Search

Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1‐DXd) is elucidated. DAC treatment significantly enhanced anti‐tumor efficacy of I1‐DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1‐DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment. [ABSTRACT FROM AUTHOR]

In clinical practice, the diagnosis of ulcerative colitis (UC) mainly relies on a comprehensive analysis of a series of signs and symptoms of patients. The current biomarkers for diagnosis of UC and prognostic prediction of anti‐TNF‐α therapy are inaccurate. The present study aimed to perform an integrative analysis of gene expression profiles in patients with UC. A total of seven datasets from the GEO database that met our strict inclusion criteria were included. After identifying differentially expressed genes (DEGs) between UC patients and healthy individuals, the diagnostic and prognostic utility of the DEGs were then analyzed via least absolute shrinkage and selection operator and support‐vector machine recursive feature elimination. Subgroup analyses of the treated and untreated groups, as well as the treatment‐response group and non‐response group, were also performed. Furthermore, the relationship between the expressions of UC‐related genes and infiltration of immune cells in the course of treatment was also investigated. Immunohistochemical (IHC) assay was used to verify the gene expression in inflamed UC tissues. When considering all the applied methods, DUOX2, PI3, S100P, MMP7, and S100A8 had priority to be defined as the characteristic genes among DEGs. The area under curve (AUC) of the five genes, which were all consistently over‐expressed, based on an external validation dataset, were all above 0.94 for UC diagnosis. Four of the five genes (DUOX2, PI3, MMP7, and S100A8) were down‐regulated between treatment‐responsive and nonresponsive patients. A significant difference was also observed concerning the infiltration of immune cells, including macrophage and neutrophil, between the two groups (treatment responsive and nonresponsive). The changes in the expression of DUOX2 and MMP7 based on the IHC assay were highly consistent with the results obtained in the current study. This confirmed the mild to moderate diagnostic and predictive value of DUOX2 and MMP7 in patients with UC. The conducted analyses showed that the expression profile of the five identified biomarkers accurately detects UC, whereas four of the five genes evidently predicted the response to anti‐TNF‐α therapy. [ABSTRACT FROM AUTHOR]

The relationship between minimum sea level pressure (MSLP) and maximum wind speed, is a commonly employed metric for assessing tropical cyclone (TC) forecast skill. However, accurately reproducing this relationship in TC forecasts is challenging. By introducing a new air‐sea momentum flux scheme considering both wave state and saturation (decrease) effect at high winds into a fully coupled atmosphere‐ocean‐wave model, our numerical results reveal that the maximum wind speed and MSLP respond oppositely to the air‐sea momentum flux change. The simulated wind‐pressure relationship aligns well with observations when the new flux scheme is used. This study highlights the large sensitivity of wind‐pressure relationship to the air‐sea momentum flux parameterization at high winds. Furthermore, the air‐sea momentum flux has a significant effect on ocean wave characteristics and sea surface temperature (SST) cooling in TC simulations. Plain Language Summary: Although great progresses have been made in TC track forecasting in recent years, the improvement of TC intensity lags far behind that of TC track. One notable challenge is to represent the observed wind‐pressure relationship. Utilizing a fully coupled atmosphere‐ocean‐wave model, this study suggests that the simulated wind‐pressure relationship is tied to air‐sea momentum flux configuration in the model. Our numerical results reveal that the maximum wind speed and minimum sea level pressure varies differently with the air‐sea momentum flux. The proposed new air‐sea momentum flux scheme successfully reproduced this relationship compared with observations. Wave properties and sea surface temperature response to momentum flux are also evaluated in this work. The findings emphasize the importance of understanding the air‐sea interaction at high wind speeds for improving TC prediction. Key Points: The maximum wind speed and minimum sea level pressure (MSLP) respond oppositely to the air‐sea momentum flux changes, considering both wave state effect and drag coefficient saturation (decrease) at high windsThe maximum surface wind of tropical cyclone (TC) is more sensitive to the air‐sea momentum flux than the MSLPThe introduction of new air‐sea momentum scheme at high winds enhances the representation of TC wind‐pressure relationship and significant wave heights [ABSTRACT FROM AUTHOR]