•Anecdotal case reports have suggested association between G-CSF and aortitis.•Relationship between G-CSF and aortitis had remained unclear.•Japanese pharmacovigilance database JADER harbors 102,014 ...subjects with malignancies.•The adjusted odds ratio for aortitis in the malignancy cases with G-CSF was 45.87 19.16, 109.8.•The difference was statistically significant. This supports the link between G-CSF and aortitis.
Granulocyte colony-stimulating factor (G-CSF) is the standard-of-care therapy for chemotherapy-associated neutropenia in patients with malignancies. Recent case reports have implied that G-CSF treatment may be associated with the development of aortitis, but the precise nature of the relationship is unclear. We investigated the association between G-CSF and risk for aortitis in patients with various malignancies.
We performed an observational study of 102,014 subjects with malignant neoplasms documented in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and February 2018. The adjusted odds ratio (OR) and 95% confidence interval (CI) for aortitis in patients treated and not treated with G-CSF were estimated using multivariate logistic regression with R software.
Among the 102,014 subjects, 25 developed aortitis. Of the 3409 and 98,630 subjects treated and not treated with G-CSF, 16 (0.47% 95% CI; 0.27, 0.76) and 9 (0.01% 0.00, 0.02) developed aortitis, respectively. Multivariate logistic regression indicated an association between G-CSF and aortitis (adjusted OR 45.87 19.16, 109.8, p < 0.001). The values for filgrastim, pegfilgrastim, and lenograstim were 0.25% (0.07, 0.63), 1.58% (0.79, 2.81), and 0.24% (0.05, 0.69), respectively.
G-CSF treatment was associated with a signal of increased risk for aortitis among patients with malignant neoplasms. Three different G-CSF agents were associated with such risk, implying that it is a class effect. However, we do not recommend changing G-CSF prescriptions, because our results may have been influenced by the limitations of the JADER database and because the benefit of G-CSF treatment outweighs the potential risk.
Transfusion of red blood cells (RBCs) is a standard and indispensable therapy in current clinical practice. In vitro production of RBCs offers a potential means to overcome a shortage of transfusable ...RBCs in some clinical situations and also to provide a source of cells free from possible infection or contamination by microorganisms. Thus, in vitro production of RBCs may become a standard procedure in the future. We previously reported the successful establishment of immortalized mouse erythroid progenitor cell lines that were able to produce mature RBCs very efficiently. Here, we have developed a reliable protocol for establishing immortalized human erythroid progenitor cell lines that are able to produce enucleated RBCs. These immortalized cell lines produce functional hemoglobin and express erythroid-specific markers, and these markers are upregulated following induction of differentiation in vitro. Most importantly, these immortalized cell lines all produce enucleated RBCs after induction of differentiation in vitro, although the efficiency of producing enucleated RBCs remains to be improved further. To the best of our knowledge, this is the first demonstration of the feasibility of using immortalized human erythroid progenitor cell lines as an ex vivo source for production of enucleated RBCs.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Innovative treatment is required to improve overall survival rates for advanced NSCLC. Oncolytic ...virotherapy using enteroviruses has emerged as a promising anticancer strategy. To identify a novel, potent virotherapy with an improved safety profile, we assessed the oncolytic activity of 28 enteroviral strains and focused on coxsackievirus A11 (CVA11). CVA11 infection caused extensive oncolytic activity in all three of the examined human NSCLC cell lines, with high intercellular adhesion molecule-1 (ICAM-1) expression associated with greater CVA11-induced cytotoxicity. In vitro inhibition analysis using a pan-caspase inhibitor and western blot detection of cleaved poly (ADP-ribose) polymerase (PARP) indicated that apoptosis partly contributed to CVA11-driven cytotoxicity. CVA11 infection-induced immunogenic cell death in vitro was strongly suggested by substantial calreticulin expression and release of high mobility group box-1 protein (HMGB1). Moreover, in vivo treatment of human NSCLC xenografts with intratumoral CVA11 injection caused complete tumor regression in all treated mice, without significant weight loss. Our findings indicate that novel oncolytic virotherapy utilizing CVA11 may be less toxic and more effective than current treatments for human NSCLC, thus warranting further investigation in clinical trial settings, especially in combination with immunotherapy.
Breast cancer is the most common cancer in women worldwide, and triple-negative breast cancer (TNBC) is highly refractory to current standard therapies. Oncolytic virotherapy has recently gathered ...attention as a new treatment candidate for refractory cancers.
We previously developed a new Coxsackievirus B3 (CVB3) virotherapy targeting lung cancers, and demonstrated that miRNA target sequence insertion into CVB3 reduced its pathogenicity, retaining its original oncolytic activity. In this study, we examined the oncolytic effects of CVB3 against breast cancer cells including TNBC cells.
CVB3 infection killed breast cancer cells in a time- and titer-dependent manner, and induced apoptosis. Nude mice transplanted with human TNBC cells were successfully treated with both CVB3-WT and CVB3-HP. Importantly, mice treated with CVB3-HP showed very few adverse events.
CVB3-HP is a strong oncolytic virus candidate for breast cancer, including TNBC, due to its remarkable oncolytic efficacy and improved safety profile.
Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use molecular pathways as the therapeutic ...targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chemically induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and experimentally validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.
Background
Exon‐skipping is a powerful genetic tool, especially when delivering genes using an AAV‐mediated full‐length gene supplementation strategy is difficult owing to large length of genes. ...Here, we used engineered human induced pluripotent stem cells and artificial intelligence to evaluate clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9‐based exon‐skipping vectors targeting genes of the retinal pigment epithelium (RPE). The model system was choroideremia; this is an X‐linked inherited retinal disease caused by mutation of the CHM gene.
Methods
We explored whether artificial intelligence detected differentiation of human OTX2, PAX6 and MITF (hOPM) cells, in which OTX2, PAX6 and MITF expression was induced by doxycycline treatment, into RPE. Plasmid encoding CHM exon‐skipping modules targeting the splice donor sites of exons 6 were constructed. A clonal hOPM cell line with a frameshift mutation in exon 6 was generated and differentiated into RPE. CHM exon 6‐skipping was induced, and the effects of skipping on phagocytic activity, cell death and prenylation of Rab small GTPase (RAB) were evaluated using flow cytometry, an in vitro prenylation assay and western blotting.
Results
Artificial intelligence‐based evaluation of RPE differentiation was successful. Retinal pigment epithelium cells with a frameshift mutation in exon 6 showed increased cell death, reduced phagocytic activity and increased cytosolic unprenylated RABs only when oxidative stress was in play. The latter two phenotypes were partially rescued by exon 6‐skipping of CHM.
Conclusions
CHM exon 6‐skipping contributed to RPE phagocytosis probably by increasing RAB38 prenylation under oxidative stress.
RPE cells derived from hiPSCs with a frameshift mutation in exon 6 of CHM showed reduced phagocytic activity under oxidative stress. The phenotype was partially rescued by exon 6‐skipping induced by the CRISPR/Cas9 system.
As the prognosis of biliary tract cancer (BTC) is extremely poor and treatment options are limited, new treatment modalities are urgently needed. We designed a phase II clinical trial to investigate ...the immune responses and clinical benefits of OCV-C01, an HLA-A*24:02-restricted three-peptide cancer vaccine targeting VEGFR1, VEGFR2, and KIF20A.
Participants were patients with advanced BTC who had unresectable tumours and were refractory to standard chemotherapy. OCV-C01 was injected weekly until the discontinuance criteria were met.
Six participants, including four patients positive for HLA-A*24:02, were enrolled in this study for assessment of efficacy. Four out of six patients exhibited vaccine-specific T-cell responses to one or more of three antigens. Log-rank tests revealed that vaccine-specific T cell responses contributed significantly to overall survival.
The cancer vaccine had positive effects on survival, indicating that this approach warrants further clinical studies.
Photocontrollable mononegaviruses Tahara, Maino; Takishima, Yuto; Miyamoto, Shohei ...
Proceedings of the National Academy of Sciences - PNAS,
06/2019, Letnik:
116, Številka:
24
Journal Article
Recenzirano
Odprti dostop
Mononegaviruses are promising tools as oncolytic vectors and transgene delivery vectors for gene therapy and regenerative medicine. By using the Magnet proteins, which reversibly heterodimerize upon ...blue light illumination, photocontrollable mononegaviruses (measles and rabies viruses) were generated. The Magnet proteins were inserted into the flexible domain of viral polymerase, and viruses showed strong replication and oncolytic activities only when the viral polymerases were activated by blue light illumination.
Nivolumab, an antibody against human programmed cell death 1 (PD-1), enhances pre-existing immune responses and has antitumor activity. However, it may also cause undesirable immune-related adverse ...events (irAEs), such as anti-PD-1-related colitis. In addition, Nivolumab can worsen pre-existing autoimmune diseases. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Its exact cause is unknown, but it may involve the dysregulation of the mucosal immune response. Thus, it is of great interest whether nivolumab can affect UC activity. This is the first report of a patient with epipharyngeal carcinoma and ulcerative colitis who was confirmed to have been safely treated with nivolumab based on autopsy findings.
The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This ...study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.
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