Additionally, no study, to our knowledge, has investigated the common genetic factors for LSc and SSc. ...it would be of significant interest to examine the susceptibility of LSc and determine ...whether there are any correlations between the genetic profiles of SSc and LSc. The combined analysis of the LSc and SSc samples revealed significant associations for SNPs rs7574865, rs10168266, rs3821236 within the STAT4 gene and SNP rs9303277 in the Ikaros family zinc finger protein 3 gene (IKZF3) (Pmeta = 1.97 × 10−7 – 8.92 × 10−6, OR = 1.30–1.35). Because SNPs rs7574865, rs10168266, and rs3821236 were all located within chromosome 2, we went on to perform linkage disequilibrium analysis which uncovered a weak correlation between rs7574865 and rs3821236 (r2 = 0.33) and a strong correlation between rs7574865 and rs10168266 (r2 = 0.80). CSK is involved in the development of fibrosis via its regulation of focal adhesion kinase (FAK), which is needed to transmit integrin signaling when fibroblasts adhere to the extracellular matrix. ...polymorphisms in the CSK gene can be linked to SSc pathogenesis making CSK mutations another potential risk factor for SSc. ...our study was limited by the relatively small number of SSc and LSc cases. ...our future research should be expanded to include a larger group of patients to allow for the validation of these SNPs and to determine if these SNPs are causative for LSc or SSc.
In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) ...and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.
We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and
knockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC.
The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPN
tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8
T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC.
OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.
In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter ...for HCC metastasis. However, the role of chemokine receptors in OPN‐induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C‐C chemokine receptor type 1 (CCR1) and C‐X‐C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN‐promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3‐kinase (PI3K)/AKT and hypoxia‐inducible factor 1α (HIF‐1α) in HCC cells. Furthermore, blockade of OPN‐CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN‐CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.
In this study, we found that OPN up‐regulated the expression of C‐C chemokine receptor‐1(CCR1) via activating phosphoinositide 3‐kinase (PI3K)/AKT and hypoxia‐inducible factor 1α(HIF‐1α). Moreover, blockade of OPN/CCR1 signaling with CCR1 antagonist significantly restrained the promoting effects of OPN on HCC progression and metastasis. Our work proved that CCR1 may be a potential therapeutic target for controlling metastasis in HCC patients with high OPN.
To report the 12-month results of the first human uterus transplantation case using robot-assisted uterine retrieval. This type of transplantation may become a treatment for permanent uterine factor ...infertility.
Case study.
University hospital.
A 22-year-old woman with complete müllerian agenesis who underwent a previous surgery for vaginal reconstruction. The live uterine donor was her mother.
The uterus transplantation procedure consisted of robot-assisted uterine procurement, orthotopic replacement and fixation of the retrieved uterus, revascularization, and end-to-side anastomoses of bilateral hypogastric arteries and ovarian-uterine vein to the bilateral external iliac arteries and veins.
Data from preoperative investigations, surgery, and follow-up (12 months).
The duration of the donor and recipient surgeries were 6 and 8 hours, 50 minutes, respectively. No immediate perioperative complications occurred in the recipient or donor. The recipient experienced menarche 40 days after transplant surgery, and she has had 12 menstrual cycles since the surgery. No rejection episodes occurred in the recipient.
These results demonstrate the feasibility of live-donor uterine transplantation with a low-dose immunosuppressive protocol and the role of DaVinci robotic assistance during human uterine procurement.
XJZT12Z06.
Objectives
Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C‐terminal loss‐of‐function mutation. Acute myeloid leukaemia (AML) patients ...harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive.
Materials and Methods
Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation.
Results
Mp30 inhibited autophagy by suppressing nucleus translocation of NF‐κB. Autophagy‐associated secretion of IL‐1β was decreased in mp30‐overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8+ T cell infiltration was upregulated in C/EBPα DM AML patients. Consistently, the proportion of CD8+CD69+ T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co‐culture with mp30 AML cell conditional culture medium. Knock‐out of IL‐1β in AML cells also enhanced CD8+ T cell activation. Accordingly, IL‐1β expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8+CD69+ T cell proportion was specifically elevated.
Conclusions
C/EBPα DM alleviates immunosuppression of CD8+ T cells by inhibiting the autophagy‐associated secretion of IL‐1β, which elucidated that repression of autophagy‐related inflammatory response in AML patients might achieve a favourable clinical benefit.
Mp30 suppresses autophagy‐associated IL‐β secretion, which ultimately alleviates the immunosuppression of CD8+ T cells in the microenvironment, contributing to favourable prognosis of AML patients.
To evaluate the mediating roles of occupational resilience and the moderationg role of perceived organizational support in the relationship between career calling and nurse burnout.
Burnout is a ...frequent and serious problem in the field of nursing, and it poses a serious threat to both nurses' health and patient safety. Although many studies have described the links between burnout, career calling, and occupational resilience, little is known about the actual mechanisms between career calling and nurse burnout.
A cross-sectional study of 615 nurses in China was conducted using a convenience sampling method. The data were analyzed using descriptive statistics and Pearson correlation analysis. Hypotheses were tested using structural equation models and bootstrapping methods. STROBE guidelines were followed.
Career calling was found to be negatively associated with nurse burnout, and occupational resilience mediated the relationship between career calling and burnout. Additionally, perceived organizational support was found to play a moderating role in the relationship between occupational resilience and burnout.
Career calling can reduce burnout by increasing nurses' levels of occupational resilience, and perceived organizational support moderates this mechanism. Hence, policies focused on encouraging and sustaining career calling should be provided by nurse managers in order to enhance stress resistance and reduce burnout.
The safety and efficacy of anti-diabetic drugs are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type ...2 diabetes (T2D). Metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified. Our current retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality. Furthermore, metformin use was significantly associated with reduced heart failure and inflammation. Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.
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•A retrospective study of 1,213 patients on metformin with COVID-19 was performed•Metformin was associated with increased incidence of acidosis in such patients•Metformin was not associated with increased 28-day all-cause mortality in the patients•Metformin was significantly associated with reduced heart failure and inflammation
In a cohort of 1,213 hospitalized patients with COVID-19 and pre-existing type 2 diabetes, Cheng et al. show that metformin use is significantly associated with higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day all-cause mortality. They also found that metformin use is significantly associated with reduced heart failure and inflammation.
Pyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear.
GEPIA web tool and ...immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of PKM2 in HCC patients. Both
CCK-8, colony formation, and transwell assays, and
xenografts were performed to evaluate the malignancy of HCC cells. PKM2 and PD-L1 levels were examined by Western blot, qRT-PCR, and IHC. The role of PKM2 on
immune response was also investigated.
PKM2 was significantly upregulated in HCC and associated with a poor prognosis of HCC patients. Knockdown of PKM2 inhibited
proliferation, migration, and invasion of HCC cells, as well as
tumor growth. Strikingly, PKM2 showed a strong correlation with the expression of immune inhibitory cytokines and lymphocyte infiltration in HCC. The overexpression of PKM2 sensitized HCC to immune checkpoint blockade, which enhanced IFN-γ positive CD8 T cells in HCC mice models.
PKM2 might be a predictor and a potential therapeutic target for immune checkpoint inhibitors in HCC.
Preparation process of CIDP-PT and schematic diagram of anti-tumor mechanism in vivo.
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•Oligopeptide-modified nanocomposites enable precise targeting in osteosarcoma ...therapy.•Acid-sensitive CaCO3 nanoparticles enhance drug release selectively in the tumor microenvironment.•Multimodal approach integrates NIR-II imaging and cisplatin, optimizing therapeutic efficacy.•High amplification capability demonstrated for ultra-small nanoparticles, enhancing treatment specificity.•Biocompatible design ensures safety, emphasizing the potential clinical impact of this targeted therapy.
Osteosarcoma, as the most prevalent primary malignant bone tumor, has consistently shown suboptimal clinical treatment outcomes. In this manuscript, we proposed an efficacious and novel phototherapy strategy for osteosarcoma based on a photoresponsive near-infrared (NIR) material, CaCO3-ICG-DDP-PEG-PT (CIDP-PT), which contained calcium carbonate (CaCO3) and Cisplatin (DDP) via the gas dispersion method, and indocyanine green (ICG) was encapsulated through a nanoprecipitation reaction by employing DSPE-PEG2000-COOH to enhance the stability and hydrophilicity. The targeting oligopeptide (PT) for osteosarcoma cells was inserted into the outer membrane of nanoparticles, thereby further enhancing the tumor-targeting capability through receptor-mediated binding. The prepared CIDP-PT nanoparticles exhibited high targeting efficiency and multifunctionality. In vitro and in vivo experiments demonstrated that CIDP-PT significantly enhanced the therapeutic efficacy for osteosarcoma via the NIR-II photoresponsive and tumor-targeting approach. It achieves efficient tumor cell eradication through multiple modalities while maintaining an exceptional level of biocompatibility. Hence, the CIDP-PT nanocarriers possess considerable practical value for future clinical applications in adjunct osteosarcoma phototherapy.
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