Examining Medical Staff Well-Being through the Application and Extension of the Job Demands-Resources Model: A Cross-Sectional Study.

For medical staff, job satisfaction is essential for advancement on an individual and organizational level. This study looked into the relationships between challenging job demands, job resources, personal resources, and well-being. Additionally, it examined the potential mediating effects of emotional exhaustion and work motivation within the framework of the job demands-resources (JD-R) model. Results from a cross-sectional study of 267 medical employees at a second-grade comprehensive hospital in Jiangsu, China's mainland, indicated that challenging job demands and job satisfaction were positively correlated and mediated via (decreasing) emotional exhaustion. The relationship between job resources and job satisfaction was found to be mediated via (decreasing) emotional exhaustion and (increasing) work motivation. The investigation also demonstrated that the two regulatory focuses serve different purposes. It was discovered that promotion focus had a favorable effect on work motivation but a negative effect on emotional exhaustion. Conversely, preventive focus only positively predicted emotional exhaustion. Thus, the JD-R model offers a valuable structure for clarifying the job satisfaction of health personnel. The implications for enhancing individual and job outcomes are discussed.

More patient-centered care, better healthcare: the association between patient-centered care and healthcare outcomes in inpatients.

Objective: The objective of this study is to explore the association between patient-centered care (PCC) and inpatient healthcare outcomes, including self-reported physical and mental health status, subjective necessity of hospitalization, and physician-induced demand behaviors. Methods: A cross-sectional survey was conducted to assess patient-centered care among inpatients in comprehensive hospitals through QR codes after discharge from September 2021 to December 2021 and had 5,222 respondents in Jiayuguan, Gansu. The questionnaire included a translated 6-item version of the PCC questionnaire, physician-induced behaviors, and patients' sociodemographic characteristics including gender, household registration, age, and income. Logistic regression analyses were conducted to assess whether PCC promoted self-reported health, the subjective necessity of hospitalization, and decreased physician-induced demand. The interactions between PCC and household registration were implemented to assess the effect of the difference between adequate and inadequate healthcare resources. Results: PCC promoted the patient's self-reported physical (OR = 4.154, p < 0.001) and mental health (OR = 5.642, p < 0.001) and subjective necessity of hospitalization (OR = 6.160, p < 0.001). Meanwhile, PCC reduced physician-induced demand in advising to buy medicines outside (OR = 0.415, p < 0.001), paying at the outpatient clinic (OR =0.349, p < 0.001), issuing unnecessary or repeated prescriptions and medical tests (OR = 0.320, p < 0.001), and requiring discharge and readmitting (OR = 0.389, p < 0.001). Conclusion: By improving health outcomes for inpatients and reducing the risk of physician-induced demand, PCC can benefit both patients and health insurance systems. Therefore, PCC should be implemented in healthcare settings.

POH1 facilitates pancreatic carcinogenesis through MYC-driven acinar-to-ductal metaplasia and is a potential therapeutic target.

Pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), a necessary process for pancreatic ductal adenocarcinoma (PDAC) initiation. However, the regulatory role of POH1, a deubiquitinase linked to several types of cancer, in ADM and PDAC is unclear. In this study, we investigated the role of POH1 in ADM and PDAC using murine models. Our findings suggest that pancreatic-specific deletion of Poh1 alleles attenuates ADM and impairs pancreatic carcinogenesis, improving murine survival. Mechanistically, POH1 deubiquitinates and stabilizes the MYC protein, which potentiates ADM and PDAC. Furthermore, POH1 is highly expressed in PDAC samples, and clinical evidence establishes a positive correlation between aberrantly expressed POH1 and poor prognosis in PDAC patients. Targeting POH1 with a specific small-molecule inhibitor significantly reduces pancreatic tumor formation, highlighting POH1 as a promising therapeutic target for PDAC treatment. Overall, POH1-mediated MYC deubiquitination is crucial for ADM and PDAC onset, and targeting POH1 could be an effective strategy for PDAC treatment, offering new avenues for PDAC targeted therapy.

Effect of Dietary Approaches on Glycemic Control in Patients with Type 2 Diabetes: A Systematic Review with Network Meta-Analysis of Randomized Trials.

BACKGROUND: Dietary patterns play a critical role in diabetes management, while the best dietary pattern for Type 2 diabetes (T2DM) patients is still unclear. The aim of this network meta-analysis was to compare the impacts of various dietary approaches on the glycemic control of T2DM patients. METHODS: Relevant studies were retrieved from PubMed, Embase, Web of Knowledge, Cochrane Central Register of Controlled Trials (CENTRAL), and other additional records (1949 to 31 July 2022). Eligible RCTs were those comparing different dietary approaches against each other or a control diet in individuals with T2DM for at least 6 months. We assessed the risk of bias of included studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. In order to determine the pooled effect of each dietary approach relative to each other, we performed a network meta-analysis (NMA) for interventions for both HbA1c and fasting glucose, which enabled us to estimate the relative intervention effects by combing both direct and indirect trial evidence. RESULTS: Forty-two RCTs comprising 4809 patients with T2DM were included in the NMA, comparing 10 dietary approaches (low-carbohydrate, moderate-carbohydrate, ketogenic, low-fat, high-protein, Mediterranean, Vegetarian/Vegan, low glycemic index, recommended, and control diets). In total, 83.3% of the studies were at a lower risk of bias or had some concerns. Findings of the NMA revealed that the ketogenic, low-carbohydrate, and low-fat diets were significantly effective in reducing HbA1c (viz., -0.73 (-1.19, -0.28), -0.69 (-1.32, -0.06), and -1.82 (-2.93, -0.71)), while moderate-carbohydrate, low glycemic index, Mediterranean, high-protein, and low-fat diets were significantly effective in reducing fasting glucose (viz., -1.30 (-1.92, -0.67), -1.26 (-2.26, -0.27), -0.95 (-1.51, -0.38), -0.89 (-1.60, -0.18) and -0.75 (-1.24, -0.27)) compared to a control diet. The clustered ranking plot for combined outcomes indicated the ketogenic, Mediterranean, moderate-carbohydrate, and low glycemic index diets had promising effects for controlling HbA1c and fasting glucose. The univariate meta-regressions showed that the mean reductions of HbA1c and fasting glucose were only significantly related to the mean weight change of the subjects. CONCLUSIONS: For glycemic control in T2DM patients, the ketogenic diet, Mediterranean diet, moderate-carbohydrate diet, and low glycemic index diet were effective options. Although this study found the ketogenic diet superior, further high-quality and long-term studies are needed to strengthen its credibility.

How serving helps leading: mediators between servant leadership and affective commitment.

Introduction: Servant leadership has long been associated with maintaining employee's affective commitment, yet the underlying mechanism remains unclear. Research from non-western cultures remains scarce. Methods: This study sought to fill in such research gap by introducing insights from social exchange theory perspective, and examined two potential mediators (viz., psychological safety and job burnout) with a largescale, representative Chinese sample. Results: A total of 931 staffs in a Chinese hospital were surveyed, and structural equation models revealed that psychological safety (indirect effect = 0.052, 95% Bootstrap CI = [0.002, 0.101]) and job burnout (indirect effect = 0.277, 95% Bootstrap CI = [0.226, 0.331]) parallelly (and partially) mediated the effect of servant leadership on affective commitment. Moreover, these effects held the same between permanent and temporary staffs, as well as between male and female staffs. Discussion: Results suggested that a leader's orientation to care, validate, and respond to their followers' needs was effective in creating a psychological safe environment and downplaying job burnout in workplace, in exchange to which, followers remained affectively committed to their organization in a long term. Not only did this study contribute to existing literature by providing non-western data for service leadership research, it also provided a deeper understanding of associated mechanisms of how servant leadership might cast on talent retain and organizational development in a long term. These mechanisms shed light on how serving helps leading and advocate servant leadership for hospitals, as well as other serving organizations.

Patient-centered care and patient satisfaction: Validating the patient-professional interaction questionnaire in China.

Objective: To introduce patient-centered approach in China and to relate it with Chinese patient satisfaction via validating the Chinese version of Patient-Professional Interaction Questionnaire (PPIQ-C). Design: This cross-sectional survey was conducted through face-to-face interviews from June to September in 2019. Participants rated their patient-centered care experience via the 16-item translated PPIQ, their experience of the received medical service, and their overall satisfaction. Setting: Kunshan Huaqiao People's Hospital in Jiangsu, China. Participants: A total of 230 participants (87 males and 143 females; 108 outpatients and 122 inpatients). Results: PPIQ-C exhibited acceptable psychometric properties. Data revealed a single factor model of the 16 PPIQ-C items [ χ ( 4 ) 2 = 12.394, p = 0.823, CFI = 1.000, TLI = 1.019, RMSEA = 0.000, SRMR = 0.032] had a superior model fit over the original first-order with four correlated factors and the second-order structures. The overall reliability was excellent (McDonald's ω = 0.975). In terms of patient satisfaction, process, treatment quality, and communication significantly predicted patient satisfaction, while environment, staff attitude, and medical ethics did not [R 2 = 0.427, F (6) = 24.887, p < 0.001]. Most importantly, the total score of PPIQ-C predicted patient satisfaction above and beyond the above-mentioned medical service perspectives (B = 0.595, SE = 0.207, p = 0.004). Finally, the constructive effect of PCC on patient satisfaction was stronger for departments of Pediatrics than Surgery. Conclusions: The Chinese version of the PPIQ scale (PPIQ-C) exhibited acceptable psychometric properties. Yet the distinction among the four factors was not supported, suggesting potential difference(s) across cultures. Patient-centered care (PCC), reflected by the overall PPIQ-C score, predicted overall patient satisfaction above and beyond other medical service perspectives. Adopting PCC approach in appropriate situations will probably advance the development of performance evaluation systems in China, thus improving the overall health care and patient satisfaction.

Gene Coexpression Network Characterizing Microenvironmental Heterogeneity and Intercellular Communication in Pancreatic Ductal Adenocarcinoma: Implications of Prognostic Significance and Therapeutic Target.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by intensive stromal involvement and heterogeneity. Pancreatic cancer cells interact with the surrounding tumor microenvironment (TME), leading to tumor development, unfavorable prognosis, and therapy resistance. Herein, we aim to clarify a gene network indicative of TME features and find a vulnerability for combating pancreatic cancer. Methods: Single-cell RNA sequencing data processed by the Seurat package were used to retrieve cell component marker genes (CCMGs). The correlation networks/modules of CCMGs were determined by WGCNA. Neural network and risk score models were constructed for prognosis prediction. Cell-cell communication analysis was achieved by NATMI software. The effect of the ITGA2 inhibitor was evaluated in vivo by using a KrasG12D -driven murine pancreatic cancer model. Results: WGCNA categorized CCMGs into eight gene coexpression networks. TME genes derived from the significant networks were able to stratify PDAC samples into two main TME subclasses with diverse prognoses. Furthermore, we generated a neural network model and risk score model that robustly predicted the prognosis and therapeutic outcomes. A functional enrichment analysis of hub genes governing gene networks revealed a crucial role of cell junction molecule-mediated intercellular communication in PDAC malignancy. The pharmacological inhibition of ITGA2 counteracts the cancer-promoting microenvironment and ameliorates pancreatic lesions in vivo. Conclusion: By utilizing single-cell data and WGCNA to deconvolute the bulk transcriptome, we exploited novel PDAC prognosis-predicting strategies. Targeting the hub gene ITGA2 attenuated tumor development in a PDAC mouse model. These findings may provide novel insights into PDAC therapy.

Psychological Safety and Affective Commitment Among Chinese Hospital Staff: The Mediating Roles of Job Satisfaction and Job Burnout.

Purpose: The affective commitment of hospital staff is important for human resources management and the sustainable development of hospitals. Psychological safety is an important factor that contributes to an emotional connection to an organization among staff, yet its functional mechanism remains unclear. This study explored how psychological safety influenced affective commitment through the mediating roles of job satisfaction and job burnout. Methods: A battery of surveys were administered to all medical staff (n = 267) in a local second-grade comprehensive hospital. The surveys included the Psychological Safety Scale, Affective Commitment Scale, Minnesota Satisfaction Questionnaire, Maslach Burnout Inventory-Human Service Survey, and Perceived Organizational Support Scale. Results: Job satisfaction and job burnout fully mediated the relationship between psychological safety and affective commitment among hospital staff. In addition, perceived organizational support moderated the mediating path via job burnout, and the indirect effect of job burnout decreased when perceived organizational support increased. Conclusion: Psychological safety may enhance the affective commitment of hospital staff through improving job satisfaction or reducing job burnout. Perceived organizational support may counteract the deleterious effect of job burnout on affective commitment. Effective strategies to improve affective commitment among hospital staff may require consideration of job burnout and job satisfaction.

Carboxymethylated pachyman induces ferroptosis in ovarian cancer by suppressing NRF1/HO-1 signaling.

Carboxymethylated pachyman (CMP) is characterized by immune regulatory, antitumor and antioxidant activities. However, whether CMP contributes to the treatment of ovarian cancer has yet to be explored. The role of CMP in ovarian cancer cell death was analyzed using CCK-8 and flow cytometry assays. The data showed that CMP induced ovarian cancer cell death in a dose-dependent manner. Furthermore, CMP-induced cell death could be largely reversed by preincubation with ferrostatin-1 (Fer-1) but not 3-methyladenine or necrostatin-1. Reverse transcription-quantitative PCR analysis indicated that CMP significantly increased prostaglandin-endoperoxide synthase 2 (PTGS2) and Chac glutathione specific γ-glutamylcyclotransferase 1 (CHAC1) mRNA levels, but preincubation with Fer-1 obviously reduced PTGS2 and CHAC1 mRNA levels in SKOV3 and Hey cells. The intracellular levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and Fe2+ were then quantified The data showed that 100 and 200 µg/ml CMP enhanced the production of SOD, MDA and Fe2+ but decreased GSH levels in SKOV3 and HEY cells. These data indicated that CMP could induce ferroptosis in ovarian cancer cells. More importantly, in vitro and in vivo studies indicated that CMP significantly suppressed nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), cystine/glutamate antiporter system X(c)(-) (xCT) and glutathione peroxidase 4 (GPX4) expression in ovarian cancer cells and tumors. In conclusion, the present study showed novel data that CMP could induce ferroptotic death in ovarian cancer cells by suppressing Nrf2/HO-1/xCT/GPX4. All these findings indicate that CMP may have great potential in anti-ovarian cancer cell therapy by inducing ferroptosis.

ETV4 potentiates nuclear YAP retention and activities to enhance the progression of hepatocellular carcinoma.

Dysregulation of the Hippo pathway that promotes cell survival, proliferation and tumorigenesis, relays on the coordinated interactions of YAP with the factors that determine YAP translocation and the related transcriptional programming. Here, we demonstrate that ETV4, a transcriptional factor participating in various protumorigenic processes, enhances YAP-mediated transactivation and hepatocellular carcinoma (HCC) progression. Mechanistically, the enhancement of YAP activities is mediated by the interaction between ETV4 and YAP, which not only increases nuclear YAP accumulation but also directly augments the YAP/TEAD4-mediated transcriptional activation in tumor cells. Functionally, the interplay of ETV4 and YAP promotes growth of liver tumor cells, and activates the genes related to myeloid cell recruitment, including CXCL1 and CXCL5, leading to an enriched presence of myeloid-derived suppressive cells and macrophages but a decreased infiltration of T cells and NK cells in transplanted tumors. More importantly, the correlations between YAP activation, the altered immune cell distribution and ETV4 expression are observed in human HCCs. Therefore, our study reveals a functional interaction between ETV4 and YAP that contributes to HCC progression, and provides mechanistic insights into the regulation of nuclear YAP retention and transactivation.

Deubiquitination of the repressor E2F6 by USP22 facilitates AKT activation and tumor growth in hepatocellular carcinoma.

Dysregulated ubiquitination of tumor-related proteins plays a critical role in tumor development and progression. The deubiquitinase USP22 is aberrantly expressed in certain types of cancer and contributes to aggressive tumor progression. However, the precise mechanism underlying the pro-tumorigenic function of USP22 in hepatocellular carcinoma (HCC) remains unclear. Here, we report that E2F6, a pocket protein-independent transcription repressor, is essential for HCC cell growth, and that its activities are controlled by USP22-mediated deubiquitination. USP22 interacts with and stabilizes E2F6, resulting in the transcriptional repression of phosphatase DUSP1. Moreover, the process involving DUSP1 repression by E2F6 strengthens AKT activation in HCC cells. Therefore, these findings provide mechanistic insights into the USP22-mediated control of oncogenic AKT signaling, emphasizing the importance of USP22-E2F6 regulation in HCC development.

USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade.

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.

The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis.

K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-rasG12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.

KIAA1522 potentiates TNFα-NFκB signaling to antagonize platinum-based chemotherapy in lung adenocarcinoma.

BACKGROUND: The platinum-based chemotherapy is the first-line regimen for the treatment of Non-small cell lung cancer (NSCLC). However, the therapeutic efficiency is largely limited by tenacious chemo-insensitivity that results in inferior prognosis in a cohort of patients. It has been known that KIAA1522 is aberrantly expressed and implicated in several types of solid tumors including NSCLC. Nowadays, knowledge about this gene is quite limited. Here, we aimed to identify the role of KIAA1522 in lung adenocarcinomas, and the molecular events that underlie KIAA1522-mediated chemoresistance to the platinum. METHODS: Immunohistochemistry were used to detect KIAA1522 expression in clinical NSCLC samples. Then, the survival analyses were performed to assess the link between KIAA1522 expression and overall survival or therapeutic outcome. In vivo depletion of KIAA1522 in adenocarcinoma cells were achieved by adeno-associated virus-mediated sgRNA/Cre delivery into the conditional KrasG12D/Cas9 expressed mice, which were designated to identify the roles of KIAA1522 in tumorigenesis and/or chemotherapy responses. The effects of KIAA1522 and downstream molecular events were studied by pharmacology in mice model and assays using in vitro cultured cells. The clinical relevance of our findings was examined by data-mining of online datasets from multiple cohorts. RESULTS: The clinical evidences reveal that KIAA1522 independently predicts both the overall survival and the outcome of platinum-based chemotherapy in lung adenocarcinomas. By using a KrasG12D-driven murine lung adenocarcinoma model and performing in vitro assays, we demonstrated that KIAA1522 is a critical positive regulator of lung adenocarcinoma and a modulator of cisplatin response. KIAA1522 potentiates the TNFα-TNFR2-NFκB signaling which in turn intensifies recalcitrance to cisplatin treatment. These results were further manifested by integrative bioinformatic analyses of independent datasets, in which KIAA1522 is tightly associated with the activity of TNFα-NFκB pathway and the cisplatin-resistant gene signatures. More strikingly, overexpression of KIAA1522 counteracts the cisplatin-induced tumor growth arrest in vivo, and this effect can be remarkably diminished by the disruption of NFκB activity. CONCLUSION: High expression of KIAA1522 is turned out to be an indicator of dismal effectiveness of platinum-based therapy in lung adenocarcinomas. KIAA1522 hyperactivates TNFα-NFκB signaling to facilitate resistance to platinum reagents. Targeting NFκB signaling through small molecule inhibitors may be a rational strategy to conquer chemoresistance and synergize platinum-based chemotherapy in KIAA1522 overexpressed lung adenocarcinomas.

Elimination of elemental mercury in flue gas by Arachis hypogaea Linn. shell generated activated carbon.

It is very necessary to produce bio-activated carbon for special use with easy procedure and low cost. One kind of huge surface area microporous bio-material was successfully prepared from agricultural residues (peanut shell, Arachis hypogaea Linn.) and beneficially applied to control elemental mercury (Hg0) in simulated coal-fired flue gas in this study. The possible effects of experimental factors including activator, reaction temperature, and flue components were investigated. The physicochemical properties of the prepared adsorbents were characterized by Brunauer-Emmett-Teller (BET), scanning electron microscopy with energy-dispersive X-ray spectrometry (SEM-EDX), and X-ray photoelectron spectroscopy (XPS). The results indicated that the peanut shell activated carbon presented excellent Hg0 removal efficiency near 90% at 150 °C. The characterization analysis indicated that the removal characteristics were governed by both physical adsorption and chemical adsorption. The chemisorbed mercury on the activated carbon was mainly distinguished into mercuric chloride (HgCl2) and mercuric oxide (HgO). The presence of C-Cl and O* promoted Hg0 into HgCl2 and HgO. Zinc chloride could not only improve the micropore quantity of activated carbon but also have remarkably positive effects on the elemental mercury removal. This study provided a practical and easy preparation method of bio-activated carbon for Hg0 removal with low cost. Graphical Abstract.

POH1 contributes to hyperactivation of TGF-ß signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-ß receptors and caveolin-1.

BACKGROUND: Hyper-activation of TGF-ß signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-ß pathway in HCC, especially at the post-translational level, are not well understood. METHODS: Associations of deubiquitinase POH1 with TGF-ß signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-ß receptors (TGFBR1 and TGFBR2) and the activation of downstream effectors were tested by western blotting. Primary mouse liver tissues from polyinosinic:polycytidylic acid (poly I:C)- treated Mx-Cre+, poh1f/f mice and control mice were used to detect the TGF-ß receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice. FINDINGS: Here we show that POH1 is a critical regulator of TGF-ß signaling and promotes tumor metastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-ß response, metastatic potential and outcomes, reveal that POH1 expression positively correlates with activities of TGF-ß signaling in tumors and with malignant disease progression. Functionally, POH1 intensifies TGF-ß signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-ß receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-ß receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-ß receptors. CONCLUSION: Our study highlights the pathological significance of aberrantly expressed POH1 in TGF-ß signaling hyperactivation and aggressive progression in HCC.

Requirement for POH1 in differentiation and maintenance of regulatory T cells.

Foxp3-expressing regulatory T (Treg) cells are essential for averting autoimmune diseases and maintaining immune homeostasis. However, the molecular mechanisms underlying the development and maintenance of Treg cells are still unclear. Here, we found that T cell-specific deletion of the gene encoding the deubiquitinase POH1 compromised the development of mature T cells, especially CD4+Foxp3+ Treg cells. Moreover, POH1 deficiency significantly attenuated the transition of CD25+ Treg cell precursors into Foxp3+ Treg cells accompanied by downregulation of interleukin 2 (IL-2)-STAT5 signaling. Deletion of POH1 in generated CD4+Foxp3+ Treg cells led to an early onset of fetal autoimmune disorders and a decrease in the pool size of peripheral Treg cells in mice, which were mostly due to decreased expansion of these cells. Thus, these results revealed that POH1 has a pivotal role in the development and maintenance of CD4+Foxp3+ Treg cells and contributes to immune tolerance.

USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis.

Metastatic progression is the main cause of mortality in breast cancer, necessitating the determination of the molecular events driving this process for the development of new therapeutic approaches. Here, we demonstrate that hyperactivation of the deubiquitinase USP1 contributes to breast cancer metastasis. Upregulated USP1 expression in primary breast cancer specimens correlates with metastatic progression and poor prognosis in breast cancer patients. USP1 enhances the expression of a number of pro-metastatic genes in breast cancer cells, promotes cell migration and invasion in vitro, and facilitates lung metastasis of breast cancer cells. Moreover, USP1-mediated deubiquitination and stabilization of KPNA2 are revealed as the downstream events crucial for USP1-pro-metastatic function. Most importantly, pharmacological intervention of USP1 function by pimozide or ML323 significantly represses breast cancer metastasis in mice, suggesting a rationale for using USP1 inhibitors for treatment of patients with breast cancer. Taken together, our results establish USP1 as a promoter of breast cancer metastasis and provide evidence for the potential practice of USP1 targeting in the treatment of breast cancer.

POH1 deubiquitinates pro-interleukin-1ß and restricts inflammasome activity.

Inflammasome activation is essential for host defence against invading pathogens, but is also involved in various forms of inflammatory diseases. The processes that control inflammasome activity are thus important for averting excessive immune responses and tissue damage. Here we show that the deubiquitinase POH1 negatively regulates the immune response triggered by inflammasome activation. POH1 deficiency in macrophages enhances mature IL-1ß production without significant alterations in inflammasome priming and ASC-caspase-1 activation. In WT macrophages, POH1 interacts with and deubiquitinates pro-IL-1ß by decreasing the K63-linked polyubiquitin chains, as well as decreases the efficacy of pro-IL-1ß cleavage. Furthermore, myeloid cell-specific deletion of POH1 aggravates lipopolysaccharide-induced systemic inflammation and alum-induced peritonitis inflammatory responses in vivo. Our study thereby reveals that POH1-mediated deubiquitination of pro-IL-1ß is an important regulatory event that restrains inflammatory responses for the maintenance of immune homeostasis.