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Relativistic collisionless shocks, which are ubiquitous in the cosmos, play a significant role in various astrophysical phenomena such as gamma-ray bursts, PeVatrons, and supernova shock breakouts. Here we present a demonstration using a compact femtosecond laser system to generate sub-relativistic collisionless shocks (0.03 c ) under astrophysically relevant conditions. We attribute the shock formation to a rapidly growing Weibel instability in a precisely tuning low-density preplasma environment, which resembles the interstellar media near an astrophysical central engine. Owing to this Weibel instability, a 5000 Tesla magnetic field is developed within 2.7 ps, leading to the collisionless shock formation and subsequent breakout at the preplasma boundaries. This platform enables direct investigation of astrophysics related to relativistic collisionless shocks. The achieved parameters bridge the gap between astrophysical observations and controlled laboratory experiments, offering unprecedented opportunities to validate cosmic shock models. Collisionless shock waves at relativistic velocities are ubiquitous in the universe and lead to the generation of energetic ions and radiation. Here, the authors demonstrate the generation of subrelativistic collisionless shock of astrophysical relevance in the laboratory, by means of table-top femtosecond laser pulses focused onto solid targets.

Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane‐type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose‐ and time‐dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase‐3, caspase‐8, and caspase‐9 and poly‐ADP ribose polymerase (PARP) cleavage. RA‐induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK‐shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c‐Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention. Our studies present the latest evidence showing the activity of RA on human osteosarcoma in vitro and in vivo in a primary orthotopic model. Our results show that RA suppresses proliferation and induces apoptosis by modulating ROS‐dependent JNK/c‐Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

HER2-targeting antibody–drug conjugates (ADCs), especially trastuzumab deruxtecan (T-DXd), have revolutionized the treatment landscape of HER2-expressing or mutant cancers. However, undesired adverse events are still inevitable and it is necessary to discover a HER2-directed ADC with better safety profiles. SHR-A1811 is composed of trastuzumab, a cleavable linker and a novel topoisomerase I inhibitor, SHR169265. The results indicated that SHR169265 shows better permeability, strong cytotoxicity and faster systemic clearance than DXd analog (SHR197971). The drug-to-antibody ratio (DAR) of SHR-A1811 was optimized as 6 via balancing efficacy and toxicity. SHR-A1811 showed HER2-dependent growth inhibition against various cell lines and desirable bystander killing capability. SHR-A1811 led to tumor growth inhibition or even regression in a dose-dependent manner, at least comparable as HRA18-C015 (a synthesized T-DXd) and anti-HER2-SHR169265 (DAR 8) in multiple mouse xenograft models with a range of HER2 expression levels. SHR-A1811 exhibited a good pharmacokinetics profile, outstanding stability in plasma across different species and a favorable preclinical safety profile. The highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 40 mg/kg with thymus as the main target organ. The above results suggested that SHR-A1811 is a potential best-in-class anti-HER2 ADC with a highly permeable payload, optimized DAR, great potency and better safety profiles. Currently SHR-A1811 has entered phase II and phase III clinical studies for breast cancer, gastric cancer, colorectal cancer, and NSCLC.

HER2-targeting antibody-drug conjugates (ADCs), especially trastuzumab deruxtecan (T-DXd), have revolutionized the treatment landscape of HER2-expressing or mutant cancers. However, undesired adverse events are still inevitable and it is necessary to discover a HER2-directed ADC with better safety profiles. SHR-A1811 is composed of trastuzumab, a cleavable linker and a novel topoisomerase I inhibitor, SHR169265. The results indicated that SHR169265 shows better permeability, strong cytotoxicity and faster systemic clearance than DXd analog (SHR197971). The drug-to-antibody ratio (DAR) of SHR-A1811 was optimized as 6 via balancing efficacy and toxicity. SHR-A1811 showed HER2-dependent growth inhibition against various cell lines and desirable bystander killing capability. SHR-A1811 led to tumor growth inhibition or even regression in a dose-dependent manner, at least comparable as HRA18-C015 (a synthesized T-DXd) and anti-HER2-SHR169265 (DAR 8) in multiple mouse xenograft models with a range of HER2 expression levels. SHR-A1811 exhibited a good pharmacokinetics profile, outstanding stability in plasma across different species and a favorable preclinical safety profile. The highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 40 mg/kg with thymus as the main target organ. The above results suggested that SHR-A1811 is a potential best-in-class anti-HER2 ADC with a highly permeable payload, optimized DAR, great potency and better safety profiles. Currently SHR-A1811 has entered phase II and phase III clinical studies for breast cancer, gastric cancer, colorectal cancer, and NSCLC.

Gaps in microresistivity imaging data pose challenges for reservoir characterization and formation analysis. To address this, we propose a novel approach that employs two cascaded deep-learning algorithms to fill these gaps. First, a conditional texture and structure dual generative (CTSDG) adversarial network is used to reconstruct the missing portions of the microresistivity imaging data. Next, a diffusion model with enhanced loss functions is employed to improve the resolution of gap-filled imaging data. The new loss function stabilizes the training process by combining traditional reconstruction loss with a weighted contrastive loss that adapts over time. Given the persistent gaps in microresistivity imaging data, we utilize acoustic borehole imaging and core data as training datasets for the CTSDG network. The trained models are then applied to microresistivity imaging data to produce microresistivity imaging data without gaps. This method was tested on data from a gas field, successfully restoring key geological features such as lithology, formation boundaries, fractures, and borehole collapse within the previously incomplete areas. The results demonstrate that the proposed method effectively recovers missing geological features, providing enhanced data for reservoir characterization and formation analysis.

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.