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Abstract Neoadjuvant immunochemotherapy (NAIC) achieves superior clinical benefits over neoadjuvant chemotherapy (NAC) in multiple types of human cancers, including gastric adenocarcinoma (GAC). However, it is poorly understood how the malignant epithelial cells and tumor immune microenvironment (TIME) might respond distinctly to NAIC and NAC that underlies therapeutic efficacy. Here treatment‐naive and paired tumor tissues from multiple centers were subjected to pathological, immunological, and transcriptomic analysis. NAIC demonstrated significantly increased rate of pathological complete response compared to NAC (pCR: 25% vs. 4%, p

Abstract Dysregulation of the transforming growth factor‐β (TGF‐β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug‐resistant CSCs. Through a genome‐wide CRISPR activation screen utilizing stem‐like drug‐resistant properties as a readout, the TGF‐β receptor‐associated binding protein 1 (TGFBRAP1) is identified as a TGF‐β‐inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF‐β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF‐β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly‐ubiquitination and proteasomal degradation. Moreover, hyperactive TGF‐β signaling in turn up‐regulates TGFBRAP1 expression in drug‐resistant CSC‐like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF‐β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF‐β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1‐mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF‐β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Abstract Immune checkpoint inhibitors (ICIs) have become a vital part of the therapeutic landscape for non‐small cell lung cancer (NSCLC) in recent years benefiting from their remarkable efficacy. However, ICIs are associated with potentially life‐threatening immune‐related adverse events (irAEs). This study aims to quantify dose dependence and additional influencing factors of both any grade and grade greater than or equal to 3 irAEs in patients with NSCLC treated by ICIs. The trial‐level irAE data was collected and pooled from 129 cohorts in 81 clinical studies. A logit‐transformed meta‐regression model was applied to derive the quantitative relationship of irAE rate and ICI exposure. Programmed cell death‐1 (PD‐1) or programmed cell death ligand‐1 (PD‐L1) inhibitors showed no dose dependence in patients with NSCLC, whereas cytotoxic T lymphocyte–associated antigen 4 (CTLA‐4) inhibitors exhibited a statistically significant dose dependence when used alone or combined with PD‐1 or PD‐L1 inhibitors. Besides, therapy line and combination of ICIs with chemotherapy or target therapy were significant covariates. Hopefully, the results of this study can improve clinicians’ awareness of irAEs and be helpful for clinical decisions during ICI treatment for NSCLC.

Under natural conditions, T-2 toxin can be easily metabolized to HT-2 toxin by deacetylation, and T-2 and HT-2 are usually co-contaminated in grain and feed at a high detected rate. Our previous information indicated that T-2 toxin could injure the function of the intestinal barrier, but the combined toxicity and mechanism of T-2 and HT-2 on the intestinal cells of porcines are still unknown. Therefore, we aimed to explore T-2 and HT-2 individually and combined on cellular viability, cell membrane integrity, the expression of tight junction-related proteins, and the generation of inflammatory factors in porcine intestinal epithelial cells (IPEC-J2). The results showed that T-2 and HT-2, individually or in combination, could induce a decrease in cell viability, an increase in LDH release and IL-1, IL-6, and TNF-α generation, and a decrease in the anti-inflammatory factor IL-10. Based on the analysis of immunofluorescence staining, real-time PCR, and western blotting, the tight junction protein expressions of Claudin-1, Occludin, and ZO-1 were significantly decreased in the T-2 and HT-2 individual or combination treated groups compared with the control. Furthermore, all the parameter changes in the T-2 + HT-2 combination group were much more serious than those in the individual dose groups. These results suggest that T-2 and HT-2, individually and in combination, could induce an intestinal function injury related to an inflammatory response and damage to the intestinal barrier function in porcine intestinal epithelial cells. Additionally, T-2 and HT-2 in combination showed a synergistic toxic effect, which will provide a theoretical basis to assess the risk of T-2 + HT-2 co-contamination in porcine feed.

Cancer metastasis is a process with multi-step complexi坟 and 学parent randomness. In this stu曲 we aimed to establish a stochastic mathematical model to describe the random process of cancer metastasis and predict the drug effect of QAP14 on metastasis in a mouse model. The data of lung metastase s on the 22山 dr after cancer cell implantation with or without the treatment of QAPI4, a new chemical compound, were collected in 4T1 breast cancer BALB/c mice. Based on the exponential growth of the primary tumor and metastatic loci, a joint distribution model of metastasis size and number was developed. Disease profession of metastasis and pre clinical efficacy of QAP14 were modeled. Parameters M and m representing maximum and tninitnutn of metastasis volume were 3.24 and 0.0184 mm5, respectively. The metastasis g-owthratey and metastasis promotion time p were estimated and fixed to be 0.0216 d_1 and 7.8 d, respectively. The efficacy of QAP14 acted on metastasis promotion time and metastasis growth rate constant in an exponential term, and the effect parameter Eecffi and Eectr were 16.6 and 0.327 gmg respectively. In the present study we comprehensively characterized the random process of lung metastasis and efficacy of QAP14 in4Tl breast cancer mice, which mi盘 provide a useful reference for the estabEdiment of a clinical population model of cancer metastasis. [ABSTRACT FROM AUTHOR]

Breast cancer is the second leading cause of cancer death in women mainly due to metastasis, which is closely related to cancer stemness. Evidence has shown that cancer stem-like cells (CSCs), which are responsible for cancer stemness, can be decreased by activating dopamine D1 receptor (D1DR). In the present study, we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21, a newly synthesized compound that can be orally administered, in metastatic breast cancer cells. Our results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4T1 and MDA-MB-231 cells. Cell mobility, including cell migration and invasion, was also remarkably inhibited. Besides, QAP21 significantly inhibited mammosphere formation and decreased CSC proportion, indicating reduced cancer stemness. We further verified that the nuclear factor-kappa B (NF-κB)/Akt/epithelial-mesenchymal transition (EMT) pathway was markedly impacted by QAP21 treatment. Moreover, QAP21 up-regulated the expressions of D1DR and its second messengers, including cAMP and cGMP, which can be increased when D1DR is activated. SCH 23390, a specific D1DR antagonist, partially or completely reversed the above-mentioned effects of QAP21, indicating that D1DR activation might be involved in the underlying mechanism of QAP21. In summary, QAP21 effectively reduced breast cancer stemness and cell mobility, indicating its potential use for metastatic breast cancer therapy. [ABSTRACT FROM AUTHOR]

Low power efficiency is a critical factor that restricts the engineering application of the vertical axis wind turbine (VAWT). In order to improve the efficiency of VAWT and reduce aerodynamic load, an improved aerodynamic performance optimization model for a large VAWT with trailing edge flaps at a medium tip speed ratio (TSR=2.65) is proposed. A numerical simulation is conducted using the SST k-ω turbulence model. The results indicate that compared with the base model, the power coefficient of the model under the synergic motion of pitch and flap can be increased by 12.2%. In addition, the synergic motion of pitch and flap can significantly reduce the thrust and lateral force on the VAWT, which are reduced by 12.4% and 7.5% respectively compared with the base model. The load fluctuation of thrust and lateral force is also significantly lower than that of the base model, which is helpful to reduce the fatigue load on wind turbine. This model is expected to be applied to MW-level VAWT.