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Resistance to KRAS therapy in pancreatic ductal adenocarcinoma (PDAC) involves cellular plasticity, particularly the epithelial-to-mesenchymal transition (EMT), which poses challenges for effective targeting. Chronic pancreatitis, a known risk factor for PDAC, elevates TGFβ levels in the tumor microenvironment (TME), promoting resistance to KRAS therapy. Mechanistically, TGFβ induces the formation of a novel protein complex composed of SMAD3, SMAD4, and the nuclear factor NFAT5, triggering EMT and resistance by activating key mediators such as S100A4. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival. Additionally, TGFβ stimulates PDAC cells to secrete CCL2, recruiting macrophages that contribute to KRAS bypass through paracrine S100A4. Our findings elucidate the role of TGFβ signaling in EMT-associated KRAS therapy resistance and identify NFAT5 as a druggable target. Targeting NFAT5 could disrupt this regulatory network, offering a potential avenue for preventing resistance in PDAC.

Yes-associated protein 1 (YAP1), a key player in the Hippo pathway, has been shown to play a critical role in tumor progression. However, the role of YAP1 in prostate cancer cell invasion, migration, and metastasis is not well defined. Through functional, transcriptomic, epigenomic, and proteomic analyses, we showed that prolyl hydroxylation of YAP1 plays a critical role in the suppression of cell migration, invasion, and metastasis in prostate cancer. Knockdown (KD) or knockout (KO) of YAP1led to an increase in cell migration, invasion, and metastasis in prostate cancer cells. Microarray analysis showed that the EMT pathway was activated in Yap1-KD cells. ChIP-seq analysis showed that YAP1 target genes are enriched in pathways regulating cell migration. Mass spectrometry analysis identified P4H prolyl hydroxylase in the YAP1 complex and YAP1 was hydroxylated at multiple proline residues. Proline-to-alanine mutations of YAP1 isoform 3 identified proline 174 as a critical residue, and its hydroxylation suppressed cell migration, invasion, and metastasis. KO of P4ha2led to an increase in cell migration and invasion, which was reversed upon Yap1KD. Our study identified a novel regulatory mechanism of YAP1 by which P4HA2-dependent prolyl hydroxylation of YAP1 determines its transcriptional activities and its function in prostate cancer metastasis.

In this study, Hou et al. set out to study the molecular mechanism underlying therapy resistance to KRAS inhibitors. Using a PDAC mouse model engineered with an inducible oncogenic KRAS (KRAS*) allele, the authors identified USP21, a protein deubiquitinase, as a driver of KRAS*-independent PDAC growth that occurs via induction of macropinocytosis.

The rotational speed is a crucial parameter for bearing condition monitor. The present study shows the influence of the rotational speed on the impact characteristics caused by a localized defect of the outer raceway. A 2Nb+ 5-degrees-of-freedom nonlinear dynamic model for a ball bearing is developed. The waviness of bearing components, a localized defect of the outer raceway, and the centrifugal forces of balls caused by rotational speed are involved in the ball bearing model. Spectral kurtosis (SK) analysis and envelope spectrum analysis are used to extract the impact signal and confirm the position of the optimal frequency band affected by the impact signal. The peak of the impact signal rises with the increase in rotational speed. The position of the optimal frequency band affected by the impact signal is a linear piecewise function of the rotational speed. These simulated results are verified through vibration experiments of a ball bearing with a localized defect of the outer raceway under an axial load. In addition, considering both a localized defect on the outer raceway and the waviness of bearing components, only when the size of the localized defect is large enough, can the impact signal overcome the influence of the structural vibration of the system to extract impact characteristics. The case studies of high-speed spindle bearing state diagnosis show that high speed is not conducive to the extraction of the impact characteristics.

Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2–4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and—in the case of PDAC—the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface—where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth—is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.

In this study, Hou et al. analyzed large-scale cancer genome data sets to identify USP21 as one of the most commonly amplified genes (22%) in PDAC. Using in vivo approaches, they go on to show USP21 deubiquitinates TCF7, a member of the Wnt pathway, promoting pancreatic cancer cell proliferation and stemness.

Purpose: This study mainly aims to examine the mediating effect of perceived organizational support (POS) and the moderating effect of locusof control and job autonomy on the relationship between customer mistreatment behavior and organizational citizenship behavior. Design/methodology/approach: Through a questionnaire survey of 231 employees and their direct supervisors of five hotels in Guangzhou. This paper analyzed five variables (customer mistreatment, POS, locusof control, job autonomy and organizational citizenship behavior) relationships through a variety of data analysis. Findings: Results indicate that customer mistreatment behavior has a negative effect on employees’ organizational citizenship behavior. The relationship between customer mistreatment behavior and employees’ organizational citizenship behavior is partially mediated by employees’ POS. Staffs’ locusof control and job autonomy can modulate the relationship between customers’ mistreatment behavior and POS. Furthermore, the indirect mediating effect of POS on customer mistreatment behavior is revealed. The organizational citizenship behavior linkage is significant only to staff who perceived they have a high level of job autonomy and a high locusof control. Practical implications: Hotels are advised to provide organizational support and the management of customer mistreatment behavior so as to reflect their employees’ value, seek service innovation and promote production efficiency in practice. Furthermore, it maintains and promotes operational efficiency for service organizations and means the organization pays more attention to meet the social, emotional and psychological needs of its employees. Originality/value: This article reveals the mechanism relationship between customer mistreatment behavior and employee organizational citizenship behavior. First, it defines the concept of customer mistreatment in the hotel industry and enriches the related research. Second, the study, from the perspective of customer mistreatment, has opened up a new view of organizational citizenship behavior research. Third, we built a research model and it is helpful to grasp the inner mechanism between customer mistreatment and employees’ organizational citizenship behavior. Fourth, this research benefits service organizations so as to maintain and improve their operation efficiency. Furthermore, it can have theoretical guidance for service-oriented organizations to develop a harmonious consumption culture and organizational culture.

In the current research, we systematically investigated the physicochemical stability of the nanoemulsions that were formulated with 90% (v/v) whey protein isolate (WPI) aqueous phase and 10% (v/v) medium chain triglyceride oil phase at neutral pH using high intensity ultrasonication. We measured the physicochemical properties of nanoemulsions stabilized by WPI at different concentrations, including particle size, zeta potential, turbidity, centrifugal stability, and rheological behavior. Besides, we also evaluated the influence of processing conditions (ionic strength, freeze-thaw cycle and thermal treatment) on the nanoemulsion stability. The particle size of WPI nanoemulsions increased by approximately 5% at 25 °C and 8% at 37 °C after 7 weeks’ storage, while the particle size and zeta potential of the nanoemulsions at 4 °C were changed. The 1% WPI stabilized nanoemulsion was very sensitive to Na+(0.1–0.5 mol/l) and freeze-thaw treatment (3 cycles) with significant increase in particle size and decrease in the absolute value of zeta potential. The turbidity of nanoemulsions decreased by over 50% after freeze-thaw cycles, especially the 1% WPI stabilized nanoemulsion. All samples were still stable under thermal conditions. Among them, the 5% WPI stabilized nanoemulsion showed the best ionic, freeze-thaw, and thermal stability. All tested nanoemulsions showed typical shear-thinning behavior, and the infinite shear viscosity of 5% WPI stabilized nanoemulsions was highest. In conclusion, the 5% WPI stabilized nanoemulsion has the best physicochemical stability under different processing conditions during storage, which has high potential in use as a delivery system for bioactive substances like ginsenoside Rg3 in food technology.