Publications by authors named "Yizhuo Wang"

39 Publications

Therapeutic Mechanism and Effect of Camptothecin on Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice.

J Immunol Res 2021 24;2021:5556659. Epub 2021 Apr 24.

Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China.

Camptothecin (CPT) is a cytotoxic quinoline alkaloid isolated from the bark and branches of the Chinese tree . CPT inhibits topoisomerase I. It possesses various antitumor activities and is mainly used in the treatment of colon, ovarian, liver, and bone cancers as well as leukemia. CPT inhibits the expressions of inflammatory genes and can prevent death from chronic inflammation. Therefore, we investigated the effect of CPT treatment in ulcerative colitis (UC) using DSS-induced UC mouse model; after that, we explored its potential mechanisms. Here, we found that CPT exerted protection on DSS-induced UC in rats. In addition, the administration prominently reduced the disease activity index as well as colon length of the model rats and remarkably reduced the inflammatory cytokines. Further, CPT significantly reduced several vital proinflammatory proteins in LPS-induced RAW264.7 cells. In summary, our findings demonstrate that CPT is hopefully to act as a therapeutic agent for UC.
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http://dx.doi.org/10.1155/2021/5556659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093050PMC
April 2021

Case report: Delayed retinoblastoma relapse in a lymph node after 9 years of complete remission.

Curr Probl Cancer 2021 Jan 8:100703. Epub 2021 Jan 8.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. Recurrence of RB often occurs within 6 months to 1 year after the end of treatment. Orbital tissue is the most common site of recurrence in children who have undergone enucleation; other sites include the central nervous system, bone, bone marrow, lymph nodes, and other organs. Here, we describe an adolescent girl who presented with RB recurrence and metastasis in a distant lymph node after 9 years of complete remission. The tumor was an incidental finding during a routine examination and was misdiagnosed as lymphadenitis. After histopathologic examination of an aspiration biopsy sample, the correct diagnosis of recurrent metastatic RB was made. Systemic chemotherapy and surgical excision were provided; the patient remained tumor-free during the 6-month follow-up period. RB often relapses within 1 year after treatment; orbital tissue is the most common site of recurrence. However, our patient's case was unique in terms of delayed relapse and the presence of a single metastatic site; these findings may provide new insights into the behavior of RB. Furthermore, this case report indicates the need for lifelong follow-up of children with RB. Oncologists should be vigilant when treating patients with a history of RB, because complete remission does not mean complete safety; long-term recurrence and metastasis may occur. Lifelong follow-up is necessary for children with RB. Complete remission might be achieved after active and standardized treatment.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100703DOI Listing
January 2021

Classification Tree-Based Machine Learning to Visualize and Validate a Decision Tool for Identifying Malnutrition in Cancer Patients.

JPEN J Parenter Enteral Nutr 2021 Jan 8. Epub 2021 Jan 8.

Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

Background: The newly proposed Global Leadership Initiative on Malnutrition (GLIM) framework is promising to gain global acceptance for diagnosing malnutrition. However, the role of machine learning in facilitating its application in clinical practice remains largely unknown.

Methods: We performed a multicenter, observational cohort study including 3998 patients with cancer. Baseline malnutrition was defined using the GLIM criteria, and the study population was randomly divided into a derivation group (n = 2998) and a validation group (n = 1000). A classification and regression trees (CART) algorithm was used to develop a decision tree for classifying the severity of malnutrition in the derivation group. Model performance was evaluated in the validation group.

Results: GLIM criteria diagnosed 588 patients (14.7%) with moderate malnutrition and 532 patients (13.3%) with severe malnutrition among the study population. The CART cross-validation identified 5 key predictors for the decision tree construction, including age, weight loss within 6 months, body mass index, calf circumference, and the Nutritional Risk Screening 2002 score. The decision tree showed high performance, with an area under the curve of 0.964 (κ = 0.898, P < .001, accuracy = 0.955) in the validation group. Subgroup analysis showed that the model had apparently good performance in different cancers. Among the 5 predictors constituting the tree, age contributed the least to the classification power.

Conclusion: Using the machine learning, we visualized and validated a decision tool based on the GLIM criteria that can be conveniently used to accelerate the pretreatment identification of malnutrition in patients with cancer.
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http://dx.doi.org/10.1002/jpen.2070DOI Listing
January 2021

Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance.

Theranostics 2021 1;11(4):1845-1863. Epub 2021 Jan 1.

Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.

Ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate the specific role of mitochondrial ROS (mtROS) in initiating mitochondrial DNA (mtDNA) damage and inflammation during IRI-AKI. The changes in renal function, mitochondrial function, and inflammation in IRI-AKI mice with or without mtROS inhibition were analyzed . The impact of mtROS on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, mitochondrial respiration, and cytokine release was analyzed in renal tubular cells . The effects of TFAM knockdown on mtDNA, mitochondrial function, and cytokine release were also analyzed . Finally, changes in TFAM and mtDNA nucleoids were measured in kidney samples from IRI-AKI mice and patients. Decreasing mtROS levels attenuated renal dysfunction, mitochondrial damage, and inflammation in IRI-AKI mice. Decreasing mtROS levels also reversed the decrease in TFAM levels and mtDNA copy number that occurs in HK2 cells under oxidative stress. mtROS reduced the abundance of mitochondrial TFAM in HK2 cells by suppressing its transcription and promoting Lon-mediated TFAM degradation. Silencing of TFAM abolished the Mito-Tempo (MT)-induced rescue of mitochondrial function and cytokine release in HK2 cells under oxidative stress. Loss of TFAM and mtDNA damage were found in kidneys from IRI-AKI mice and AKI patients. mtROS can promote renal injury by suppressing TFAM-mediated mtDNA maintenance, resulting in decreased mitochondrial energy metabolism and increased cytokine release. TFAM defects may be a promising target for renal repair after IRI-AKI.
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http://dx.doi.org/10.7150/thno.50905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778599PMC
January 2021

Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Mitochondrial Damage and Inflammation by Stabilizing Mitochondrial DNA.

ACS Nano 2021 01 28;15(1):1519-1538. Epub 2020 Dec 28.

Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.

Mitochondrial dysfunction is a key feature of injury to numerous tissues and stem cell aging. Although the tissue regenerative role of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) is well known, their specific role in regulating mitochondrial function in target cells remains elusive. Here, we report that MSC-EVs attenuated mtDNA damage and inflammation after acute kidney injury (AKI) and that this effect was at least partially dependent on the mitochondrial transcription factor A (TFAM) pathway. In detail, TFAM and mtDNA were depleted by oxidative stress in MSCs from aged or diabetic donors. Higher levels of TFAM mRNA and mtDNA were detected in normal control (NC) MSC-EVs than in TFAM-knockdown (TFAM-KD) and aged EVs. EV-mediated TFAM mRNA transfer in recipient cells was unaffected by transcriptional inhibition. Accordingly, the application of MSC-EVs restored TFAM protein and TFAM-mtDNA complex (nucleoid) stability, thereby reversing mtDNA deletion and mitochondrial oxidative phosphorylation (OXPHOS) defects in injured renal tubular cells. Loss of TFAM also led to downregulation of multiple anti-inflammatory miRNAs and proteins in MSC-EVs. , intravenously injected EVs primarily accumulated in the liver, kidney, spleen, and lung. MSC-EVs attenuated renal lesion formation, mitochondrial damage, and inflammation in mice with AKI, whereas EVs from TFAM-KD or aged MSCs resulted in poor therapeutic outcomes. Moreover, TFAM overexpression (TFAM-OE) improved the rescue effect of MSC-EVs on mitochondrial damage and inflammation to some extent. This study suggests that MSC-EVs are promising nanotherapeutics for diseases characterized by mitochondrial damage, and TFAM signaling is essential for maintaining their regenerative capacity.
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http://dx.doi.org/10.1021/acsnano.0c08947DOI Listing
January 2021

Silencing LINC00482 inhibits tumor-associated inflammation and angiogenesis through down-regulation of MMP-15 FOXA1 in bladder cancer.

Aging (Albany NY) 2020 12 11;13(2):2264-2278. Epub 2020 Dec 11.

Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China.

Multiple studies have previously demonstrated that long intergenic non-coding RNAs (lincRNAs) play an important role in the development of bladder cancer. However, little is known regarding the underlying molecular mechanisms of LINC00482 functions in bladder cancer. The current study aimed to elucidate the role of LINC00482 in the progression of bladder cancer. The initial step was to detect the expressions of LINC00482 and MMP15 in bladder cancer cells and tissue. According to the results from the RT-qPCR, LINC00482 and MMP15 were both highly expressed in bladder cancer cells and tissue. The relationship among LINC00482, FOXA1 and MMP15 was studied dual-luciferase reporter assay. LINC00482 was positively correlated with MMP15. LINC00482 promoted MMP15 expression by recruiting FOXA1. Using the gain- and loss-of-function approaches, silencing of LINC00482 resulted in the downregulation of VEGF and NF-κB protein levels, decreased expression of inflammatory factors, and inhibited angiogenesis. Silencing of LINC00482 also suppressed tumor-associated inflammation and angiogenesis , which was found to be reversed by the overexpression of MMP15. The present study demonstrated that LINC00482 induced the expression of MMP15 by interacting with FOXA1, thereby contributing to the inflammation and angiogenesis in bladder cancer.
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http://dx.doi.org/10.18632/aging.202247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880329PMC
December 2020

Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases.

Cell Death Dis 2020 10 28;11(10):924. Epub 2020 Oct 28.

Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

Macrophages (Mφ) are primary innate immune cells that exhibit diverse functions in response to different pathogens or stimuli, and they are extensively involved in the pathology of various diseases. Extracellular vesicles (EVs) are small vesicles released by live cells. As vital messengers, macrophage-derived EVs (Mφ-EVs) can transfer multiple types of bioactive molecules from macrophages to recipient cells, modulating the biological function of recipient cells. In recent years, Mφ-EVs have emerged as vital mediators not only in the pathology of multiple diseases such as inflammatory diseases, fibrosis and cancers, but also as mediators of beneficial effects in immunoregulation, cancer therapy, infectious defense, and tissue repair. Although many investigations have been performed to explore the diverse functions of Mφ-EVs in disease pathology and intervention, few studies have comprehensively summarized their detailed biological roles as currently understood. In this review, we briefly introduced an overview of macrophage and EV biology, and primarily focusing on current findings and future perspectives with respect to the pathological and therapeutic effects of Mφ-EVs in various diseases.
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http://dx.doi.org/10.1038/s41419-020-03127-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595091PMC
October 2020

Clinical Features and Survival of Chinese Children With Trilateral Retinoblastoma During 2006-2019: A Retrospective Multicenter Study.

Am J Ophthalmol 2021 03 10;223:184-192. Epub 2020 Oct 10.

Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China. Electronic address:

Purpose: To summarize the clinical features and survival of Chinese patients with trilateral retinoblastoma (TRb), which may help guide early diagnosis and more effective treatments.

Design: Retrospective case series.

Methods: Clinical records of patients with TRb were reviewed to identify clinical characteristics and outcomes. TRb was diagnosed mainly based on imaging findings of an enlarged solid pineal or sellar mass. Mutation screening was performed using peripheral blood leucocyte DNA from 3 patients.

Results: Fourteen patients with TRb were identified from among 3,789 patients with retinoblastoma (0.4%). Thirteen patients had bilateral retinoblastoma and 1 patient had unilateral disease. The follow-up results revealed that 2 patients survived, 3 patients were lost to follow-up, and 9 patients died. The mean overall survival was 9.8 months (95% confidence interval: 2.3-17.2), and the 2-year survival rate was 18.8% (95% confidence interval: 2.9-45.1) based on Kaplan-Meier estimates. Cox regression multivariate analysis showed metastasis at TRb diagnosis was an independent variable of overall survival (hazard ratio: 15.8; 95% confidence interval: 0.24-5.29; P = .032). Three germline mutations in the RB1 gene were detected via next-generation sequencing.

Conclusions: TRb is a rare intracranial mid-line neuroblastic disease. Increased awareness of this disease could guide early detection, which has been associated with improved outcomes.
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http://dx.doi.org/10.1016/j.ajo.2020.10.002DOI Listing
March 2021

Prognostic analysis for children with hepatoblastoma with lung metastasis: A single-center analysis of 98 cases.

Asia Pac J Clin Oncol 2020 Sep 13. Epub 2020 Sep 13.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, P.R. China.

Aims: To analyze the factors affecting the prognosis of hepatoblastoma (HB) with lung metastasis in children.

Methods: The HB patients with lung metastases admitted to Beijing Tongren Hospital, Capital Medical University were collected. The clinical data, overall results, and prognostic factors were analyzed. Multivariate analysis was done by the Cox proportional hazards model for patients' prognosis.

Results: Finally, 98 HB patients (64 boys and 34 girls) with lung metastasis met the inclusion criteria, in which 64 patients had lung metastases at diagnosis (median age, 22.3 months) and 34 patients developed lung metastases while on treatment (median time, 6.5 months). The survival time and 5-year survival rate of patients with standard treatment were significantly longer than that of without standard treatment (P < .001). The survival time and 3-year survival rate had no difference between patients underwent lung metastasectomy and without lung metastasectomy (P = .099), between different diagnosis time of lung metastasis in HB patients (P = .37), between each histology type (P = .313), and different PRETEXT stage (P = .353). While the survival time and 3-year survival rate of patients with lung metastasis alone were significantly longer than that of patients with extrapulmonary involvement (P = .007). Multivariate Cox proportional hazards model revealed that the lung metastasis accompanied with extrapulmonary involvement was a risk factor affecting prognosis (HR = 0.460, 95% CI 0.239-0.888).

Conclusions: For HB children with lung metastatic, extrapulmonary involvement might be a high-risk factor of prognosis and standardized treatment with lung metastasectomy might prolong the survival time of them.
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http://dx.doi.org/10.1111/ajco.13421DOI Listing
September 2020

Considerations in treating patients with advance lung cancer during the epidemic outbreak of novel coronavirus (SARS-CoV-2).

Med Oncol 2020 Aug 3;37(9):78. Epub 2020 Aug 3.

Cancer Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin, China.

The outbreak of pneumonia caused by novel coronavirus (SARS-CoV-2) in Wuhan, China, at the end of 2019 quickly escalated into a global health emergency. Since its outbreak until the 29th of April 2020, the pandemic has affected more than 3 million of people and caused 207,973 deaths globally. SARS-CoV-2 belongs to the β-coronavirus genus of the Coronavirus family, and it shares the same subfamily with severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV), all of which lead to severe pneumonia. For cancer patients, especially those with lung cancers, their immune systems are compromised due to the disease itself as well as the treatment for cancer. The weakened immunity of these patients puts them at a higher risk of not only developing diseases but severe diseases. In this study, through a literature review and data collection, we focus on the selection and consideration of antitumor treatment strategies for advanced lung cancer during the coronavirus disease 2019 (COVID-19) epidemic.
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http://dx.doi.org/10.1007/s12032-020-01401-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396726PMC
August 2020

Successful treatment of a patient with NSCLC carrying uncommon compound EGFR G719X and S768I mutations using osimertinib: A case report.

J Int Med Res 2020 Jun;48(6):300060520928793

Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China.

The discovery of epidermal growth factor receptor () somatic mutations and the availability of tyrosine kinase inhibitors (TKIs) as targeted therapies have altered the therapeutic prospects of advanced non-small-cell lung cancer (NSCLC). G719X and S768I are uncommon mutations, and they often exist as compound mutations. A few reports have described the efficacy of first- and second-generation EGFR-TKIs. However, the efficacy of osimertinib in patients with these uncommon compound mutations is unknown. In this study, we reported the postoperative outcome of a patient with NSCLC and uncommon compound G719X and S768I mutations. After postoperative recurrence, the patient was treated with osimertinib, and an excellent and long-lasting clinical response was achieved. The patient has taken osimertinib for 31.0 months and exhibited a partial response, and her follow-up is ongoing.
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http://dx.doi.org/10.1177/0300060520928793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273558PMC
June 2020

orchestrates intrachromosomal loop structure required for maintaining stem cell pluripotency.

Int J Biol Sci 2020 6;16(11):1861-1875. Epub 2020 Apr 6.

Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

Induced pluripotent stem cells (iPSCs), derived from reprogramming of somatic cells by a cocktail of transcription factors, have the capacity for unlimited self-renewal and the ability to differentiate into all of cell types present in the body. iPSCs may have therapeutic potential in regenerative medicine, replacing injured tissues or even whole organs. In this study, we examine epigenetic factors embedded in the specific 3-dimensional intrachromosomal architecture required for the activation of endogenous pluripotency genes. Using chromatin RNA reverse transcription sequencing (CRIST-seq), we identified an - binding long noncoding RNA, referred as to , that is present in association with pluripotency status. was highly expressed in iPSCs and E14 embryonic stem cells, but it was silenced in fibroblasts. By using shRNA to knock down , we found that this lncRNA was required for the maintenance of pluripotency. Overexpression of activated endogenous stem cell core factor genes. Mechanistically, participated in the formation of an intrachromosomal looping structure that is required to activate stem cell core factors during reprogramming. In summary, we have demonstrated that lncRNA is a chromatin architecture modulator of pluripotency-associated master gene promoters, highlighting its critical epigenetic role in reprogramming.
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http://dx.doi.org/10.7150/ijbs.45112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211171PMC
April 2020

Impact of Systemic Chemotherapy and Delayed Enucleation on Survival of Children with Advanced Intraocular Retinoblastoma.

Ophthalmol Retina 2020 06 4;4(6):630-639. Epub 2020 Mar 4.

Department of Ophthalmology, Hospital for Sick Children, Toronto, Canada; Krembil Research Institute, Toronto, Canada; Techna Institute, Toronto, Canada. Electronic address:

Purpose: Primary enucleation is a well-established method to achieve cure for advanced intraocular retinoblastoma. Recent treatment advances have induced a trend toward trial eye salvage using chemotherapy or other modalities. We investigated how pre-enucleation/postenucleation systemic chemotherapy and the resulting delayed enucleation affect patient survival after failed trial eye salvage.

Design: Multicenter, retrospective cohort study.

Participants: Children with Group D and E retinoblastoma primarily or secondarily enucleated at 29 Chinese treatment centers.

Methods: Data reviewed included clinical staging, time from diagnosis to enucleation, numbers of cycles of carboplatin, etoposide/teniposide and vincristine chemotherapy, disease-specific survival (DSS), histopathology, and follow-up.

Main Outcome Measures: Primary outcome was DSS. Secondary outcome was histopathology of enucleated eyes.

Results: Primarily enucleated eyes had significantly shorter delay from diagnosis to enucleation than eyes treated with pre-enucleation chemotherapy (P < 0.001). Delay between diagnosis and enucleation >3.5 months (Group D) and >2 months (Group E) decreased survival (Group D: P = 0.018; Group E: P = 0.017). Compared with primarily enucleated children, children with 1 to 3 cycles of pre-enucleation chemotherapy for Group E eyes had no significant difference in survival (P = 0.74), but those who received ≥4 cycles had worse survival (P = 0.025). After pre-enucleation chemotherapy, more children with Group E (but not Group D) eyes had high-risk histopathology (pT3/pT4) (Group D: P = 0.076; Group E: P < 0.001) and worse survival than those primarily enucleated (P < 0.001). Postenucleation chemotherapy improved survival of children with high-risk histopathology (pT3/pT4) (P = 0.001) but did not change survival of children with low-risk histopathology (pT1/pT2) (P = 0.52).

Conclusions: We observed that pre-enucleation chemotherapy offered no survival benefit and timely enucleation minimized risk of metastatic death. Postenucleation chemotherapy improved survival of children with high-risk histopathology but was not useful for those with low-risk histopathology. These findings facilitate informed discussion on the risks and benefits of delayed enucleation, the use of systemic chemotherapy for trial salvage of eyes with advanced intraocular retinoblastoma, and the specific children who benefit from postenucleation chemotherapy.
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http://dx.doi.org/10.1016/j.oret.2020.02.015DOI Listing
June 2020

LncRNA Functions as a New Emerging Epigenetic Factor in Determining the Fate of Stem Cells.

Front Genet 2020 31;11:277. Epub 2020 Mar 31.

Cancer Center, The First Hospital of Jilin University, Changchun, China.

Pluripotent stem cells have broad applications in regenerative medicine and offer ideal models for understanding the biological process of embryonic development and specific diseases. Studies suggest that the self-renewal and multi-lineage differentiation of stem cells are regulated by a complex network consisting of transcription factors, chromatin regulators, signaling factors, and non-coding RNAs. It is of great interest to identify RNA regulatory factors that determine the fate of stem cells. Long non-coding RNA (lncRNA), a class of non-coding RNAs with more than 200 bp in length, has been shown to act as essential epigenetic regulators of stem cell pluripotency and specific lineage commitment. In this review, we focus on recent research progress related to the function and epigenetic mechanisms of lncRNA in determining the fate of stem cells, particularly pluripotency maintenance and lineage-specific differentiation. We discuss the role of the and promoter-interacting lncRNA as identified by Chromatin RNA reverse Transcription sequencing (CRIST-seq). Further understanding of their potential actions will provide a basis for the development of regenerative medicine for clinical application. This work offers comprehensive details and better understanding of the role of lncRNA in determining the fate of stem cells and paves the way for clinical stem cell applications.
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http://dx.doi.org/10.3389/fgene.2020.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137347PMC
March 2020

Aggravation of depigmentation for a non-small-cell lung cancer patient with pre-existing vitiligo using anti-programmed cell death-1 therapy: case report.

Immunotherapy 2020 02 17;12(3):175-181. Epub 2020 Feb 17.

Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

Immune checkpoint inhibitors can enhance the antitumor activity of the immune system by mainly promoting CD8 T lymphocyte immune function. However, they can also induce immune-related adverse events, especially skin toxicity. Some studies found that patients with autoimmune or inflammatory disease are susceptible to immune checkpoint inhibitors and were associated with a significantly increased risk of immune-related adverse events. In our present report, we described a newly diagnosed non-small-cell lung cancer patient who suffered from focal vitiligo for approximately ten years and was treated with the anti-programmed cell death-1 receptor antibody camrelizumab (SHR-1210), which accelerated the aggravation of depigmentation of the skin over the whole body in just half a year.
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http://dx.doi.org/10.2217/imt-2019-0090DOI Listing
February 2020

Cross-reactive antibody-dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission.

Clin Transl Immunology 2019 20;8(11):e1092. Epub 2019 Nov 20.

Li Ka Shing Faculty of Medicine School of Public Health WHO Collaborating Centre for Infectious Disease Epidemiology and Control The University of Hong Kong Hong Kong.

Objectives: Influenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre-existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune-mediated protection from influenza infection.

Methods: We examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody-dependent cytotoxic (ADCC) antibodies and T-cell responses in functional assays. Antibodies were assessed in a cell-based NK cell degranulation assay by flow cytometry, and T-cell responses were assessed by IFN-γ intracellular cytokine staining flow cytometry assay.

Results: The magnitude of antibody responses and ADCC function for multiple influenza-specific proteins was lower in participants who became infected, consolidating the role of pre-existing antibodies in protection from seasonal influenza virus infection. Among H1N1-infected contacts, we found that higher levels of pre-existing H1-haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin-, neuraminidase- and nucleoprotein-specific ADCC antibodies. Limited T-cell samples precluded conclusions on the role of pre-existing T-cell responses.

Conclusions: Overall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation.Influenza-specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.
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http://dx.doi.org/10.1002/cti2.1092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864499PMC
November 2019

M-phase phosphoprotein 8 promotes gastric cancer growth and metastasis via p53/Bcl-2 and EMT-related signaling pathways.

J Cell Biochem 2020 03 6;121(3):2330-2342. Epub 2019 Nov 6.

Department of Cancer Center, First Hospital of Jilin University, Changchun, China.

Background: The main issue of this study is to demonstrate whether M-phase phosphoprotein 8 (MPP8) affect gastric tumor growth and metastasis.

Methods: Retrospective study was proceeded in 280 patients' surgical specimens with different disease stages. Loss-of-function assays, including 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, flow cytometry, and transwell assays were performed to evaluate the biological function of MPP8 in gastric cancer cells. Apoptosis and metastasis relative biomarkers were measured by quantitative real-time polymerase chain reaction and Western blot analysis.

Results: Compared with normal adjacent tissues, obviously elevated MPP8 expression was found in gastric cancer tissues. Elevated MPP8 expression was associated with male sex (vs female sex), intermediate differentiation (vs poorly differentiated cancer), and later stage (vs earlier stage). Furthermore, MPP8 overexpression in tumor tissues was marginally associated with a poor prognosis, with a significant relationship between MPP8 overexpression and prognosis among patients with poorly differentiated gastric cancer. Inhibition of MPP8 in these cells significantly suppressed proliferation and colony formation, promoted apoptosis, and repressed invasion. Furthermore, silencing of MPP8 remarkably increased apoptosis-related proteins (p53, Bax, and PARP) expression, but downregulated Bcl-2 expression. Silencing of MPP8 also decreased the expression of metastasis pathway-related proteins (N-cadherin and vimentin), and as well as the levels of anti-oncogene ZEB1, MET, and KRAS mRNA.

Conclusion: Our findings demonstrated that MPP8 might be an oncogene by positively regulating gastric cancer cell function through the p53/Bcl-2 and epithelial to mesenchymal transition-related signaling pathways.
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http://dx.doi.org/10.1002/jcb.29456DOI Listing
March 2020

Evidence of long-lasting anti-CD19 activity of engrafted CD19 chimeric antigen receptor-modified T cells in a phase I study targeting pediatrics with acute lymphoblastic leukemia.

Hematol Oncol 2019 Dec 15;37(5):601-608. Epub 2019 Sep 15.

CAR-T Research Center, Hebei Senlang Biotechnology Co., Ltd., Shijiazhuang, China.

Ninety percent of relapse/refractory B-cell acute lymphatic leukemia (R/R B-ALL) patients can achieve complete remission (CR) after CD19-targeting chimeric antigen receptor T (CAR-T) cell therapy. However, around 50% of them relapse in 1 year. Persistent CAR-T cell engraftment is considered as the key to remain durable remission. Here, we initiated a phase I study to treat 10 pediatric B-ALL patients using a CD19-targeted second generation CAR with a 4-1BB intracellular costimulatory domain. All patients received a standard fludarabine and cyclophosphamide (FC) preconditioning regiment, followed by a CAR-T infusion with a median number of 0.5 (0.3-1.58) × 10 CAR+ T cells/kg. The pretreatment tumor burdens were high with a median bone marrow (BM) blasts percentage of 59.2% (7.31%-86.2%), excluding one patient only with brain infiltration of leukemia cells (0% BM blasts). The initial CR rate was 80% (n = 8/10). Four patients (40%) experienced serious (grade > 2) cytokine release syndrome (CRS) and three patients (30%) with obvious neurotoxicity. Monthly assessments of CD19+ minimal residual disease (MRD) and CAR-T engraftment demonstrated the anti-CD19 activity of long-term engrafted CAR-T cell clones in one patient for more than 2 years.
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http://dx.doi.org/10.1002/hon.2672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973049PMC
December 2019

Clinical characteristics, treatment and prognosis of paediatric patients with metastatic neuroblastoma to the brain.

Clin Neurol Neurosurg 2019 Sep 23;184:105372. Epub 2019 May 23.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, West South road 2, Yizhuang Economic and Technological Development Zone, Beijing, 100176, PR China.

Objective: Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Metastatic involvement of brain is rare in NB. This study was established to evaluate the clinical characteristics, treatment and prognosis of NB patients with brain metastases.

Patients And Methods: From September 2005 to December 2016, the clinical data of 15 cases with brain metastases among 264 NB patients admitted to Beijing Tongren Hospital, Capital Medical University were collected and retrospectively analysed. The clinical features of the 15 patients were summarised, and the patients were grouped according to different treatment methods and followed up for a median time of 41 months. The survival curves were plotted, and the Log-rank test was performed to compare the effect of different treatment methods on the prognosis.

Results: The proportion of brain metastases in NB patients in our hospital is 5.68% (15/264). For the prognosis of 15 NB cases, the survival time of combined radiotherapy and/or autologous peripheral blood stem cell transplantation group was longer than that of simple operation and chemotherapy group (61.79 ± 9.59 vs. 30.00 ± 5.99 months, P = 0.03). Among the 15 patients, 4 cases underwent intracranial tumor resection, 4 cases received craniospinal irradiation, and the rest received maintenance chemotherapy. The 2-year survival rate was 82.2%, and the 5-year survival rate was 19.9%. The survival time of combined intracranial surgery and/or radiotherapy group was significantly longer than that of the chemotherapy group (46.67 ± 6.69 vs. 16.42 ± 1.42 months, P = 0.003).

Conclusions: The incidence of brain metastases NB in children is relatively small, but the prognosis is very poor. Active chemotherapy, radiotherapy and surgery-based comprehensive treatment can prolong the survival time.
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http://dx.doi.org/10.1016/j.clineuro.2019.105372DOI Listing
September 2019

Reply.

Ophthalmology 2018 07;125(7):e50-e51

Departments of Ophthalmology & Vision Science, Hospital for Sick Children and University of Toronto, Toronto, Canada; Techna Institute, University Health Network, Toronto, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2018.02.033DOI Listing
July 2018

Efficacy and safety of sorafenib versus apatinib in the treatment of intermediate and advanced hepatocellular carcinoma: a comparative retrospective study.

Onco Targets Ther 2018 12;11:3407-3413. Epub 2018 Jun 12.

Department of Interventional Oncology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong, People's Republic of China.

Objective: To compare the efficacy and safety profiles of sorafenib and apatinib in patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC).

Methods: This was a single-center, retrospective study where we collected the clinical data of 72 patients, diagnosed with intermediate or advanced HCC from January 2014 to December 2016. Depending on the treatment received, 38 patients were categorized into group S (sorafenib group) and 34 into group A (apatinib group). The patients in group A received the initial recommended dose of 750 mg once daily (QD), which was reduced to 250 mg QD in the case of any class 3 or 4 adverse event (AE). Sorafenib was administered orally 400 mg twice daily (BID), and dose was modified to 400 mg or 200 mg QD in the case of grade 3 or 4 AEs. The median overall survival (OS), progression-free survival (PFS), and AEs reported in the two groups were analyzed and compared.

Results: Among the 38 patients treated with sorafenib, one patient had complete response (CR), 5 patients had partial response (PR), and 10 patients had stable disease (SD), and among the 34 patients treated with apatinib, 6 patients had PR and 7 patients had SD with no cases of CR. PFS in group S was significantly longer compared with that in group A (7.39 vs 4.79 months, respectively, =0.031). Similar observations were made for median OS (10.4 months in group S vs 7.18 months in group A, =0.011). However, there was no significant difference in the objective response rates (ORRs) among the study population (15.7 vs 17.6%, =0.829). Common AEs in group S included hand and foot syndrome (HFS) and diarrhea, whereas common AEs in group A included hypertension, proteinuria, and increased transaminase.

Conclusion: Our study showed promising clinical outcome with apatinib, but the sorafenib group exhibited better clinical efficacy with no significant difference in safety profile.
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http://dx.doi.org/10.2147/OTT.S161023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003281PMC
June 2018

Characterization, treatment and prognosis of retinoblastoma with central nervous system metastasis.

BMC Ophthalmol 2018 Apr 23;18(1):107. Epub 2018 Apr 23.

Department of Pediatrics, Beijing Tongren Hospital, West South road 2, Yizhuang Economic and Technological Development Zone, Daxing District, Beijing, 100176, China.

Background: Retinoblastoma is the most common primary intraocular tumor and more and more attention has been paid to the developing countries. This study was aimed to evaluate the clinical features, treatment, and prognosis of retinoblastoma patients with central nervous system (CNS) metastasis in Beijing Tongren Hospital, one of the largest tertiary eye centers in China.

Methods: Clinical data of 31 consecutive retinoblastoma patients with CNS metastases, who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between September 2005 and December 2015, were retrospective analyzed.

Results: The median age at presentation was 29 months (range from 5 to 108 months). Magnetic resonance imaging (MRI) results indicated that 16 patients (56.6%, 16/31) presented with meningeal involvement, 12 (38.7%, 12/31) presented with intracranial mass, 11 (35.5%, 11/31) presented with thickened optic nerve, and 5 (16.1%, 5/31) presented with concurrent meningeal and spinal cord membrane involvement. Retinoblastoma cells were detected in the cerebrospinal fluid (CSF) of 12 patients (44.4%, 12/27). Laboratory examinations on the blood and CSF were performed for 11 patients who had received six cycles of systemic chemotherapy, indicated that the serum level of neurone-specific enolase (NSE) after chemotherapy was significantly lower than that before chemotherapy (P < 0.05). At the end of the follow-up, 25 patients were dead with a median survival time of 6 months (1 d - 21 months), and 6 cases were alive and continued to receive treatment.

Conclusion: Our results were basically consistent with previous reports in the developing countries, and it could be guidance for clinical treatment, prognosis and prevention of CNS metastases in retinoblastoma.
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http://dx.doi.org/10.1186/s12886-018-0772-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914066PMC
April 2018

Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma.

Ophthalmology 2018 02 16;125(2):320-322. Epub 2017 Nov 16.

Departments of Ophthalmology & Vision Science, Hospital for Sick Children and University of Toronto, Toronto, Canada; Techna Institute, University Health Network, Toronto, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2017.10.015DOI Listing
February 2018

Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma.

Cytotherapy 2018 01 19;20(1):134-148. Epub 2017 Oct 19.

Cancer Center, The First Hospital of Jilin University, Changchun, China. Electronic address:

Background: Despite the availability of multiple treatment strategies, patients with advanced colon carcinoma (CC) have poor prognoses. The aim of this study was to evaluate the efficacy and safety of natural killer (NK) cell therapy in combination with chemotherapy in patients with locally advanced CC.

Methods: We assessed the cytotoxicity of NK cells to CC cells (CCs) and CC stem cells (CSCs) pre-treated with 5-fluorouracil or oxaliplatin in vitro. Then, an open-label cohort study was conducted with locally advanced CC patients who had received radical resection. Patients received either NK cell therapy combined with chemotherapy (NK cell group, 27 patients) or pure chemotherapy (control group, 33 patients). Progression-free survival (PFS), overall survival (OS) and adverse effects were investigated.

Results: Chemotherapy sensitized CCs and CSCs to NK cell cytotoxicity through regulation of NK cell-activating/inhibitory receptor ligands. Poorly differentiated CCs were more susceptible to NK cells than well-differentiated ones. In the cohort study, the 5-year PFS and OS rates in the NK cell group were significantly higher than those in the control group (51.1% versus 35%, P= 0.044; 72.5% versus 51.6%, P= 0.037, respectively). Among patients with poorly differentiated carcinomas and low expression of human leukocyte antigen (HLA)-1, the median PFS in the NK cell group versus the control group was 23.5 versus 12.1 months (P= 0.0475) and 33.1 versus 18.5 months (P= 0.045), respectively. No significant adverse reactions were reported.

Conclusion: NK cell therapy in combination with chemotherapy in locally advanced CC prevented recurrence and prolonged survival with acceptable adverse effects, especially for poorly differentiated carcinomas.
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http://dx.doi.org/10.1016/j.jcyt.2017.09.009DOI Listing
January 2018

G protein subunit α q regulates gastric cancer growth via the p53/p21 and MEK/ERK pathways.

Oncol Rep 2017 Apr 13;37(4):1998-2006. Epub 2017 Mar 13.

Cancer Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.

Genetic alterations in G protein subunit α q (GNAQ) have been reported in numerous types of human cancer. However, the role of GNAQ in human gastric cancer (GC) has not been explored. In the present study, we found that GNAQ was highly expressed in GC patient samples and GNAQ expression was related to patient age, GC differentiation status and adjuvant therapy, as determined by immunohistochemical assay. Lentivirus delivery of short hairpin RNA (shRNA) targeting GNAQ was used to explore the function of GNAQ in GC cells. Silencing of GNAQ markedly suppressed proliferation and colony formation in GC cells, and arrested the cell cycle at the S phase. Mechanistic analysis revealed that knockdown of GNAQ significantly increased the expression of p53 and p21, and decreased cyclin A and p-CDK2 protein expression. Moreover, the phosphorylation of ERK and MEK was also decreased after knockdown of GNAQ as determined by western blotting assay. Overall, our results suggest that GNAQ plays a critical role in regulating GC cell growth and survival via canonical oncogenic signaling pathways including MAPK and p53, and therefore serves as a promising new therapeutic target in GC.
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http://dx.doi.org/10.3892/or.2017.5500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367349PMC
April 2017

Evaluation of Circulating Tumor Cells in Predicting Therapeutic Response in Small Cell Lung Cancer Patients.

Arch Med Res 2016 Aug;47(6):454-459

Cancer and Stem Cell Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, PR China. Electronic address:

Background And Aims: Circulating tumor cells (CTCs) have prognostic significance in patients with metastatic cancer, but their utility in predicting the response to tumor therapy is unknown. This study examined the correlation of CTCs with the therapeutic response in small cell lung cancer (SCLC).

Methods: Clinical and pathological data from 96 SCLC patients were evaluated in this study. CellSearch kits were used to detect CTCs in peripheral blood samples. Statistical analysis was performed using Fisher exact test and Mann-Whitney U test.

Results: At baseline, 47 (50.0%) SCLC patients had detectable CTC counts. Serum neuron-specific enolase (NSE) was found to be associated with CTC thresholds. However, no significant differences were observed for an association of any threshold CTC count with the treatment response, with gender, age (≤60 or >60 years), smoking status, syndrome of inappropriate antidiuretic hormone (SIADH), or Ki67 expression.

Conclusion: Detection of CTCs in SCLC patients was associated with serum NSE but not with response to cancer therapy.
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http://dx.doi.org/10.1016/j.arcmed.2016.10.003DOI Listing
August 2016

Adjuvant treatment combining cellular immunotherapy with chemotherapy improves the clinical outcome of patients with stage II/III gastric cancer.

Cancer Med 2017 01 27;6(1):45-53. Epub 2016 Oct 27.

Cancer Center, the First Hospital of Jilin University, Changchun, China.

Postsurgical relapse remains a common issue for resectable gastric cancer (GC). Here, we investigated the efficacy and safety of an adjuvant treatment combining chemotherapy with cellular immunotherapy (CIT) using autologous natural killer cells, γδT cells, and cytokine-induced killer cells in the treatment of stage II/III GC. A pilot prospective cohort study was conducted in 169 patients with stage II/III GC who had undergone gastrectomy with D2 lymph node dissection. Patients were assigned into two groups according to the patient choice of treatment, including chemotherapy alone (chemo) or chemotherapy combined with CIT (chemo/CIT). Disease-free survival (DFS), overall survival (OS), and adverse events were evaluated. Univariate and multivariate Cox models were used to analyze the impact of chemo/CIT on DFS and OS. Kaplan-Meier analysis with the log-rank test was used to compare the clinical outcome between two groups. Three-year DFS rate was 60.6% and 74.7% (P = 0.036) and 3-year OS rate was 64.9% and 83% (P = 0.051) for the chemo and chemo/CIT group, respectively. TNM stage and chemo/CIT were independent prognostic factors for both DFS (for TNM stage, P < 0.001, hazard ratio [HR]: 5.599, 95% confidence interval [CI]: 2.791-11.232; for chemo/CIT, P = 0.013, HR: 0.478, 95% CI: 0.266-0.858) and OS (for TNM stage, P < 0.001, HR: 6.559, 95% CI: 2.903-14.817; for chemo/CIT, P = 0.04, HR: 0.506, 95% CI: 0.264-0.970). In subgroup analysis, 3-year DFS and OS rates of patients with stage III GC in the chemo/CIT group were significantly higher than those in the chemo group (38.4% vs. 57.1%, P = 0.038; and 45.9% vs. 76%, P = 0.06, respectively), while there was no significant difference between the two groups in patients with stage II GC. Only 15.9% of patients (10/63) in the chemo/CIT group had mild and manageable fever (grades 1 and 2), while no other side effects were observed. The adjuvant treatment combining chemotherapy with cellular immunotherapy is well tolerated and significantly improves the clinical outcome of patients with stage II/III GC, when compared with chemotherapy alone, therefore warrants further attention in treatment for relapsed GC after tumor resection.
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http://dx.doi.org/10.1002/cam4.942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269688PMC
January 2017

Anomalous Temperature-Dependent Upconversion Luminescence of α-NaYF₄:Yb³⁺/Er³⁺ Nanocrystals Synthesized by a Microwave-Assisted Hydrothermal Method.

J Nanosci Nanotechnol 2016 Jan;16(1):816-21

Yb³⁺/Er³⁺co-doped cubic-(α-) phase NaYF₄ nanocrystals were prepared through a microwave- assisted hydrothermal method. Temperature-dependent upconversion luminescence (UCL) and sensing properties were systematically studied. It is interesting that anomalous temperature- dependent UCL behavior is observed. With increasing temperature (303-573 K), the UCL intensity of Er³⁺ does not quench monotonously but reaches a minimum around 483 K and then increases. However, it was found that the UCL spectra change in a different way with decreasing temperature (573-303 K) from the one measured with increasing temperature. The fluorescence intensity ratio of ²H₁₁/₂ --> ⁴I₁₅/₂ to ⁴S₃/₂ --> ⁴I₁₅/₂ at any measured temperature point remains almost constant in all measurement processes, indicating the consistency of temperature in each spectrum measurement at all temperature points regardless of the heating or the cooling process in our experiments. The results demonstrate that NaYF₄:Yb³⁺/Er³⁺ UC nanocrystal has good sensing stability and may have potential application in the nanoscale thermal sensor.
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http://dx.doi.org/10.1166/jnn.2016.10889DOI Listing
January 2016

In Vitro Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71.

Antimicrob Agents Chemother 2016 09 22;60(9):5357-67. Epub 2016 Aug 22.

Pathogen Diagnostic Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

Enterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections.
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http://dx.doi.org/10.1128/AAC.01073-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997834PMC
September 2016