Caprin-1 influences autophagy-induced tumor growth and immune modulation in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. METHODS: Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. RESULTS: Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. CONCLUSIONS: Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.

Analysis of tigecycline in the cerebrospinal fluid and serum of patients with Acinetobacter baumannii central nervous system infection.

Aim: This study aimed to establish a method to determine tigecycline (TGC) in the cerebrospinal fluid (CSF) and serum of 12 patients with multidrug-resistant Acinetobacter baumannii (MDRAB) central nervous system infection (CNSI) and evaluate the correlation of TGC in CSF and serum samples. Materials & methods: TGC in CSF and serum was detected by high-performance liquid chromatography with tandem mass spectrometry. Results: In all 12 patients, the CSF-to-serum ratio of TGC at a steady-state trough concentration ranged from 21.46 to 44.46%, and the mean value was 31.61 ± 8.13%. The correlation of TGC in CSF and serum was 0.5065. Conclusion: CNSI might have no potential to increase the penetration ability of TGC into the CSF. The correlation between the concentrations of TGC in CSF and serum at steady state was demonstrated to be positive.

Erratum: Moxidectin induces Cytostatic Autophagic Cell Death of Glioma Cells through inhibiting the AKT/mTOR Signalling Pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.46697.].

Gut microbiota affects pancreatic fibrotic progression through immune modulation in chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by chronic progressive pancreatic inflammation, which leads to the permanent damage of exocrine and endocrine cells. CP causes irreversible morphological and functional changes, and the clinical manifestations includes abdomen pain, steatorrhea and diabetes. CP induces changes in the composition of gut microbiota that could be used as potential biomarkers for pancreatic fibrosis evaluation. Gut microbiota has emerged as key regulator of immunomodulation and gut microbiota-induced immune activation has not been explored in CP. In current study, we profiled gut microbial signatures in mouse CP model, and found that higher proportion of Streptomyces, Turicibacter, Methylobacterium, Enterococcus and Candidatus_Paenicardiniummore were positively associated with the occurrence of pancreatic fibrosis. We then identified increased CD3+T cells and macrophage infiltration in mouse and human CP tissues by transcriptome sequencing data from GEO database. Subsequently, we demonstrated that fecal microbiota transplantation (FMT) from CP mouse (FMT-CP) exacerbated pancreatic fibrosis by increasing CD4+T cells and macrophage infiltration compared to fecal samples obtained from healthy mouse donor (FMT-HC). Our study describes the link between gut microbiota dysbiosis and immune activation in pancreatic fibrotic progression, and highlights the potential therapeutic roles of FMT and CP treatment.

Interferon-α2b induced anemia in severe coronavirus disease 2019 patients: a single centered, retrospective study.

BACKGROUND: The current outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread throughout the world. During treatment, we found that the majority of patients had a decrease in hemoglobin (Hb). Interferon-α2b (IFN-α2b) was the primary suspected drug that was related to Hb reduction. Thus, the study aimed to investigate whether IFN-α2b could induce Hb reduction in severe patients with COVID-19 and its potential mechanism. MATERIAL AND METHODS: A total of 50 patients who were admitted to the First Affiliated Hospital of Harbin Medical University with severe COVID-19 infection were enrolled from February 12th to 24th, 2020. The demographics, baseline characteristics, clinical data, and therapeutic regimen were collected retrospectively. The patients were divided into two groups according to the declined use of IFN-α2b on day 14. The Hb levels on admission, day 7, day14, and day 21 were collected and analyzed. The primary endpoint was the level of Hb on day 21. RESULTS: A total of 31 patients in the IFN-stop group and 19 patients in the non-IFN-stop group were reviewed. The age, gender, comorbidities, clinical symptoms, nutritional status, disease severity, complications, and other factors of the patients were compared, no difference was found between the IFN-stop group and the non-IFN-stop group. The Hb levels of all patients significantly decreased on day 7 compared with that on admission (p < .0001). In the IFN-stop group, the Hb level was increased in 7 days after IFN-α2b was stopped (p = .0008), whereas no difference was found between day 14 and day 21 in the non-IFN-stop group (p = .3152). CONCLUSIONS: IFN-α2b was associated with Hb reduction in the treatment of severe patients of COVID-19. Clinicians should be aware of the high incidence of Hb reduction for patients treated by IFN-α2b.

Moxidectin induces Cytostatic Autophagic Cell Death of Glioma Cells through inhibiting the AKT/mTOR Signalling Pathway.

Moxidectin (MOX), a broad-spectrum antiparasitic drug, has been characterized as a potential anti-glioma agent. The main objective of this study was to explore autophagy induced by MOX in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, the effects of autophagy on apoptosis in glioma cells were tested. Autophagy was measured by transmission electron microscopy (TEM), immunofluorescence, western blot and immunohistochemistry. Cell viability was detected with MTT and colony formation assay. The apoptosis rate was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Additonally, autophagy inhibition was achieved by using 3-Methyladenine (3-MA) and chloroquine (CQ). U251-derived xenografts were established for examination of MOX-induced autophagy on glioma in vivo. Firstly, our research found that MOX stimulated autophagy of glioma cells in a dose-dependent manner. Secondly, we found that MOX induced autophagy by inhibiting the AKT/mTOR signalling pathway. Thirdly, inhibition of autophagy could reduce apoptosis in MOX-treated glioma cells. Finally, MOX induced autophagy, and autophagy increased the apoptosis effect of MOX on U251 in vivo. In conclusion, our data provide evidence that MOX can induce autophagy in glioma cells, and autophagy could increase MOX-induced apoptosis through inhibiting the AKT/mTOR signalling pathway. These findings provided a new prospect for the application of MOX and a novel targeted therapy for the treatment of gliomas.

Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system.

BACKGROUND: Although colitis has been reported in patients treated with immune checkpoint inhibitors (ICIs), associations between colitis and ICIs had not been thoroughly assessed in real-world studies. Here, we identified and characterized significant colitis-associated with ICIs. METHODS: Based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019, the disproportionality analysis and Bayesian analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were adopted to data mining of the suspected adverse events of colitis after ICIs administrating. Clinical characteristics of patients with ICIs-associated colitis and the time to onset of colitis following different ICI regimens were collected. RESULTS: A total of 3786 reports of colitis adverse events were identified with ICIs. Seven ICI monotherapies were associated with the reporting of colitis. Statistically significant ROR, PRR, information component (IC), and empirical Bayesian geometric mean (EBGM) emerged for all ICI monotherapies and combination therapies. ICIs-associated colitis affected mostly male (53.51%), with a wide mean age range (60.65 to 72 years). Colitis adverse events were commonly reported in patients with melanoma and lung cancer. Adverse outcomes of colitis concerning ICI were mainly outcomes of hospitalization-initiated or prolonged and other serious. Among colitis cases, 17.43% cases of colitis concerning ICI lead to death. The adverse event ofcolitis occurred earliest in ipilimumab monotherapy with a median time to onset of 64.21 days (IQR: 27-69 days) among all monotherapies. CONCLUSIONS: ICI may lead to severe and disabling ICIs-associated colitis during therapy. Analysis of FAERS data identified signals for adverse events of colitis with ICI regimens. Practitioners should consider the factors that may increase the likelihood of colitis. The findings support a continued surveillance and risk factor identification studies.

Small Molecule Inhibitor C188-9 Synergistically Enhances the Demethylated Activity of Low-Dose 5-Aza-2'-Deoxycytidine Against Pancreatic Cancer.

Aberrant DNA methylation, especially hypermethylation of tumor suppressor genes, has been associated with many cancers' progression. 5-Aza-2'-deoxycytidine (DAC) can reverse hypermethylation-induced gene silencing via regulating DNA methyltransferases (DNMTs) activity, In addition, low-dose of DAC was proved to exert durable antitumor effects against solid tumor cells. Nevertheless, no clinical effect of DAC has been made when fighting against pancreatic cancer. Hence, it is necessary to raise a novel therapeutic strategy that further enhance the efficacy of DAC but not increase side effect, which impede the utilization of DAC. In the present study, we have discovered that C188-9, a novel signal transduction activator of transcription (STAT) inhibitor, could improve the antitumor effects of low-dose DAC in vivo and in vitro. Further study demonstrated that such improvement was attributed to re-expression of Ras association domain family member 1A (RASSF1A), a well-known tumor suppressor gene. Bisulfite sequencing PCR (BSP) assay showed that C188-9 combined with DAC treatment could significantly reverse the hypermethylation status of RASSF1A promoter, which indicated that C188-9 could enhance the demethylation efficacy of DAC. Our data demonstrated that DNA methyltransferase 1 (DNMT1) was the underlying mechanism that C188-9 regulates the demethylation efficacy of DAC. Overall, these findings provide a novel therapeutic strategy combining low-dose DAC and C188-9 to improve therapeutic efficacy by inhibiting DNMT1-inducing promoter methylation.

Risk Factors of Multidrug Resistant Pathogens Induced Infection in Severe Acute Pancreatitis.

PURPOSE: A retrospective study was first performed to assess the multidrug resistant (MDR) pathogen in severe acute pancreatitis (SAP) patients who were treated using the step-up approach. We aim to assess the risk factors between MDR pathogen and potential covariates in SAP patients. METHODS: The clinical data of 51 SAP patients who were treated from June, 2013 to December, 2016 were retrospectively collected. A total of 23 patients in the MDR group and 28 patients in the non-MDR group were reviewed. The risk factors for MDR pathogen-induced infections in SAP patients were analyzed. RESULTS: Hyperlipidemia was the leading cause of SAP in our study. The mean duration of hospital stay was significantly longer in the patients with MDR pathogen infections (P=0.0135). The hospitalization expenses of MDR group were much higher than those in non-MDR group. The mortality of MDR group (56.5%) was higher than that in non-MDR group (28.6%) (P=0.0436). Gram-negative isolates (63.8%) were commonly detected in SAP patients. Acinetobacter baumannii was the most common MDR pathogens. Systemic disease (P = 0.0136), initial use of carbapenem (P = 0.0438), and open necrosectomy (P = 0.0002) were the potential risk factors for MDR pathogen-induced infections in SAP. Furthermore, the logistic regression analysis revealed that open necrosectomy was the independent variable for MDR infections (OR: 15.6, 95% CI: 2.951-82.469, P = 0.0012). CONCLUSIONS: MDR pathogen-induced infections were common in SAP patients and Acinetobacter baumannii was the main pathogen. Meanwhile, open necrosectomy was the independent risk factor for the infection of MDR pathogen.

Inhibition of RIPK1-dependent regulated acinar cell necrosis provides protection against acute pancreatitis via the RIPK1/NF-κB/AQP8 pathway.

Currently, preliminary results have confirmed the existence of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis of pancreatic acinar cells during early acute pancreatitis (AP), which might be a potential target for the effective regulation of necroinflammatory injury. However, the exact effect of receptor-interacting protein kinase 1 (RIPK1)-dependent regulated acinar cell necrosis on AP is still uncertain. In our study, we first explored the changes in the degree of local and systemic inflammation in AP rats when the activation of acinar cell RIPK1 was inhibited. The RIPK1 inhibitor Nec-1 was used to treat rats, and the levels of related inflammatory markers, necrosis indicators and apoptotic indicators were measured. Changes in pancreatic nuclear factor κB (NF-κB) and aquaporin 8 (AQP8) expression were noted. Next, the expression of AQP8 in AR42J cells was inhibited, and the degree of cell necrosis and inflammatory damage was found to be significantly reduced. Most importantly, we demonstrated that the RIPK1/NF-ĸB/AQP8 axis might be a potential regulatory pathway mediating RIPK1-dependent regulated acinar cell necrosis in early AP. Finally, we used the NF-κB inhibitor PDTC and Nec-1 to treat rats in different groups and measured the degree of pathological pancreatic injury, the activation of RIPK1, and the expression of NF-κB and AQP8. In summary, we hypothesized that there might be a RIPK1/NF-ĸB/AQP8 pathway controlling RIPK1-dependent regulated necrosis of acinar cells in AP, which might be a promising therapeutic target against AP-related injury.

MicroRNA­1 downregulation induced by carvedilol protects cardiomyocytes against apoptosis by targeting heat shock protein 60.

Myocardial infarction (MI) is the most common event in cardiovascular disease. Carvedilol, a ß­blocker with multiple pleiotropic actions, is widely used for the treatment cardiovascular diseases. However, the underlying mechanisms of carvedilol on alleviating MI are not fully understood. The aim of the present study was to investigate whether the beneficial effects of carvedilol were associated with regulation of microRNA­1 (miR­1). It was demonstrated that carvedilol ameliorated impaired cardiac function and decreased infarct size in a rat model of MI induced by coronary artery occlusion. Similarly, carvedilol reversed the H2O2­induced decrease in cardiomyocyte viability in a dose­dependent manner. The in vivo and in vitro models demonstrated the downregulation of miR­1 following treatment with carvedilol. Overexpression of miR­1, a known pro­apoptotic miRNA, decreased cell viability and induced cell apoptosis. Transfection of miR­1 abolished the beneficial effects of carvedilol. The expression of heat shock protein 60 (HSP60), a direct target of miR­1, was identified to be decreased in MI and H2O2­induced apoptosis, which was associated with a decrease in Bcl­2 and an increase in Bax; expression was restored following treatment with carvedilol. It was concluded that carvedilol partially exhibited its beneficial effects by downregulating miR­1 and increasing HSP60 expression. miR­1 has become a member of the group of carvedilol­responsive miRNAs. Future studies are required to fully elucidate the potential overlapping or compensatory effects of known carvedilol­responsive miRNAs and their underlying mechanisms of action in the pathophysiology of cardiovascular diseases.