Integrating POLE/POLD1 mutated for immunotherapy treatment planning of advanced stage non-small cell lung cancer.

BACKGROUND: In this study, we evaluated the potential of DNA polymerase epsilon (POLE) and DNA polymerase delta 1 (POLD1) as prognostic biomarkers for immune checkpoint inhibitor (ICI) treatment in patients with advanced stage non-small cell lung cancer (NSCLC). METHODS: Disease stage, PD-L1 positivity, histological subtypes, POLE/POLD1 mutation status, tumor mutation burden (TMB), and response to ICIs in NSCLC cases were derived from AACR GENIE dataset (n = 24 120), TCGA-Pan Lung Cancer dataset (n = 1144), AACR GENIE BPC NSCLC v2.0-public (n = 2004), and Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets dataset (n = 350). The smoking history from TCGA and AACR GENIE datasets was grouped into current, former or never-smokers. RESULTS: POLE and POLD1 genetic alterations were identified in 5% and 2.6% of NSCLC patients, respectively. Current smokers had 9% and 4% of POLE/POLD1 mutations, respectively, versus 1.7% for both POLE and POLD1 mutations prevalence in never-smokers. POLE/POLD1 mutations were associated with elevated mutation counts than those with wild-type (median mutation counts 16 vs. 7, p < 0.0001), more advanced disease stages (stage I disease 15.19% vs. 29.42%), more prevalent squamous histology subtype (21.69% vs. 9.05%, p = 0.0427), and a higher percentage of PD-L1 positivity (66.67% vs. 43.87%, p < 0.001). Treatment with ICIs improved survival in patients with both POLE/POLD1 mutated and those with TMB > 18 (p < 0.001). CONCLUSION: Current smokers have a five-fold increased risk of having POLE mutations than never-smokers. POLE/POLD1 mutation status and TMB > 18 can be a composite biomarker for selecting NSCLC patients with survival benefits to ICI treatment.

HAZMAT Vehicle Reidentification in Road Tunnels Based on the Fusion of Appearance and Spatiotemporal Information.

Vehicles transporting hazardous material (HAZMAT) pose a severe threat to highway safety, especially in road tunnels. Vehicle reidentification is essential for identifying and warning abnormal states of HAZMAT vehicles in road tunnels. However, there is still no public dataset for benchmarking this task. To this end, this work releases a real-world tunnel HAZMAT vehicle reidentification dataset, VisInt-THV-ReID, including 10,048 images with 865 HAZMAT vehicles and their spatiotemporal information. A method based on multimodal information fusion is proposed to realize vehicle reidentification by fusing vehicle appearance and spatiotemporal information. We design a spatiotemporal similarity determination method for vehicles based on the spatiotemporal law of vehicles in tunnels. Compared with other reidentification methods based on multimodal information fusion, i.e., PROVID, Visual + ST, and Siamese-CNN, experimental results show that our approach significantly improves the vehicle reidentification recognition precision.

HMD-Net: A Vehicle Hazmat Marker Detection Benchmark.

Vehicles carrying hazardous material (hazmat) are severe threats to the safety of highway transportation, and a model that can automatically recognize hazmat markers installed or attached on vehicles is essential for intelligent management systems. However, there is still no public dataset for benchmarking the task of hazmat marker detection. To this end, this paper releases a large-scale vehicle hazmat marker dataset named VisInt-VHM, which includes 10,000 images with a total of 20,023 hazmat markers captured under different environmental conditions from a real-world highway. Meanwhile, we provide an compact hazmat marker detection network named HMD-Net, which utilizes a revised lightweight backbone and is further compressed by channel pruning. As a consequence, the trained-model can be efficiently deployed on a resource-restricted edge device. Experimental results demonstrate that compared with some established methods such as YOLOv3, YOLOv4, their lightweight versions and popular lightweight models, HMD-Net can achieve a better trade-off between the detection accuracy and the inference speed.

AMOT130 linking F-actin to YAP is involved in intervertebral disc degeneration.

OBJECTIVES: Dysregulation of YAP by the Hippo signalling is associated with intervertebral disc degeneration (IDD). However, the relationship between the F-actin and Hippo pathway in IDD, and their effects on YAP remain poorly understood. METHODS: The characteristics of Hippo pathway and F-actin the in the NP (nucleus pulposus) and annulus fibrosus of immature, mature, ageing and disc degeneration model rats were observed by immunofluorescence, western blot and qPCR. Nucleus pulposus cells (NPCs) were transfected with lentivirus Sh-LATS A, Sh-LATS B and harvested for SA-ß-gal staining, qPCR, western blotting and immunofluorescence staining to investigate the mechanism of Hippo pathway and F-actin interact in NPCs. RESULTS: We observed moderate decreases in F-actin and YAP expression with age in healthy intervertebral discs (IVDs). F-actin stress fibres distributed throughout the cytoplasm disappeared following treatment with latrunculin B (Lat B), resulting in a punctate distribution. Depletion of large tumour suppressor homologues 1/2 (LATS1/2) did not decrease the rate of cellular senescence, and YAP remained in the cytoplasm following Lat B treatment. Furthermore, angiomotin 130 (AMOT130) was associated with F-actin through a conserved actin-binding domain to retain YAP in the cytoplasm. CONCLUSIONS: This study showed that a mechanism by which Hippo pathway and F-actin synergize to modulate YAP activation and localization in the context of IDD and help to control NPCs proliferation.

Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence.

The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age. Surprisingly, Hippo pathway suppression was accompanied by overexpression of YAP, caused by acute disc injury, suggesting a limited ability for self-repair in IDD. We also demonstrated that YAP is inhibited by cell-to-cell contact via the Hippo pathway in vitro. Phosphorylation by large tumor suppressor kinases 1/2 (LATS1/2) led to cytoplasmic translocation and inactivation of YAP. YAP dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence. Moreover, NPCs were transfected with shYAP and it accelerates the premature senescence of cells by interfered Hippo pathway through YAP. Therefore, our results indicate that the Hippo pathway plays an important role in maintaining the homeostasis of intervertebral discs and controlling NPC proliferation.

Acid-Sensing Ion Channel 1a Regulates Fate of Rat Nucleus Pulposus Cells in Acid Stimulus Through Endoplasmic Reticulum Stress.

Acid-sensing ion channel 1a (ASIC1a) participates in human intervertebral disc degeneration (IVDD) and regulates the destiny of nucleus pulposus cells (NPCs) in acid stimulus. However, the mechanism of ASIC1a activation and its downstream pathway remain unclear. Endoplasmic reticulum (ER) stress also participates in the acid-induced apoptosis of NPCs. The main purpose of this study was to investigate whether there is any connection between ASIC1a and ER stress in an acid-induced nucleus pulposus degeneration model. The IVDs of Sprague-Dawley rats were stained by immunohistochemical staining to evaluate the expression of ASIC1a in normal and degenerated rat nucleus pulposus. ASIC1a expression was also quantified by quantitative real-time-polymerase chain reaction and Western blotting analysis. NPCs were exposed to the culture media with acidity at pH 7.2 and 6.5 for 24 h, with or without 4-phenylbutyrate (4-PBA, a blocker of the ER stress pathway). Cell apoptosis was examined by Annexin V/Propidium Iodide (PI) staining and was quantified using flow cytometry analysis. ASIC1a-mediated intracellular calcium was determined by Ca2+ imaging using Fura-2-AM. Acidity-induced changes in ER stress markers were studied using Western blotting analysis. In vivo, ASIC1a expression was upregulated in natural degeneration. In vitro, acid stimulus increased intracellular calcium levels, but this effect was blocked by knockdown of ASIC1a, and this reversal was partly inhibited by 4-PBA. In addition, blockade of ASIC1a reduced expression of ER stress markers, especially the proapoptotic markers. ASIC1a partly regulates ER stress and promotes apoptosis of NPCs under acid stimulus and may be a novel therapeutic target in IVDD.