SAP deletion promotes malignant insulinoma progression by inducing CXCL12 secretion from CAFs via the CXCR4/p38/ERK signalling pathway.

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute-phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1-Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1-Tag2;SAP-/- mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C-X-C motif chemokine ligand 12 (CXCL12) secreted by cancer-associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease.

Paxlovid for hospitalized COVID-19 patients with chronic kidney disease.

BACKGROUND: COVID-19 causes significant mortality during the recent pandemic. Data regarding the effectiveness of Paxlovid on COVID-19 patients with chronic kidney disease (CKD, eGFR <90 ml/min) are limited. METHODS: A retrospective cohort study was performed on the clinical data of the hospitalized adult patients with confirmed COVID-19 infection collected at Renji Hospital from April 7, 2022 to June 21, 2022. The association of Paxlovid treatment with early (within 5 days post diagnosis) or late (5 days or later post diagnosis) initiation time with clinical outcomes was assessed by Cox proportional hazards regression model with time-dependent covariates. RESULT: 1279 of 2387 enrollees were included in the study. Patients with early initiation of Paxlovid had a lower all-cause death rate compared to those with late initiation or without Paxlovid treatment (P = 0.046). For the CKD patients with Charlson comorbidity index (CCI) > 7, the early initiation of Paxlovid was associated with a lower all-cause death rate compared to the later initiation or the lack of Paxlovid treatment (P = 0.041). Cox regression analyses revealed that eGFR (HR 4.21 [95%, CI 1.62-10.99]), Paxlovid treatment (0.32 [0.13-0.77]), CCI (4.32 [1.64-11.40]), ICU admission (2.65 [1.09-6.49]), hsCRP (3.88 [1.46-7.80]), chronic liver disease (4.02 [1.09-14.85]) were the independent risk factors for all-cause death for CKD patients after adjusting for demographics and biochemical indexes. CONCLUSIONS: All-cause death, invasive ventilation, and ICU admission were all significantly lowered by an early initiation of Paxlovid treatment in COVID-19 patients with severe CKD.

Adaptive immune dysfunction in patients with COVID-19 and impaired kidney function during the omicron surge.

BACKGROUND: Little is known about the characteristics of lymphocyte subsets and the association with patient outcomes in COVID-19 with and without impaired kidney function. METHODS: Lymphocyte subsets were compared in COVID-19 patients with or without kidney dysfunction. The primary outcome was a composite of all-cause mortality or intensive care unit admission. Secondary outcomes included duration of viral shedding, length of hospital stay, and acute kidney injury. RESULTS: Lymphocyte subset cell counts demonstrated the lowest in patients with severe/critical COVID-19 and kidney dysfunction. Among all lymphocyte subset parameters, Th cell count was the most significant indicator for outcomes. ROC of the combined model of Th cell count and eGFR presented better predictive value than that of the other parameters. Th cell count <394.5 cells/µl and eGFR <87.5 ml/min/1·73m2 were independently associated with poor outcomes. The propensity score matching analysis revealed consistent results. CONCLUSIONS: Reduced Th cell count and eGFR may be applied as promising predictive indicators for identifying COVID-19 patients with high risk and poor outcomes.

MicroRNA­93 inhibits the apoptosis and inflammatory response of tubular epithelial cells via the PTEN/AKT/mTOR pathway in acute kidney injury.

Renal tubular epithelial cell injury is the main cause of septic acute kidney injury (AKI), which is characterized by the excessive inflammatory response and apoptosis. Numerous studies have demonstrated that miRNAs are associated with inflammatory response and apoptosis in numerous diseases. The present study mainly focuses on investigating the association between microRNA (miRNA/miR) expression and inflammatory response and apoptosis in the pathogenesis of AKI. In vitro and in vivo models of AKI were simulated using Escherichia coli lipopolysaccharide (LPS)­administrated kidney epithelial cells and mice, respectively. The miRNA expression profile was examined using miRNA microarray in kidney tissues. Next, the effects of miR­93 upregulation on the apoptosis, cytokine expression and oxidative stress in the LPS­stimulated TCMK­1 were tested. The target genes of this miRNA were investigated, and the regulatory association between miR­93 and the AKT/mTOR pathway was investigated. The results demonstrated that miR­93 was the most downregulated miRNA in mice kidney. Furthermore, in LPS­induced renal tubular epithelial cells (TECs) injury model, that upregulation of miR­93 was found to attenuate the apoptosis and inflammatory response, as well as reactive oxygen species generation. Mechanistically, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was identified as a target of miR­93. Further experiments revealed that LPS­induced the decrease of phosphorylated (p)­AKT and p­mTOR protein expression in vitro are reversed by the overexpression of miR­93. The results of the present study suggested that the protective effect of miR­93 on AKI may be associated with the activation of PTEN/AKT/mTOR pathway. miR­93 may serve as a potential therapeutic target in sepsis­induced AKI.

Association of abdominal aortic calcification estimated by plain radiography with outcomes in haemodialysis patients: A 6-year follow-up study.

AIM: Vascular calcification has played a vital role in increasing the prevalence of cardiovascular disease (CVD) and mortality in maintenance haemodialysis (MHD) patients. This study is aimed at exploring the prognostic value of abdominal aortic calcification (AAC) estimated by plain lateral abdominal radiography in MHD patients. METHODS: Lateral abdominal radiography was used to determine the abdominal aortic calcification score (AACS). The serum level of fibroblast growth factor-23 was tested by enzyme-linked immunosorbent assay. Patients were divided into two groups: no or minor calcification group (AACS < 5) and moderate to severe calcification group (AACS ≥ 5). All patients were followed up to death or the end of the study (30 November 2016). RESULTS: A total of 114 patients were enrolled in this study, including 64 males (56.1%), and the mean age was 57.42 ± 13.48 years. Seventy-six patients (66.7%) exhibited AAC. Independent predictors for moderate to severe calcification were older age (odds ratio (OR) 1.06 (1.02-1.10), P = 0.003), longer dialysis vintage (OR 1.01 (1.00-1.02), P = 0.039), presence of smoking (OR 3.01 (1.18-7.70), P = 0.021) and higher Log fibroblast growth factor-23 serum levels (OR 2.83 (1.01-7.94), P = 0.048). During a median follow-up of 6.0 (5.6, 6.1) years, 22 patients (19.3%) died of all-cause death, and 17 cases (14.9%) died of CVD. Kaplan-Meier survival curves showed that patients in the moderate to severe calcification group had significantly higher all-cause (28.3 vs 11.5%, P = 0.028) and CVD mortality (22.6 vs 8.2%, P = 0.035) than that in the no or minor calcification group. A multivariate Cox regression showed that AACS (hazard ratio 1.08 (1.01-1.15), P = 0.022) was an independent predictor of CVD mortality. Compared with the no or minor calcification group, the risk of CVD mortality was increased by a factor of 3.14 in patients in the moderate to severe calcification group (hazard ratio 3.14 (1.04-9.44), P = 0.042). CONCLUSION: Our data suggest that AAC is prevalent in MHD patients and could provide potential predictive information for CVD mortality. Plain lateral abdominal radiography, which is simple and cheap and involves lower radiation, might represent an appropriate screening method for evaluating vascular calcification in daily clinical practice.