Inducible downregulation of miR-93 feedback promotes innate responses against RNA virus by amplifying interferon signaling.

Type I interferons (IFN) and their downstream effector signaling pathways play critical roles in the innate antiviral response. The underlying mechanisms that regulate IFN production and their effector signaling, especially by microRNAs, are well understood. We found that the expression of miR-93 was significantly downregulated by RNA virus infection in innate cells. miR-93 expression was also downregulated in influenza virus-infected patients. Furthermore, we showed that JAK1 is targeted by miR-93 to inhibit type I IFN's antiviral activity. Functionally, antagomir of miR-93 markedly reduced influenza virus replication in mice in vivo and prevented their death. Therefore, hosts recognize the invading RNA virus infection and activate RIG-I/JNK pathways to decrease miR-93 expression. The reduction of miR-93 feedback enhances the antiviral innate immune response by activating the IFN-JAK-STAT effectors type I, indicating miR-93 as a possible therapeutic target for infection with RNA viruses.

Orthotopic and Heterotopic Murine Models of Pancreatic Cancer Exhibit Different Immunological Microenvironments and Different Responses to Immunotherapy.

For decades, tumor-bearing murine models established using tumor cell lines have been the most commonly used models to study human cancers. Even though there are several studies reported that implant sites caused disparities in tumor behaviors, few of them illuminated the positional effect on immunotherapy. Herein, we describe surgical techniques for a novel orthotopic implantation of syngeneic pancreatic ductal adenocarcinoma (PDAC) tissue slices. This method has a high success modeling rate and stable growth kinetics, which makes it useful for testing novel therapeutics. Pathological examination indicated that the orthotopic tumor displayed poor vascularization, desmoplastic stromal reaction, and a highly immunosuppressive tumor microenvironment. This unique microenvironment resulted in limited response to PD1/CTLA4 blockade therapy and anti-MUC1 (αMUC1) CAR-T transfer treatment. To reverse the suppressive tumor microenvironment, we developed gene modified T-cells bearing a chimeric receptor in which activating receptor NKG2D fused to intracellular domains of 4-1BB and CD3ζ (NKG2D CAR). The NKG2D CAR-T cells target myeloid-derived suppressor cells (MDSCs), which overexpress Rae1 (NKG2D ligands) within the TME. Results indicated that NKG2D CAR-T cells eliminated MDSCs and improved antitumor activity of subsequently infused CAR-T cells. Moreover, we generated a bicistronic CAR-T, including αMUC1 CAR and NKG2D CAR separated by a P2A element. Treatment with the dual targeted bicistronic CAR-T cells also resulted in prolonged survival of orthotopic model mice. In summary, this study describes construction of a novel orthotopic PDAC model through implantation of tissue slices and discusses resistance to immunotherapy from the perspective of a PDAC microenvironment. Based on the obtained results, it is evident that elimination MDSCs by NKG2D CAR could rescue the impaired CAR-T cell activity.

Influence of Three-Dimensional Visual Reconstruction Technology Combined with Virtual Surgical Planning of CTA Images on Precise Resection of Liver Cancer in Hepatobiliary Surgery.

Hepatobiliary malignancies, such as hepatocellular carcinoma (HCC) and biliary tract cancers, namely, gallbladder carcinoma and cholangiocarcinoma, are linked to a high rate of morbidity and mortality, depending on the phase of the disease. The intricate hepatobiliary anatomy and the need for accurate peroperative management, especially in patients with advanced liver disease, make these tumors difficult to treat. Surgical resection is a notable therapy for hepatobiliary cancers. Unnecessary or excessive liver excision influences patient rehabilitation, normal liver function, and postoperative complications. Hepatobiliary operations must therefore include accurate liver removal. The present advancements in imaging technology are aimed at improving the diagnostic efficacy of liver injury even more. Three-dimensional visual reconstruction is becoming more important in the diagnosis as well as treatment of a variety of disorders. In this paper, we proposed a novel three-dimensional visual reconstruction technology using enhanced nonuniform rational basis spline (ENURBS) combined with virtual surgical planning of Computed Tomography Angiography (CTA) images for precise liver cancer resection. The purpose of this project is to rebuild 2D CTA scan images of liver cancer into a 3D reconstructed model for efficient visualization and diagnosis of liver cancer and to prepare an effective preoperative surgical plan for precise liver excision based on a 3D recreated liver model. This method's performance is compared to that of 2D planning in terms of accuracy and time taken to complete the plan. It is concluded that our proposed technique outperforms the planning technique based on 2D images.

Machine learning approach to predict acute kidney injury after liver surgery.

BACKGROUND: Acute kidney injury (AKI) after surgery appears to increase the risk of death in patients with liver cancer. In recent years, machine learning algorithms have been shown to offer higher discriminative efficiency than classical statistical analysis. AIM: To develop prediction models for AKI after liver cancer resection using machine learning techniques. METHODS: We screened a total of 2450 patients who had undergone primary hepatocellular carcinoma resection at Changzheng Hospital, Shanghai City, China, from January 1, 2015 to August 31, 2020. The AKI definition used was consistent with the Kidney Disease: Improving Global Outcomes. We included in our analysis preoperative data such as demographic characteristics, laboratory findings, comorbidities, and medication, as well as perioperative data such as duration of surgery. Computerized algorithms used for model development included logistic regression (LR), support vector machine (SVM), random forest (RF), extreme gradient boosting (XGboost), and decision tree (DT). Feature importance was also ranked according to its contribution to model development. RESULTS: AKI events occurred in 296 patients (12.1%) within 7 d after surgery. Among the original models based on machine learning techniques, the RF algorithm had optimal discrimination with an area under the curve value of 0.92, compared to 0.87 for XGBoost, 0.90 for DT, 0.90 for SVM, and 0.85 for LR. The RF algorithm also had the highest concordance-index (0.86) and the lowest Brier score (0.076). The variable that contributed the most in the RF algorithm was age, followed by cholesterol, and surgery time. CONCLUSION: Machine learning algorithms are highly effective in discriminating patients at high risk of developing AKI. The successful application of machine learning models may help guide clinical decisions and help improve the long-term prognosis of patients.

Inhibition of miR-93 promotes interferon effector signaling to suppress influenza A infection by upregulating JAK1.

Type I interferons play a critical role in host defense against influenza virus infection. Interferon cascade induces the expression of interferon-stimulated genes then subsequently promotes antiviral immune responses. The microRNAs are important regulators of innate immunity, but microRNAs-mediated regulation of interferon cascade during influenza infection remains to be fully identified. Here we found influenza A virus (IAV) infection significantly inhibited miR-93 expression in alveolar epithelial type II cells through RIG-I/JNK pathway. IAV-induced downregulation of miR-93 was found to upregulate JAK1, the target of miR-93, and then feedback promote antiviral innate response by facilitating IFN effector signaling. Importantly, in vivo administration of miR-93 antagomiR markedly suppressed IAV infection, protecting mice form IAVs -associated death. Hence, the inducible downregulation of miR-93 feedback suppress IAV infection by strengthening IFN-JAK-STAT pathway via JAK1 upregulation, and in vivo inhibition of miR-93 bears considerable therapeutic potential for suppressing IAV infection.

Two case reports and literature review for hepatic epithelioid angiomyolipoma: Pitfall of misdiagnosis.

BACKGROUND: Hepatic epithelioid angiomyolipoma (HEAML) is a rare liver disease and is easily misdiagnosed. Enhanced recognition of HEAML is beneficial to the differential diagnosis of rare liver diseases. CASE SUMMARY: We presented two cases of HEAML in Changzheng Hospital, Naval Medical University, and then collected and analyzed all reports about HEAML recorded in PubMed, MEDLINE, China Science Periodical Database, and VIP database from January 2000 to March 2018. A total of 409 cases of HEAML in 97 reports were collected, with a ratio of men to women of 1:4.84 and an age range from 12 years to 80 years (median 44 years). Among the patients with clinical symptoms mentioned, 61.93% (205/331) were asymptomatic, 34.74% (115/331) showed upper or right upper quadrant abdomen discomfort, while a few of them showed abdominal mass, gastrointestinal symptoms, low fever, or weight loss. The misdiagnosis rate of HEAML was as high as 40.34% (165/409) due to its nonspecific imaging findings. Most of the tumors were solitary and round in morphology, with clear boundaries. Ultrasound scan indicated low echo with internal nonuniformity and rich blood supply in most cases. Computer tomography/magnetic resonance imaging enhanced scan showed varied characteristics. The ratio of fast wash-in and fast wash-out, fast wash-in and slow wash-out, and delayed enhancement was roughly 4:5:1. A definite diagnosis of HEAML depended on the pathological findings of the epithelioid cells in lesions and the expression of human melanoma black 45, smooth muscle actin, melanoma antigen, and actin by immunohistochemical staining. HEAML had a relatively low malignant rate of 3.91%. However, surgical resection was the main treatment for HEAML, due to the difficulty diagnosing before operation. CONCLUSION: HEAML is a rare and easily misdiagnosed disease, and it should be diagnosed carefully, taking into account clinical course, imaging, pathological ,and immunohistochemical findings.