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Pacific Meridional Mode (PMM) is known to be significantly correlated with tropical cyclone (TC) genesis over the western North Pacific (WNP), while the stability of their relationship remains unknown. Here we found that their relationship is nonstationary, which depends on the phase of Pacific Decadal Oscillation (PDO). During the PDO warm phases, the PMM‐emanated cyclonic circulation and ascending motion can propagate to the entire WNP due to the enhanced background convection. In contrast, during the PDO cold phases, the PMM‐resulted cyclonic circulation and ascending motion are confined to the eastern WNP, while the compensated descending motion prevails in the western WNP. Accordingly, the PMM‐induced consistent (inconsistent) changes in large‐scale conditions across the western and eastern WNP act to strengthen (weaken) the relationship between the PMM and WNP TC genesis during the PDO warm (cold) phases. The result provides further guidance for improving seasonal prediction of TC genesis. Plain Language Summary Billions of people in the Pacific islands and Asian coastal regions are subject to enormous tropical cyclone (TC) induced disasters. The Pacific Meridional Mode (PMM), a seasonally evolving mode of coupled climate variability, has a prominent impact on TC genesis in the western North Pacific (WNP) and is usually used as an important predictor for seasonal forecasting of TC genesis. However, stability in the relationship between PMM and TC genesis remains unclear. Here we found that their relationship is nonstationary and depends on the phase of the Pacific Decadal Oscillation (PDO), a decadal fluctuation of the Pacific Ocean. The result highlights the crucial role of PDO in modulating the relationship between the PMM and WNP TC genesis and thus provides further guidance for seasonal forecasting scheme of TC genesis. Key Points The relationship between the Pacific Meridional Mode (PMM) and tropical cyclone genesis over the western North Pacific is nonstationary The nonstationary relationship stems from the diverse atmospheric responses to PMM that depend on the phase of Pacific Decadal Oscillation

Epigallocatechin gallate (EGCg), an abundant phytochemical in green tea, is an antioxidant that also binds proteins and complex metals. After gastrointestinal absorption, EGCg binds to serum albumin in the hydrophobic pocket between domains IIA and IIIA and overlaps with the Sudlow I site. Serum albumin also has two metal binding sites, a high-affinity N-terminal site (NTS) site that selectively binds Cu(II), and a low-affinity, less selective multi-metal binding site (MBS). We proposed to determine whether EGCg binds or reacts with Cu(II)-serum albumin using fluorescence, UV–Visible and electron paramagnetic resonance (EPR) spectroscopy. Our results suggest that when serum albumin is loaded with Cu(II) in both sites, EGCg binds to the MBS-Cu(II) and reduces the copper to Cu(I). EGCg does not bind to or react with Cu(II) in the high-affinity NTS site. Potential consequences include changes in copper homeostasis and damage from pro-oxidative Fenton reactions.

Prostate cancer (PCa) has the second highest incidence of malignancies occurring in men worldwide. The first-line therapy of PCa is androgen deprivation therapy (ADT). Nonetheless, most patients progress to castration-resistant prostate cancer (CRPC) after being treated by ADT. As a second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ) is the current mainstay of new endocrine therapies for CRPC in clinical use. However, almost all patients develop resistance during AR antagonist therapy due to various mechanisms. At present, ENZ resistance (ENZR) has become challenging in the clinical treatment of CRPC. AR splice variant 7 (AR-V7) refers to a ligand-independent and constitutively active variant of the AR and is considered a key driver of ENZR in CRPC. In this review, we summarize the mechanisms and biological behaviors of AR-V7 in ENZR of CRPC to contribute novel insights for CRPC therapy.

Examined the synergistic development and spatio-temporal evolution of China’s multi-level medical insurance system (MMIS) on a macroscopic level. We assess the comprehensive development of the MMIS across China’s 31 provinces from 2011 to 2020 by constructing a comprehensive indicators evaluation model. Subsequently, a coupling coordination index (CCI) model is employed to provide precise insights into the coupling coordination effects among various medical insurance schemes comprising MMIS. Lastly, spatial autocorrelation analysis is conducted to evaluate both the global and local spatio-temporal evolutionary characteristics of MMIS. The CCI of MMIS at the national average level exhibited a fluctuating upward trend, progressing from the moderate disorder recession degree (0.287) in 2011 to the well-coordinated degree (0.887) in 2020. However, the majority of provinces (83.87%) still lingered within the realm of barely coordinated degree ([0.500–0.600]). Specifically, the CCI within the eastern coastal region surpassed that of the western and central regions, with the central region showing the most pronounced increase in CCI. Over the past decade, MMIS demonstrated significant spatial agglomeration, as evidenced by the global Moran’s I ranging from [0.1668–0.3037]. Furthermore, findings from local spatial autocorrelation analysis suggest a gradual attenuation in the spatial clustering disparity of CCI across various provinces. Government ought to focus on the spatio-temporal evolution patterns of MMIS, and strengthen cooperation between the government and market in health governance, while utilizing information technology and data sharing to improve the overall quality of medical insurance benefits.

The alveolar epithelium plays a critical role in respiratory function, facilitating air exchange and serving as a barrier against inhaled pathogens. Its unique three-dimensional architecture, in which epithelial cells grow on spherical alveolar structures, significantly increases the surface area-to-volume ratio for efficient gas exchange but poses challenges for in vitro reconstruction. Here, we present a biomimetic alveolar model based on gelatin methacryloyl (GelMA) hydrogel microspheres with precisely controlled sizes and composition fabricated via microfluidic technology. These microspheres function as micro-scaffolds for cell adhesion and growth, and an oxygen-permeable honeycomb microwell array facilitates the rapid assembly of cell-laden microspheres into physiologically relevant alveolar-like structures. Using this model, the effects of toxic gas exposure and pathogen infection, and demonstrated its potential use for both basic physiological studies and pathological applications, was investigated. This system recapitulates key features of the alveolar microenvironment and offers a versatile platform for respiratory research and drug screening.

PurposeTo compare the efficacy and safety of bipolar and monopolar transurethral resection of bladder tumors (TURBT) in non-muscle invasive bladder cancer (NMIBC) treatment.MethodsA systematic search of all Randomized Controlled Trials (RCTs), which compared bipolar TURBT (bTURBT) and monopolar TURBT (mTURBT) in NMIBC treatment, were performed in PubMed, Web of Science, Cochrane Library and Embase up to February 1, 2019. We evaluated their efficacy by operative time, hospitalization time, catheterization time, and recurrence rate. While obturator jerk, bladder perforation, thermal damage, and overall complications were used to evaluate their safety.ResultsA total of 13 RCTs, involving 2379 patients, were included. There were no statistically significant differences in efficacy between bTURBT and mTURBT in NMIBC treatment, such as operative time (p = 0.12), hospitalization time (p = 0.13), catheterization time (p = 0.50), and recurrence rate (p = 0.88). Compared to the safety in mTURBT in NMIBC treatment, no significant advantages were observed in that in bTURBT as well, such as obturator jerk (p = 0.12), bladder perforation (p = 0.11), thermal damage (p = 0.24), and overall complications (p = 0.65).ConclusionsOur analysis demonstrated that bTURBT has no significant advantages in efficacy and safety in NMIBC treatment compared to that in mTURBT. Thus, bTURBT could not completely replace mTURBT as a safer and more effective NMIBC treatment.

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness. Graphical Abstract

Despite progression in its treatment, the clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) remains not ideal. Anoikis is a unique form of programmed apoptosis, owing to insufficient cell-matrix interactions. Anoikis plays a crucial role in tumor migration and invasion, and tumor cells could protect themselves through the capacity of anoikis resistance. Anoikis-related genes (ARGs) were obtained from Genecards and Harmonizome portals. The ARGs related to ccRCC prognosis were identified through univariate Cox regression analysis, then we utilized these ARGs to construct a novel prognostic model for ccRCC patients. Moreover, we explored the expression profile of ARGs in ccRCC using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. We also conducted Real-Time Polymerase Chain Reaction (RT-PCR) to probe ARGs expression of the risk score. Finally, we performed correlation analysis between ARGs and tumor immune microenvironment. We identified 17 ARGs associated with ccRCC survival, from which 7 genes were chosen to construct a prognostic model. The prognostic model was verified as an independent prognostic indicator. The expression of most ARGs was higher in ccRCC samples. These ARGs were closely correlated with immune cell infiltration and immune checkpoint members, and had independent prognostic value respectively. Functional enrichment analysis demonstrated that these ARGs were significantly associated with multiple types of malignances. The prognostic signature was identified to be highly efficient in predicting ccRCC prognosis, and these ARGs were closely related to tumor microenvironment.

The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. 6tEEBExTKemuj5aDnm7Wtt Video Abstract

Prostatic cancer (PCa) is a common malignant neoplasm in men worldwide. Most patients develop castration-resistant prostate cancer (CRPC) after treatment with androgen deprivation therapy (ADT), usually resulting in death. Therefore, investigating new therapeutic targets and drugs for PCa patients is urgently needed. Nuclear Dbf2-related kinase 1 (NDR1), also known as STK38, is a serine/threonine kinase in the NDR/LATS kinase family that plays a critical role in cellular processes, including immunity, inflammation, metastasis, and tumorigenesis. It was reported that NDR1 inhibited the metastasis of prostate cancer cells by suppressing epithelial-mesenchymal transition (EMT), and decreased NDR1 expression might lead to a poorer prognosis, suggesting the enormous potential of NDR1 in antitumorigenesis. In this study, we characterized a small-molecule agonist named aNDR1, which specifically bound to NDR1 and potently promoted NDR1 expression, enzymatic activity and phosphorylation. aNDR1 exhibited drug-like properties, such as favorable stability, plasma protein binding capacity, cell membrane permeability, and PCa cell-specific inhibition, while having no obvious effect on normal prostate cells. Meanwhile, aNDR1 exhibited good antitumor activity both in vitro and in vivo . aNDR1 inhibited proliferation and migration of PCa cells and promoted apoptosis of PCa cells in vitro . We further found that aNDR1 inhibited subcutaneous tumors and lung metastatic nodules in vivo , with no obvious toxicity to the body. In summary, our study presents a potential small-molecule lead compound that targets NDR1 for clinical therapy of PCa patients.