Antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the advantages of highly specific ...targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Since the first ADC, Mylotarg
(gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as "biological missiles", is leading a new era of targeted cancer therapy. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ADCs. Moreover, we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations, which provide insights for the research and development of novel cancer therapeutics using ADCs.
Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant ...cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy.
The development regulation of the uterine–vaginal junction (UVJ) epithelial folds during the sexual maturation of female birds played crucial roles in the adults’ sperm storage duration and ...fertilization capability. However, there is a lack of studies on it in the breeding field of laying hens. In this study, White Leghorn was used for the morphological and developmental studies. According to the morphological characteristics, the development of the UVJ epithelial folds was classified into 4 stages (morphological stage T1–T4). Significant individual differences were observed simultaneously, which is one of the factors leading to the adults’ UVJ morphological differences. Bulk RNA-seq suggested the different regulations of UVJ epithelial folds were classified into 3 stages (developmental stage S1–S3). Genes enriched in cell proliferation, differentiation, polarity, migration, adhesion and junction were supposed to regulate UVJ epithelial fold formation. Single-cell RNA-sequencing (scRNA-seq) showed significant differences between different types of cells within UVJ at the developmental stage S2. Immunohistochemical studies confirmed that the different proliferation rates between the epithelium and nonepithelium were one of the key factors leading to the formation of UVJ epithelial folds. Genes in the TGF-beta and WNT pathways may play roles in regulating the proliferation and differentiation of epithelium. Some factors, such as CHD2, CDC42, and carbonic anhydrases, were important participants in forming UVJ epithelial folds. This study will provide new thoughts on the differential regulation of fertilization traits from the developmental biology perspective.
In actual farms, individual livestock identification technology relies on large models with slow recognition speeds, which seriously restricts its practical application. In this study, we use deep ...learning to recognize the features of individual cows. Alexnet is used as a skeleton network for a lightweight convolutional neural network that can recognise individual cows in images with complex backgrounds. The model is improved for multiple multiscale convolutions of Alexnet using the short-circuit connected BasicBlock to fit the desired values and avoid gradient disappearance or explosion. An improved inception module and attention mechanism are added to extract features at multiple scales to enhance the detection of feature points. In experiments, side-view images of 13 cows were collected. The proposed method achieved 97.95% accuracy in cow identification with a single training time of only 6 s, which is one-sixth that of the original Alexnet. To verify the validity of the model, the dataset and experimental parameters were kept constant and compared with the results of Vgg16, Resnet50, Mobilnet V2 and GoogLenet. The proposed model ensured high accuracy while having the smallest parameter size of 6.51 MB, which is 1.3 times less than that of the Mobilnet V2 network, which is famous for its light weight. This method overcomes the defects of traditional methods, which require artificial extraction of features, are often not robust enough, have slow recognition speeds, and require large numbers of parameters in the recognition model. The proposed method works with images with complex backgrounds, making it suitable for actual farming environments. It also provides a reference for the identification of individual cows in images with complex backgrounds.
In planetary science, it is an important basic work to recognize and classify the features of topography and geomorphology from the massive data of planetary remote sensing. Therefore, this article ...proposes a lightweight model based on VGG-16, which can selectively extract some features of remote sensing images, remove redundant information, and recognize and classify remote sensing images. This model not only ensures the accuracy, but also reduces the parameters of the model. According to our experimental results, our model has a great improvement in remote sensing image classification, from the original accuracy of 85%-98% now. At the same time, the model has a great improvement in convergence speed and classification performance. By inputting the remote sensing image data of ultra-low pixels (64 * 64) into our model, we prove that our model still has a high accuracy rate of 95% for the remote sensing image with ultra-low pixels and less feature points. Therefore, the model has a good application prospect in remote sensing image fine classification, very low pixel, and less image classification.
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and ...low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
Acute heat stress could induce high mortality and cause huge economic losses in the poultry industry. Although many studies have revealed heat stress-induced injuries of multiple tissues, the main ...target tissue and molecular mechanism of death under acute heat stress was largely unknown. This study systematically compared the transcriptome data of five main visceral tissues in chickens to reveal the response of multiple tissues to acute heat stress and determine the main target tissue of acute heat stress, further revealing the injuries of main target tissue and their potential mechanism by combing pathological section and qRT-PCR technologies. The transcriptome data of five visceral tissues revealed that acute heat stress broadly caused inflammatory response and damaged tissues metabolic homeostasis. Among the five tested visceral tissues, the number of differentially expressed genes in the lung was the highest, and their fold changes were the greatest, indicating that the lung was the main target tissue of acute heat stress. The results of pathological section revealed severe inflammation, emphysema and pulmonary hemorrhage in the lung under acute heat stress. Our study found that some pro-inflammatory genes, including CNTFR, FURIN, CCR6, LIFR and IL20RA, were significantly up-regulated both in the heat-stress and heat-death groups, and their fold changes in the heat-death group were significantly greater than that in the heat-stress group. We also found an anti-inflammatory gene, AvBD9, exhibiting an extremely high expression in the heat-stress group but a low expression in the heat-death group. Our study found that acute heat stress caused multiple tissue injuries broadly and the lung was the main target tissue of acute heat stress in chicken. Acute heat stress caused a severe inflammatory response, emphysema, and pulmonary haemorrhage, The severe inflammatory response in the heat-death group was related to the up-regulation of pro-inflammatory genes and down-regulation of anti-inflammatory genes.
The color of rapeseed (
L.) petal is usually yellow but can be milky-white to orange or pink. Thus, the petal color is a popular target in rapeseed breeding programs. In his study, metabolites and ...RNA were extracted from the yellow (Y), yellow/purple (YP), light purple (LP), and purple (P) rapeseed petals. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), RNA-Seq, and quantitative real-time (qRT-PCR) analyses were performed to analyze the expression correlation of differential metabolites and differential genes. A total of 223 metabolites were identified in the petals of the three purple and yellow rapeseed varieties by UPLC-MS/MS. A total of 20511 differentially expressed genes (DEGs) between P, LP, YP, versus Y plant petals were detected. This study focused on the co-regulation of 4898 differential genes in the three comparison groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation and quantitative RT-PCR analysis showed that the expression of
(
) affects the synthesis of downstream peonidin and delphinidin and is a key gene regulating the purple color of petals in
L. The gene may play a key role in regulating rapeseed flower color; however, further studies are needed to verify this. These results deepen our understanding of the molecular mechanisms underlying petal color and provide the theoretical and practical basis for flower breeding targeting petal color.
A powerful strategy to obtain complex supramolecular materials is the bottom-up construction of noncovalently bound materials by hierarchical self-assembly. This assembly process involves stepwise, ...uniform increases to the architectural complexity of a substrate, starting from discrete precursors and growing in dimensionality through controlled reactivity to a final product. Herein, two orthogonal processes are exploited: coordination-driven self-assembly and hydrogen bonding. The former relies on the predictable formation of metal–ligand bonds wherein the directionalities of the rigid precursors used determines the structural outcome. The latter uses 2-ureido-4-pyrimidinone interfaces that are structurally robust by virtue of the quadruple hydrogen bonding that can occur between subunits. By combining these two processes into a single system, it is possible to generate hierarchical materials that preserve the attractive tunability associated with discrete supramolecular coordination complexes. For instance, the synthesis of a one-dimensional chain comprising linked metalla-rhomboids is readily adapted to a 2D cross-linked hexagonal network by simply selecting a different metal acceptor precursor as an assembly component. The specific interactions between subunits, in this case platinum(II)-pyridyl bonds and the quadruple H-bonding of ureidopyrimidinone, are unchanged, establishing a unique strategy to obtain supramolecular polymers with marked topological differences with minimal synthetic redesign. In addition, the structural rigidity imposed by the inclusion of the platinum metallacycles serves to minimize the formation of cyclic oligomers, increasing the efficacy of formation and improving the properties of the resultant materials. Furthermore, this study taps the potential of organoplatinum(II) metallacycles in materials science.
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