 fps.
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