An outbreak of coronavirus disease 2019 (COVID-19) is a public health emergency of international concern and poses a big challenge to medical staff and general public. The aim is to investigate ...psychological impact of COVID-19 epidemic on medical staff in different working posts in China, and to explore the correlation between psychological disorder and the exposure to COVID-19.
A multicenter WeChat-based online survey was conducted among medical staff in China between 26 February and 3 March 2020. Medical staff deployed to Hubei province from other provinces and medical staffs in different posts outside Hubei were selected to represent diverse exposure intensities to the threat of COVID-19. Anxiety, depression, sleep quality, stress and resilience were evaluated using scales including GAD-7, PHQ-9, PSQI, PSS-14, and CD-RISC-10. Latent class analysis was performed to identify potential staff requiring psychological support.
A total of 274 respondents were included, who serving at 4 posts as follows, staff backing Hubei province, isolation wards outside Hubei, fever clinic and infectious disease department, and other departments outside Hubei. The total scores of anxiety, depression, sleep quality and stress were statistically different among groups, meanwhile an increasing tendency of anxiety, depression and sleep quality scores with increasing risk of exposure to COVID-19 was found (p < 0.05). Subsequent post-hoc analysis indicated that the staff backing Hubei had higher scores of anxiety, depression, sleep quality and perceived stress (adjusted p < 0.05). The combined prevalence of anxiety, depression and insomnia of staff backing Hubei reached as high as 38%. Four-class latent class analysis showed 3 categories of population (69.4%) may need psychological support.
High prevalence of anxiety, depression and insomnia exist in medical staff related to COVID-19. The higher the probability and intensity of exposure to COVID-19 patients, the greater the risk that medical staff will suffer from mental disorders, suggesting continuous and proper psychiatric intervention are needed.
Several studies suggest that glial scars pose as physical and chemical barriers that limit neurite regeneration after spinal cord injury (SCI). Evidences suggest that the activation of the ...PI3K/Akt/mTOR signaling pathway is involved in glial scar formation. Therefore, inhibition of the PI3K/Akt/mTOR pathway may beneficially attenuate glial scar formation after SCI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates the PI3K/Akt/mTOR pathway. Therefore, we hypothesized that the overexpression of PTEN in the spinal cord will have beneficial effects after SCI. In the present study, we intrathecally injected a recombinant adenovirus carrying the pten gene (Ad-PTEN) to cause overexpression of PTEN in rats with contusion injured spinal cords. The results suggest overexpression of PTEN in spinal cord attenuated glial scar formation and led to improved locomotor function after SCI. Overexpression of PTEN following SCI attenuated gliosis, affected chondroitin sulfate proteoglycan expression, and improved axon regeneration into the lesion site. Furthermore, we suggest that the activation of the PI3K/Akt/mTOR pathway in astrocytes at 3days after SCI may be involved in glial scar formation. Because delayed treatment with Ad-PTEN enhanced motor function recovery more significantly than immediate treatment with Ad-PTEN after SCI, the results suggest that the best strategy to attenuate glial scar formation could be to introduce 3days after SCI. This study's findings thus have positive implications for patients who are unable to receive immediate medical attention after SCI.
•I.t. Ad vector overexpression of astrocytic PTEN in normal and injured spinal cord.•Overexpression of PTEN following SCI led to improved locomotor function after SCI.•Overexpression of PTEN following SCI attenuated the glial scar formation.•Activation of the PI3K/Akt/mTOR pathway may be involved in glial scar formation.
Abstract
Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 ...single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
Background
In pancreatic cancer, methods to predict early recurrence (ER) and identify patients at increased risk of relapse are urgently required.
Purpose
To develop a radiomic nomogram based on MR ...radiomics to stratify patients preoperatively and potentially improve clinical practice.
Study Type
Retrospective.
Population
We enrolled 303 patients from two medical centers. Patients with a disease‐free survival ≤12 months were assigned as the ER group (n = 130). Patients from the first medical center were divided into a training cohort (n = 123) and an internal validation cohort (n = 54). Patients from the second medical center were used as the external independent validation cohort (n = 126).
Field Strength/Sequence
3.0T axial T1‐weighted (T1‐w), T2‐weighted (T2‐w), contrast‐enhanced T1‐weighted (CET1‐w).
Assessment
ER was confirmed via imaging studies as MRI or CT. Risk factors, including clinical stage, CA19‐9, and radiomic‐related features of ER were assessed. In addition, to determine the intra‐ and interobserver reproducibility of radiomic features extraction, the intra‐ and interclass correlation coefficients (ICC) were calculated.
Statistical Tests
The area under the receiver‐operator characteristic (ROC) curve (AUC) was used to evaluate the predictive accuracy of the radiomic signature in both the training and test groups. The results of decision curve analysis (DCA) indicated that the radiomic nomogram achieved the most net benefit.
Results
The AUC values of ER evaluation for the radiomics signature were 0.80 (training cohort), 0.81 (internal validation cohort), and 0.78 (external validation cohort). Multivariate logistic analysis identified the radiomic signature, CA19‐9 level, and clinical stage as independent parameters of ER. A radiomic nomogram was then developed incorporating the CA19‐9 level and clinical stage. The AUC values for ER risk evaluation using the radiomic nomogram were 0.87 (training cohort), 0.88 (internal validation cohort), and 0.85 (external validation cohort).
Data Conclusion
The radiomic nomogram can effectively evaluate ER risks in patients with resectable pancreatic cancer preoperatively, which could potentially improve treatment strategies and facilitate personalized therapy in pancreatic cancer.
Level of Evidence: 4
Technical Efficacy: Stage 4
J. Magn. Reson. Imaging 2020;52:231–245.
: PD1/PD-L1 immune checkpoint inhibitors have shown promising results for several malignancies. However, PD1/PD-L1 signaling and its therapeutic significance remains largely unknown in intrahepatic ...cholangiocarcinoma (ICC) cases with complex etiology.
: We investigated the expression and clinical significance of CD3 and PD1/PD-L1 in 320 ICC patients with different risk factors. In addition, we retrospectively analyzed 7 advanced ICC patients who were treated with PD1 inhibitor.
: The cohort comprised 233 patients with HBV infection, 18 patients with hepatolithiasis, and 76 patients with undetermined risk factors. PD-L1 was mainly expressed in tumor cells, while CD3 and PD1 were expressed in infiltrating lymphocytes of tumor tissues. PD1/PD-L1 signals were activated in tumor tissues, and expression was positively correlated with HBV infection and lymph node invasion. More PD1
T cells and higher PD-L1 expression were observed in tumor tissues of ICC patients with HBV infection compared to patients with hepatolithiasis or undetermined risk factors. More PD1
T cells and/or high PD-L1 expression negatively impacted the prognosis of patients with HBV infection but not those with hepatolithiasis. Multivariate analysis showed PD1/PD-L1 expression was an independent indicator of ICC patient prognosis. Advanced ICC patients with HBV infection and less PD1
T cells tended to have good response to anti-PD1 therapy.
: Hyperactivated PD1/PD-L1 signals in tumor tissues are a negative prognostic marker for ICCs after resection. HBV infection- and hepatolithiasis-related ICCs have distinct PD1/PD-L1 profiles. Further, PD1
T cells could be used as a biomarker to predict prognosis and assay the efficiency of anti-PD1 immunotherapy in ICC patients with HBV infection.
Bile acid transporters maintain bile acid homeostasis. Little is known about the functions of some transporters in cholestasis or their regulatory mechanism. We investigated the hepatic expression of ...solute carrier organic anion transporter family member 3A1 (SLCO3A1, also called OATP3A1) and assessed its functions during development of cholestasis.
We measured levels of OATP3A1 protein and messenger RNA and localized the protein in liver tissues from 22 patients with cholestasis and 21 patients without cholestasis, using real-time quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. We performed experiments with Slco3a1-knockout and C57BL/6J (control) mice. Mice and Sprague-Dawley rats underwent bile duct ligation (BDL) or a sham operation. Some mice were placed on a 1% cholic acid (CA) diet to induce cholestasis or on a control diet. Serum and liver tissues were collected and analyzed; hepatic levels of bile acids and 7-α-C4 were measured using liquid chromatography/mass spectrometry. Human primary hepatocytes and hepatoma (PLC/PRF/5) cell lines were used to study mechanisms that regulate OATP3A1 expression and transport.
Hepatic levels of OATP3A1 messenger RNA and protein were significantly increased in liver tissues from patients with cholestasis and from rodents with BDL or 1% CA diet–induced cholestasis. Levels of fibroblast growth factor 19 (FGF19, FGF15 in rodents) were also increased in liver tissues from patients and rodents with cholestasis. FGF19 signaling activated the Sp1 transcription factor and nuclear factor κB to increase expression of OATP3A1 in hepatocytes; we found binding sites for these factors in the SLCO3A1 promoter. Slco3a1-knockout mice had shorter survival times and increased hepatic levels of bile acid, and they developed more liver injury after the 1% CA diet or BDL than control mice. In hepatoma cell lines, we found OATP3A1 to take prostaglandin E2 and thyroxine into cells and efflux bile acids.
We found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.
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Semaphorin 7A (SEMA7A) is a membrane‐bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we ...report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC‐MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance‐associated protein‐2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.
SYNOPSIS
A new type of progressive familial intrahepatic cholestasis (PFIC) was caused by the homozygous R148W mutation in SEMA7A. Preliminary mechanistic studies revealed that the mutation reduced hepatic expression of canalicular membrane bile acid (BA) efflux transporters Bsep and Mrp2, resulting in intrahepatic cholestasis.
A female child patient presented with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology.
A SEMA7AR148W homozygous mutation was identified in the child patient.
The Sema7aR145W (human R148W) homozygous mice displayed elevated levels of serum ALT, AST, and TBA, as well as hepatocyte hydropic degeneration and intrahepatic accumulation of conjugated BAs.
The Sema7aR145W homozygous mutation reduced the expression of canalicular membrane Bsep and Mrp2 in mouse livers and sandwich‐cultured primary hepatocytes.
Administration with ursodeoxycholic acid (UDCA) and a dietary supplement glutathione (GSH) were effective for this new type of PFIC.
A new type of progressive familial intrahepatic cholestasis (PFIC) was caused by the homozygous R148W mutation in SEMA7A. Preliminary mechanistic studies revealed that the mutation reduced hepatic expression of canalicular membrane bile acid (BA) efflux transporters Bsep and Mrp2, resulting in intrahepatic cholestasis.
Depression is a common mental disorder and is one of the main causes of disability. Berberine (BBR), the major constituent alkaloid originally from the famous Chinese herb Huanglian (Coptis ...chinensis), has been shown to exert antidepressant-like effects. This study was to investigate the hypothesis that BBR treats depressive-like behavior by shifting the balance of the kynurenine (KYN)/serotonin (5-HT) pathway toward the 5-HT pathway through downregulated indoleamine 2,3-dioxygenase 1 (IDO1), monoamine oxidase A (MAOA) and upregulated dopamine decarboxylase (DDC) in hippocampus.
A chronic unpredictable mild stress (CUMS) mice model of depression was established via 21 days unpredictable stimulation. Then the mice were randomly assigned into six groups, namely control, model, fluoxetine FLU, (10 mg/kg), BBRL (25 mg/kg), BBRM (50 mg/kg), and BBRH (100 mg/kg) groups. Behavioral assessments were conducted to evaluate the antidepressant effects of BBR. The levels of 5-HT, KYN, tryptophan (TRP), and 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus were estimated using high performance liquid chromatography (HPLC). The mRNA and protein levels of DDC, MAOA and IDO1 in hippocampus were detected by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot (WB), respectively.
The results showed that a successful CUMS mice model was established through 21 days of continuous unpredictable stimulation, as indicated by the significant decrease in locomotor activity and increase in immobility time, reduction in body weight and sucrose preference rate etc. Compared with the normal group, the concentrations of KYN/TRP had significantly increased (p## <0.01) and 5-HT/5-HIAA had decreased (p#<0.05) at day 21 in the control group, but then improved after drug treatment with FLU and BBR. Compared with the normal group, the mRNA of IDO1 and MAOA were significantly upregulated (p#<0.05) in the control group, MAOA and IDO1 gene were downregulated by FLU and BBR treatment. Protein expressions of IDO1 and MAOA was significantly increased (p#<0.05) and DDC downregulated (p##<0.01). BBR treatment downregulated IDO1 and MAOA, upregulated DDC.
BBR reversed the abnormalities of the KYN/5-HT pathway in depressed mice and achieved an excellent antidepressant effect. Its direct impact may be observed as changes in biological indicators in mice hippocampus tissue.
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•Berberine alleviated CUMS-induced depressive behaviors in mice.•Berberine induces the expression of IDO1, MAOA and DDC in the hippocampus.•Berberine may exert antidepressant effects by regulating kynurenine/serotonin signaling pathway.
Asparaginase (ASP) is the cornerstone drug in the treatment of extranodal NK/T-cell lymphoma (ENKTCL), and the mechanisms of resistance to ASP remain largely unknown. Long non-coding RNAs play ...important roles in chemotherapy resistance in various cancers. However, the expression of BCYRN1 and its role in ENKTCL still remain unidentified.
Lentivirus-mediated BCYRN1 overexpression and knockdown were performed in SNK-6 cells. Cell autophagy was analyzed by adenovirus expressing GFP-LC3B fusion protein. RNA pull-down and RNA Binding Protein Immunoprecipitation Assay were performed to investigate the relationship between BCYRN1 and p53. Western blot analysis was performed to assess the effect of BCYRN1 on different autophagy pathways. Finally, in vivo xenograft tumor model was constructed to analyze the effect of BCYRN1 on tumor growth and ASP resistance.
BCYRN1 was overexpressed in ENKTCL than normal NK cells, and patients with higher expression had significantly inferior progression-free survival (PFS). The IC50 value of ASP was significantly increased in BCYRN1-overexpressed SNK-6 cells and BCYRN1 overexpression could resist the inhibitory effect of ASP on proliferation. ASP could induce concurrent apoptosis and autophagy in ENKTCL, and the latter process was enhanced by overexpression of BCYRN1, mainly through affecting both PI3K/AKT/mTOR and p53/mTOR pathways. BCYRN1 could induce the degradation of p53 via ubiquitination, thus resulting in enhancement of autophagy and ASP resistance, which could be reversed by drug-induced autophagy inhibition. The effect of BCYRN1 on tumor growth and autophagy were confirmed in vivo xenograft model.
It was found that BCYRN1 was a valuable prognostic biomarker in ENKTCL. BCYRN1 could promote resistance to ASP by inducing autophagy, which could be reversed by inhibition of autophagy. Our findings highlight the feasibility of combining autophagy inhibition and ASP in the treatment of ENKTCL.
Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being ...characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2
ACE2
small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2
ACE2
cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27
memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2
ACE2
small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2
ACE2
cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.
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