Anti-HER-2 engineering antibody ChA21 inhibits growth and induces apoptosis of SK-OV-3 cells

<p>Abstract</p> <p>Background and Aims</p> <p>Anti-HER-2 antibodies targeting distinct epitopes have different biological functions on cancer cells. In a previous study, we demonstrated that anti-HER-2 engineering antibody ChA21 was able to bind to subdomain I of HER-2 extracellular domain. In this study, The effects of ChA21 on growth and apoptosis against ovarian carcinoma cell SK-OV-3 over-expressing HER-2 <it>in vitro </it>and <it>in vivo </it>were investigated.</p> <p>Methods</p> <p>Cell growth inhibition was evaluated by MTT assay. Apoptosis was detected by TUNEL stain, transmission electron microscopy and flow cytometry on cultured cells and tissue sections from nude mice xenografts. The apoptosis-related proteins Bax and Bcl-2 were assessed by immunohistochemistry.</p> <p>Results</p> <p>We found that treatment of ChA21 caused a dose-dependent decrease of cell proliferation <it>in vitro </it>and a significant inhibition of tumor growth <it>in vivo</it>. ChA21 therapy led to a significant increase in the induction of apoptosis, and up-regulated the expression of Bax, while the expression of Bcl-2 was down-regulated.</p> <p>Conclusion</p> <p>These data suggest that ChA21 inhibits the growth and induces apoptosis of SK-OV-3 via regulating the balance between Bax and Bcl-2.</p

Free-ATM: Exploring Unsupervised Learning on Diffusion-Generated Images with Free Attention Masks

Despite the rapid advancement of unsupervised learning in visual representation, it requires training on large-scale datasets that demand costly data collection, and pose additional challenges due to concerns regarding data privacy. Recently, synthetic images generated by text-to-image diffusion models, have shown great potential for benefiting image recognition. Although promising, there has been inadequate exploration dedicated to unsupervised learning on diffusion-generated images. To address this, we start by uncovering that diffusion models' cross-attention layers inherently provide annotation-free attention masks aligned with corresponding text inputs on generated images. We then investigate the problems of three prevalent unsupervised learning techniques ( i.e., contrastive learning, masked modeling, and vision-language pretraining) and introduce customized solutions by fully exploiting the aforementioned free attention masks. Our approach is validated through extensive experiments that show consistent improvements in baseline models across various downstream tasks, including image classification, detection, segmentation, and image-text retrieval. By utilizing our method, it is possible to close the performance gap between unsupervised pretraining on synthetic data and real-world scenarios

Regulators of complement activity mediate inhibitory mechanisms through a common C3b‐binding mode

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Simulation analysis on seismic dynamic response of pile supported tunnels in deep backfill area of soil-rock mixture

To reveal the seismic dynamic response of the pile-supported tunnel group in the soil-rock mixture deep backfill region, a three-dimensional finite element model was established based on the engineering conditions of the subway section and three tunnels with close access lines. Subsequently, the seismic dynamic response of the tunnel lining structure was studied. The results show that: Under the action of seismic, the soil-rock mixture stratum presents nonlinear characteristics with shear failure and plastic deformation. In addition, the acceleration and earth pressure of the soil-rock mixture stratum is in a “saturated” state; The seismic dynamic response of the three tunnels influences each other. The bending moments in the X and Y directions of the tunnel lining cross-section are distributed in “X” and inverted “V” shapes, respectively. Meanwhile, the tensile stress and shear stress are distributed in an “X” shape; Under the action of seismic, the main failure form of tunnel lining is tension shear failure, and the most vulnerable position is the left and right arch foot, followed by the left and right arch shoulder; The bending moment of the pile body changes nonlinearly in the height direction. The most significant bending moment value appears at the top 1/5 of the pile length and the junction of different strata. Furthermore, the most significant horizontal displacement of the lining structure occurs at the tunnel vault

Genome-wide analysis reveals regulatory mechanisms and expression patterns of TGA genes in peanut under abiotic stress and hormone treatments

IntroductionThe TGA transcription factors, plays a crucial role in regulating gene expression. In cultivated peanut (Arachis hypogaea), which faces abiotic stress challenges, understanding the role of TGAs is important.MethodsIn this study, we conducted a comprehensive in analysis of the TGA gene family in peanut to elucidate their regulatory mechanisms and expression patterns under abiotic stress and hormone treatments. Furthermore, functional studies on the representative AhTGA gene in peanut cultivars were conducted using transgenic Arabidopsis and soybean hair roots.ResultsThe genome-wide analysis revealed that a total of 20 AhTGA genes were identified and classified into five subfamilies. Collinearity analysis revealed that AhTGA genes lack tandem duplication, and their amplification in the cultivated peanut genome primarily relies on the whole-genome duplication of the diploid wild peanut to form tetraploid cultivated peanut, as well as segment duplication between the A and B subgenomes. Promoter and Protein-protein interaction analysis identified a wide range of cis-acting elements and potential interacting proteins associated with growth and development, hormones, and stress responses. Expression patterns of AhTGA genes in different tissues, under abiotic stress conditions for low temperature and drought, and in response to hormonal stimuli revealed that seven AhTGA genes from groups I (AhTGA04, AhTGA14 and AhTGA20) and II (AhTGA07, AhTGA11, AhTGA16 and AhTGA18) are involved in the response to abiotic stress and hormonal stimuli. The hormone treatment results indicate that these AhTGA genes primarily respond to the regulation of jasmonic acid and salicylic acid. Overexpressing AhTGA11 in Arabidopsis enhances resistance to cold and drought stress by increasing antioxidant activities and altering endogenous hormone levels, particularly ABA, SA and JA.DiscussionThe AhTGA genes plays a crucial role in hormone regulation and stress response during peanut growth and development. The findings provide insights into peanut's abiotic stress tolerance mechanisms and pave the way for future functional studies

Personalized antiplatelet therapy guided by clopidogrel pharmacogenomics in acute ischemic stroke and transient ischemic attack: A prospective, randomized controlled trial

Background: Clopidogrel is frequently used in patients with ischemic stroke or transient ischemic attack (TIA), but its efficacy is hampered by inter-individual variability, due to genetic differences associated with clopidogrel metabolism. We conducted this randomized controlled trial to validate whether the personalized antiplatelet therapy based on clopidogrel pharmacogenomics and clinical characteristics leads to better clinical outcomes compared with standard treatment.Methods: Patients were randomly divided into the standard group or pharmacogenetic group, in which the pharmacogenetic group required the detection of the genotyping of CYP2C19*2, CYP2C19*3, and CYP2C19*17. Patients were followed up for 90 days for the primary efficacy endpoint of new stroke events, secondary efficacy endpoint of individual or composite outcomes of the new clinical vascular events, and the incidence of disability. The primary safety outcome was major bleeding.Results: A total of 650 patients underwent randomization, among which 325 were in the pharmacogenomics group while 325 were in the standard group. Our study found after a 90-day follow-up, the risk of stroke and composite vascular events in the pharmacogenomics group was lower than that in the standard group. The incidence of disability significantly decreased in the pharmacogenomics group. In addition, no statistically significant differences were observed in bleeding events between the two groups.Conclusion: The present study demonstrates that personalized antiplatelet therapy guided by clopidogrel pharmacogenomics and clinical characteristics can significantly improve the net clinical benefit of ischemic stroke or TIA patients during the 90-day treatment period without increasing bleeding risk

Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors

With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-Å resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs