Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which ...subtype patients will be responsive to checkpoint blockade are not fully understood.
We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.
We observed that
mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the
comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of
Meanwhile,
or
-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that
or
mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that
or
mutation patients, especially those with co-occurring
mutations, showed remarkable clinical benefit to PD-1 inhibitors.
This work provides evidence that
and
mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy.
.
Since the founding of the People's Republic of China in 1949, significant achievements have been made in cotton production in China. China has maintained its position as the world's largest cotton ...producer for 33 years (1983–2015), with average annual increases of 3.5 and 3.9% in the unit yield and total output of cotton, respectively. Cotton production has played an extremely important role in the development of the national economy and the improvement of living standards. Although the cotton planting area has been reduced in recent years, the total output has remained relatively unchanged due to the continuous increase in the unit yield. China's dominant position in global cotton production is undoubtedly attributed to the progress and development of cotton cultivation technology. Over the past 70 years, China has established a high-yielding and high-efficiency cotton cultivation mode that corresponds to its national conditions, including a large population and a limited land area. Furthermore, cotton cultivation technology is constantly being innovated and developed to keep pace with the times. In this paper, we review the development of cotton production and cultivation in China over the past 70 years, with a particular focus on the innovation and development of cotton cultivation technology with Chinese characteristics. This review is intended to provide guidance for the sustainable development of China's cotton production in the future and to provide a reference for global cotton production.
Chemotherapy and radiotherapy predominantly improve the clinical outcomes of patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC). Whether this superiority ...goes on when treated with immune checkpoint inhibitors is still unclear. This study sought to determine the predictive value and potential mechanisms of HPV status for the treatment of programmed cell death 1 (PD-1)/ligand 1(PD-L1) inhibitors. We conducted an integrated analysis of the relationships between HPV status and PD-L1, tumor mutation burden (TMB) and inflammation-related immune cells and molecules, based on the analysis of repository databases and resected HNSCC specimens. The pooled analysis of overall survival (OS) and objective response rate (ORR) suggested that HPV-positive patients benefited more from PD-1/PD-L1 inhibitors than HPV-negative patients (OS: hazard ratio (HR) = 0.71, p = 0.02; ORR: 21.9% vs 14.1%, odds ratio (OR) = 1.79, p = 0.01). Analysis of public databases and resected HNSCC specimens revealed that HPV status was independent of PD-L1 expression and TMB in HNSCC. However, HPV infection significantly increased T-cell infiltration, immune effector cell activation and the diversity of T-cell receptors. Notably, HPV-positivity correlated with increased immune cytolytic activity and a T-cell-inflamed gene expression profile. This work provides evidence that HPV status can be used to predict the effectiveness of PD-1 inhibitors in HNSCC, independently of PD-L1 expression and TMB, and probably results from an inflamed immune microenvironment induced by HPV infection.
In the domain of few-shot classification tasks for remote sensing images, the impact of data augmentation is often overlooked, and conventional methods offer only modest gains in classification ...performance. To better exploit the potential of data augmentation in few-shot learning, we propose an innovative data augmentation method tailored to optimize few-shot remote sensing scene classification. We begin by dissecting the relationship between various types of feature distortions and classification performance, introducing an optimal distortion magnitude estimation method for different feature types. Subsequently, we integrate multiple distortion magnitude optimization pathways into the model learning process, achieving a dual optimization of model parameters and distortion magnitudes. The extended data provide the model with distorted samples from multiple feature perspectives, and the dynamic optimization of distortion magnitudes enhances the effectiveness of the extended data for classification. Ultimately, we evaluate the performance of our method on general remote sensing datasets, demonstrating a significant advantage in classification accuracy over baseline methods. This approach offers a new perspective in robustness research for few-shot remote sensing scene classification models based on data augmentation.
The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and ...PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of BT-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8^＋ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.
Human pluripotent stem cells (hPSCs) offer a unique platform for elucidating the genes and molecular pathways that underlie complex traits and diseases. To realize this promise, methods for rapid and ...controllable genetic manipulations are urgently needed. By combining two newly developed gene-editing tools, the TALEN and CRISPR/Cas systems, we have developed a genome-engineering platform in hPSCs, which we named iCRISPR. iCRISPR enabled rapid and highly efficient generation of biallelic knockout hPSCs for loss-of-function studies, as well as homozygous knockin hPSCs with specific nucleotide alterations for precise modeling of disease conditions. We further demonstrate efficient one-step generation of double- and triple-gene knockout hPSC lines, as well as stage-specific inducible gene knockout during hPSC differentiation. Thus the iCRISPR platform is uniquely suited for dissection of complex genetic interactions and pleiotropic gene functions in human disease studies and has the potential to support high-throughput genetic analysis in hPSCs.
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•Rapid and efficient generation of biallelic gene knockouts•Rapid one-step creation of biallelic mutations in multiple genes•Efficient introduction of biallelic, precise nucleotide alterations•Inducible gene knockout during specific stages of hPSC differentiation
iCRISPR, a powerful genome-engineering platform, enables rapid and versatile genome editing in human pluripotent stem cells (hPSCs) and is uniquely suited for studies of human development, physiology, and disease mechanisms.
Human pluripotent stem cells, including induced pluripotent stem cells (iPSCs) and embryonic stem cells, hold great promise for cell‐based therapies, but safety concerns that complicate consideration ...for routine clinical use remain. Installing a “safety switch” based on the inducible caspase‐9 (iCASP9) suicide gene system should offer added control over undesirable cell replication or activity. Previous studies utilized lentiviral vectors to integrate the iCASP9 system into T cells and iPSCs. This method results in random genomic insertion of the suicide switch and inefficient killing of the cells after the switch is “turned on” with a small molecule (eg, AP1903). To improve the safety and efficiency of the iCASP9 system for use in iPSC‐based therapy, we precisely installed the system into a genomic safe harbor, the AAVS1 locus in the PPP1R12C gene. We then evaluated the efficiencies of different promoters to drive iCASP9 expression in human iPSCs. We report that the commonly used EF1α promoter is silenced in iPSCs, and that the endogenous promoter of the PPP1R12C gene is not strong enough to drive high levels of iCASP9 expression. However, the CAG promoter induces strong and stable iCASP9 expression in iPSCs, and activation of this system with AP1903 leads to rapid killing and complete elimination of iPSCs and their derivatives, including MSCs and chondrocytes, in vitro. Furthermore, iPSC‐derived teratomas shrank dramatically or were completely eliminated after administration of AP1903 in mice. Our data suggest significant improvements on existing iCASP9 suicide switch technologies and may serve as a guide to other groups seeking to improve the safety of stem cell‐based therapies.
Therapeutic cells made from induced pluripotent stem cells (iPSCs) have many clinical applications but carry risks. Our improved “suicide switch” is designed to eliminate potentially dangerous cells and protect patients.
Deep convolutional neural networks (CNN) have been widely applied in various fields, especially in the field of object detection. Deep CNN-based models showed great advantages over many traditional ...methods, even so, there are still many specific problems in the application of certain scenarios. In very high resolution (VHR) remote-sensing image datasets, the uncertainty of the object direction angle causes big trouble to the learning of the detector. Although the pooling operation can slightly alleviate the deviation caused by small angle, the feature learning of the objects with larger angle rotation still relies mainly on the sufficiency of sample data or effective data augmentation, which means the insufficiency of the training instances may cause serious performance degradation of the detector. In this paper, we propose a multi-angle box-based rotation insensitive object detection structure (MRI-CNN), which is an extended exploration for typical region-based CNN methods. On the one hand, we defined a set of directionally rotated bounding boxes before learning, and restricted the classification scene in a small angular range by rotated RoI (Region of Interest) pooling. On the other hand, we proposed a more effective screening method of bounding boxes, enabling the detector to adapt to diverse ground truth annotation methods and learn more accurate object localization. We trained our detector with different datasets containing different amount of training data, and the test results showed that the method proposed in this paper performs better than some mainstream detection methods when limited training data are provided in VHR remote-sensing datasets.
Understanding how vascular wall endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) sense and transduce the stimuli of hemodynamic forces (shear stress, cyclic strain, and ...hydrostatic pressure) into intracellular biochemical signals is critical to prevent vascular disease development and progression. ECs lining the vessel lumen directly sense alterations in blood flow shear stress and then communicate with medial SMCs and adventitial FBs to regulate vessel function and disease. Shear stress mechanotransduction in ECs has been extensively studied and reviewed. In the case of endothelial damage, blood flow shear stress may directly act on the superficial layer of SMCs and transmural interstitial flow may be elevated on medial SMCs and adventitial FBs. Therefore, it is also important to investigate direct shear effects on vascular SMCs as well as FBs. The work published in the last two decades has shown that shear stress and interstitial flow have significant influences on vascular SMCs and FBs. This review summarizes work that considered direct shear effects on SMCs and FBs and provides the first comprehensive overview of the underlying mechanisms that modulate SMC secretion, alignment, contraction, proliferation, apoptosis, differentiation, and migration in response to 2-dimensional (2D) laminar, pulsatile, and oscillating flow shear stresses and 3D interstitial flow. A mechanistic model of flow sensing by SMCs is also provided to elucidate possible mechanotransduction pathways through surface glycocalyx, integrins, membrane receptors, ion channels, and primary cilia. Understanding flow-mediated mechanotransduction in SMCs and FBs and the interplay with ECs should be helpful in exploring strategies to prevent flow-initiated atherosclerosis and neointima formation and has implications in vascular tissue engineering.
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