Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: ZMYND10 (cancer-related)
Melikyan AL, Subortseva IN, Gilyazitdinova EA, et al.Cepeginterferon alfa-2b in the treatment of chronic myeloproliferative diseases.
Ter Arkh. 2018; 90(7):23-29 [PubMed
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AIM: A comparative evaluation of the effectiveness of different therapeutic strategies in patients with polycythemia vera (PV) and essential thrombocythemia (ET).
MATERIALS AND METHODS: Patients with PV or ET, diagnosed according to the criteria WHO 2016 were included in the study. The primary endpoint - 6 months of therapy (clinical-hematological and molecular responses). The secondary endpoint - 12 months of therapy (clinico-hematologic, molecular, histological responses). Sixty three patients were included in the analysis: the first group consisted of 33 patients who received the therapy with ce-pegiterferone alpha-2b (ce-pegalpha-INF-α-2b), 10 of them received previous treatment; the second group - 23 patients btained hydroxycarbamide; the third group - 7 patients were treated with recombinant interferon alpha therapy (rINFα). In comparison groups, differences in age were revealed: patients receiving hydroxycarbamide therapy were older. Phlebotomy occurred in 36% of patients in the first group, 9% in the second group, and 14% in the third group.
RESULTS: By the 6th month of therapy, 43% of the patients receiving the ce-pegalpha-INF-α-2b had complete clinical-hematologic response, 36% had partial clinical-hematologic remission and stabilization of the disease was established in 21% cases. No disease progression occured. By the 12th month of therapy, statistically significant differences in terms of efficacy between the different therapeutic groups (p = 0.2462, Fisher's exact test). In all three groups, the allelic load of JAK2V617F decreased: from 50 to 19%, from 22.3 to 15.8%, from 50 to 7.19%, respectively. The lower the allele load positively correlated with better response to therapy, which was observed in all analyzed groups. Hematologic adverse events (AEs) were more frequently observed in patients receiving ce-pegalpha-INF-α-2b therapy. Local reactions developed on 3-7 days of therapy as a hyperemic macula at the injection site. Both these reactions and hair loss did not influence on patient's condition. In the second group (patients with hydroxycarbamide therapy) there were changes in the skin and mucous membranes: dry skin, stomatitis, and in older patients new keratomas appeared. The flu-like syndrome was the most common adverse event associated with the therapy of ce-pegalpha-INF-α-2b, which fully relived during the first month of therapy. There was only one case with the flu-like syndrome we observed at the 11th month of therapy. As a rule, the biochemical blood test changes did not influence on patient's condition, were mostly associated with dietary violations, had a tendency to self-resolution and did not require medical interventions. Serious AEs were reported in one case - pulmonary embolism in a patient treated with rINFα. The reasons for the therapy discontinue in group 1: toxic hepatitis, intolerance, by the request of the patient, inadequate efficacy of therapy; in group 2: skin toxicity, in group 3: thromboses.
CONCLUSION: Treatment of ce-pegalpha-INF-α-2b in patients with PV and ET is highly effective - the most patients pbtained clinical and hematological responses. There were no statistically significant differences in these parameters in comparison with hydroxycarbamide and rINFα. The use of the ce-pegalpha-INF-α-2b had an acceptable safety profile. The estimated therapeutic dose should be calculated according to body weight. To reduce the frequency of hematologic AE, titration of the drug dose is required.
Lee JH, Kim C, Lee J, et al.Arctiin is a pharmacological inhibitor of STAT3 phosphorylation at tyrosine 705 residue and potentiates bortezomib-induced apoptotic and anti-angiogenic effects in human multiple myeloma cells.
Phytomedicine. 2019; 55:282-292 [PubMed
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BACKGROUND: Arctiin is a main component from the fruits of Arctium lappa L., that can be prescribed for cold or flu in East Asian countries; it has also been found to exert chemopreventive actions against various tumor cells.
HYPOTHESIS: In view of this evidence, we examined arctiin for its ability to trigger apoptosis and inhibit the activation of signal transducer and activator of transcription 3 (STAT3) in human multiple myeloma (MM) cells.
METHODS: We evaluated the effect of arctiin on STAT3 signaling cascades and its regulated functional responses in MM cells.
RESULTS: Arctiin effectively blocked the constitutive activation of STAT3 phosphorylation in the residue of tyrosine 705. Arctiin also abrogated the constitutive activation of Src phosphorylation and Janus-activated kinases (JAKs) 1/2. Furthermore, it was found that arctiin treatment clearly enhanced the mRNA and protein levels of protein tyrosine phosphatase ε (PTPε), and the silencing of PTPε caused a reversal of the arctiin-induced PTPε expression and the blockadge of STAT3 phosphorylation. Interestingly, arctiin could not repress IL-6-induced STAT3 activation in serum-starved U266 cells and when arctiin was incubated with a complete culture medium in RPMI 8226 and MM.1S cells. Arctiin suppressed cell proliferation, accumulated cells in the G2/M cell-cycle phase, and induced apoptosis within U266 cells, although the knockdown of PTPε prevented PARP cleavage and caspase-3 activation induced by the arctiin. In addition, arctiin exerted cytotoxicity in MM cells, but did not do so in peripheral blood mononuclear cells. Arctiin down-modulated diverse oncogenic gene products regulated by STAT3, although the induction of apoptosis by arctiin was abrogated upon transfection with pMXs-STAT3C in mouse embryonic fibroblast (MEF) cells. Arctiin also potentiated bortezomib-induced antitumor effects in U266 cells.
CONCLUSION: On the whole, our results indicate that arctiin is a potentially new inhibitor of constitutive STAT3 activation through the induction of PTPε in MM, cells and therefore has great value in treating various tumors sheltering constitutively activated STAT3.
Shtam T, Naryzhny S, Samsonov R, et al.Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling.
Breast Cancer Res Treat. 2019; 174(1):129-141 [PubMed
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PURPOSE: The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter-cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon.
METHODS: Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis.
RESULTS: Plasma exosomes stimulated the adhesive properties, two-dimensional random migration, and transwell invasion of BC cells in vitro as well as their in vivo metastatic dissemination in a dose-dependent manner. This stimulatory effect was mediated by interactions of surface exosome proteins with BC cells and consequent activation of focal adhesion kinase (FAK) signaling in the tumor cells.
CONCLUSIONS: Plasma exosomes have a potency to stimulate the metastasis-promoting properties of BC cells. This pro-metastatic property of normal plasma exosomes may have impact on the course of the disease and on its prognosis.
Kim JY, Son JY, Lee BM, et al.Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms.
Anticancer Res. 2018; 38(9):5149-5157 [PubMed
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BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment.
MATERIALS AND METHODS: Based on the relatively low dose or IC
RESULTS: DON or SID reduced cell viability, increased G
CONCLUSION: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.
Kim JY, Tae IH, Lee BM, et al.Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells.
Anticancer Res. 2018; 38(9):5101-5108 [PubMed
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BACKGROUND/AIM: The present study was designed to identify conditions that would increase the sensitivity of resistant cancer cells to anti-mitotic drugs.
MATERIALS AND METHODS: Previously, we showed that KBV20C cancer cells highly resistant to Halaven® (HAL) were sensitized by co-treatment with fluphenazine (FLU). In this study, we found that low doses of aripiprazole (ARI), another antipsychotic drug, sensitized HAL-resistant KBV20C cancer cells. We then investigated the mechanisms and roles of ARI in the sensitization of HAL-treated KBV20C cancer cells.
RESULTS: First-generation P-glycoprotein (P-gp) inhibitor verapamil required a dose that was nearly four-fold higher than that of ARI for P-gp inhibition, which suggested that ARI had a high specificity for P-gp binding to prevent efflux of anti-mitotic drugs. ARI was also found to sensitize HAL-treated KBV20C cells at a low dose, approximately 4-fold lower than that of verapamil. Co-treatment of ARI with another anti-mitotic drug, vincristine, also increased the sensitization of KBV20C cells. ARI caused a reduction in cell viability, increased G
CONCLUSION: Cancer cells that are highly resistant to HAL can be sensitized with the antipsychotic drug, ARI, which exerts specific P-gp inhibitory effects at a low dose.
Khongnomnan K, Poomipak W, Praianantathavorn K, et al.Human MicroRNAs Expression Profiles in Influenza B Virus-Infected Cells based on Illumina MiSeq Platform.
Microrna. 2018; 7(3):204-214 [PubMed
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BACKGROUND: Influenza B virus causes influenza-like illness in humans. MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression through mRNA degradation or translational repression. MiRNAs have evolved to regulate many cellular processes including the viral infection response.
OBJECTIVE: This study aims to investigate the miRNA profiles of human cells infected with influenza B virus.
METHODS: A549 cells were infected with influenza B viruses (MOI = 0.5). MiRNAs were extracted at 24 and 48 hours post-infection. MiRNAs were used to construct four DNA libraries: influenza Binfected and an uninfected control for both time points. Then high-throughput sequencing was performed using the Miseq platform (Illumina). Sequencing data were analyzed by Miseq reporter software. The miRNAs were categorized and counted based on the frequency of reads. All filtered contigs were aligned with data from miRbase. The relative expression of each miRNA between uninfected and influenza B-infected cells was calculated.
RESULTS: There were 13 down-regulated miRNAs and 21 up-regulated miRNAs observed in influenza B infected cells at 24 hours post infection. At 48 hours post infection, 14 miRNAs were downregulated, whereas 8 miRNAs were up-regulated.
CONCLUSION: This study suggested that miRNAs may play important roles in host gene regulation in response to viral infection.
Lee S, Hirohama M, Noguchi M, et al.Influenza A Virus Infection Triggers Pyroptosis and Apoptosis of Respiratory Epithelial Cells through the Type I Interferon Signaling Pathway in a Mutually Exclusive Manner.
J Virol. 2018; 92(14) [PubMed
] Free Access to Full Article Related Publications
Respiratory epithelial cell death by influenza virus infection is responsible for the induction of inflammatory responses, but the exact cell death mechanism is not understood. Here we showed that influenza virus infection induces apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced only in malignant tumor cells infected with influenza virus. In human precancerous respiratory epithelial cells (PL16T), the number of apoptotic cells increased at early phases of infection, but pyroptotic cells were observed at late phases of infection. These findings suggest that apoptosis is induced at early phases of infection but the cell death pathway is shifted to pyroptosis at late phases of infection. We also found that the type I interferon (IFN)-mediated JAK-STAT signaling pathway promotes the switch from apoptosis to pyroptosis by inhibiting apoptosis possibly through the induced expression of the
Li L, Xu J, Qiu G, et al.Epigenomic characterization of a p53-regulated 3p22.2 tumor suppressor that inhibits STAT3 phosphorylation via protein docking and is frequently methylated in esophageal and other carcinomas.
Theranostics. 2018; 8(1):61-77 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim.
METHODS: The patients were treated with the vaccine at 1 × 10
RESULTS: The vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-α and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients'quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence.
CONCLUSIONS: We provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients' quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.
Rotunno R, Campana LG, Quaglino P, et al.Electrochemotherapy of unresectable cutaneous tumours with reduced dosages of intravenous bleomycin: analysis of 57 patients from the International Network for Sharing Practices of Electrochemotherapy registry.
J Eur Acad Dermatol Venereol. 2018; 32(7):1147-1154 [PubMed
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BACKGROUND: Electrochemotherapy (ECT) is currently used to treat unresectable superficial tumours of different histotypes through the combination of cytotoxic chemotherapy and local application of electric pulses. In 2006, a collaborative project defined the ESOPE (European Standard Operating Procedures of Electrochemotherapy) guidelines to standardize the procedure. The International Network for Sharing Practices of Electrochemotherapy (InspECT) aims to refine the ESOPE and improve clinical practice. Limiting patient exposure to systemic chemotherapy would be advisable to ameliorate ECT safety profile.
OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicity of ECT with reduced chemotherapy dosages.
METHODS: In a retrospective analysis of a prospectively maintained database (InspECT registry), we evaluated the outcome of patients who received ECT with reduced dosages of bleomycin (7500, 10 000 or 13 500 IU/m
RESULTS: We identified 57 patients with 147 tumours (melanoma, 38.6%; squamous cell carcinoma, 22.8%; basal cell carcinoma, 17.5%; breast cancer 7%; Kaposi sarcoma 7%; other histotypes, 7.1%). Per-tumour complete response (CR) rate at 60 days was 70.1% (partial, 16.3%); per-patient CR was 57.9% (partial, 21.1%). Local pain was the most frequently reported side-effect (n = 22 patients [39%]), mostly mild; two patients experienced flu-like symptoms, one patient nausea. We observed the same CR rate (55%) in patients with melanoma treated by reduced or conventional bleomycin dosages (P = 1.00).
CONCLUSIONS: Electrochemotherapy performed with reduced bleomycin dosages could be as effective as with currently recommended dose. Patients with impaired renal function or candidate to multiple ECT cycles could benefit from a reduced dose protocol. Our findings need prospective confirmation before being adopted in clinical practice.
Natural Killer (NK) cells employ activating receptors like the Natural Cytotoxicity Receptors (NCRs: NKp30, NKp44 and NKp46), of which only NKp46 has a mouse orthologue (Ncr1), to eliminate abnormal cells. NKp46/Ncr1 is considered a selective marker for NK cells, although it is also found on a subset of ILCs, where it appears to be without function. The influenza virus hemagglutinin (HA) was the first ligand identified for Ncr1/NKp46 followed by other viral, bacterial and even fungal ligands. NKp46/Ncr1 also recognizes unknown self and tumor ligands. Here we describe the generation of a transgenic mouse where the Ncr1 gene is expressed in the Rosa locus, preceded by a floxed stop sequence allowing Ncr1/NKp46 expression in various tissues upon crossing with Cre transgenic mouse lines. Surprisingly, while several crossings were attempted, Ncr1 overexpression was successful only where cre recombinase expression was dependent on the Ncr1 promoter. Ncr1 overexpression in NK cells increased NK cell immunity in two hallmark Ncr1 related pathologies, influenza virus infection and B16 melanoma. These data suggest that increasing NK cell cytotoxicity by enforced NKp46/Ncr1 expression serves as a potential therapeutic opportunity for the treatment of various pathologies, and in immunotherapy.
Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methylation compared to normal cells. The functional annotation of hypermethylated CGI revealed that the hypermethylation was associated with homeobox domain genes and targets marked by repressive histone modifications. The strongest methylation variation was observed in transitional areas of CGI, termed shores. 5'-shores of promoter-associated CGI in lung cancer cell lines were higher methylated than 3'-shores. Within two tandem-oriented genes, a significant hypermethylation of the downstream-located CGI promoters was revealed. Hypermethylation correlates with the length of the intergenic region between such tandem genes. As the RASSF1A tumor suppressor gene represents such a downstream tandem gene, its silencing was analyzed using an inducible system. It was determined that the induction of an upstream gene led to a repression of RASSF1A through a process involving histone deacetylases and CPSF1. A tumor-specific increase in expression of histone deacetylases and CPSF1 was detected in lung cancer. Our results suggest that the downstream gene could be susceptible to epigenetic silencing when organized in a tandem orientation.
Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor. Eleven patients were treated with CARTs. The infusions were safe, and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1, but the lymphodepletion induced by Cy/Flu increased circulating levels of the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further enhance expansion or persistence. Antitumor responses at 6 weeks were modest. We observed a striking expansion of CD45/CD33/CD11b/CD163
Lachová V, Škorvanová L, Svetlíková D, et al.Comparison of transcriptional profiles of interferons, CXCL10 and RIG-1 in influenza infected A549 cells stimulated with exogenous interferons.
Acta Virol. 2017; 61(2):183-190 [PubMed
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Type I and type III interferons (IFNs) are induced by viral infection. It was concluded that these IFN species are identical in regulation and biological functions. However, these two systems differ in the tissue expression of their receptors and their transcriptional regulation is fundamentally different as well as cellular signaling pathways that drive expression of each IFN. Here, we have investigated the transcriptional profile of endogenous IFNs after stimulation of cells with exogenous IFNs and subsequent infection of A549 cells with A/chicken/Germany/27 [H7N7] influenza virus. Both type I and type III IFNs exhibit high degree of the cross-induction. Our results show that type III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3) are better inducers of CXCL10 than type I IFNs. The IFN-β1a and IFN-λ2 were the most potent IFNs and they highly increased the level of IFN-α, IFN-β, IFN-λ, and CXCL10 mRNAs. Since type I IFNs up regulated expression of retinoic acid-inducible gene 1 (RIG-1) mRNA, type III IFNs-λ down regulated expression of RIG-1 mRNA in influenza infected cells. IFN-α and IFN-ω induced similar amount of IFN-α, IFN-β and IFN-λ mRNA but differ in induction of CXCL10 and RIG-1 mRNA.
Yoshimi A, Kato K, Hosaka S, et al.Haploidentical peripheral blood stem cell transplantation without irradiation or busulfan after reduced-intensity conditioning for KMT2A(MLL)-rearranged infant B-cell precursor acute lymphoblastic leukemia: Report of two cases.
Pediatr Transplant. 2017; 21(4) [PubMed
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We present two infants with KMT2A(MLL)-gene-R-associated BCP-ALL, who received HLA haploidentical PBSCT after RIC. The patients developed ALL at age 6 months and 3 months, respectively. Case 1 underwent PBSCT at the second CR with detectable KMT2A-AFF1(MLL-AF4) fusion gene transcript at 11 months of age, and Case 2 at the first CR without KMT2A-MLLT1(MLL-ENL) fusion gene transcript at 8 months of age. Both patients received G-CSF-mobilized unmanipulated peripheral blood mononuclear cells from their HLA haploidentical mothers after administration of FLU, MEL, and ATG. Tacrolimus, methotrexate, and mPSL were administered as prophylaxis against GVHD. Engraftment was rapidly obtained with complete chimerism in both patients. Acute adverse events included acute GVHD in Case 1 and bacterial sepsis in Case 2. At last clinical check at age 5 years and 4 years, respectively, both patients were recurrence-free and attained normal growth and development. We conclude that PBSCT from an HLA haploidentical mother with non-TBI and non-BU regimen seems feasible and efficacious, offering favorable life quality for infants.
A putative tumor suppressor BLU mapped on the chromosomal 3p21 region, is frequently lost in human tumors including nasopharyngeal carcinoma (NPC). To explore the underlying mechanism of tumor suppression by BLU, its potential to promote apoptosis induced by TRAIL, an effector molecule elaborated by natural killer-T (NKT) cells was investigated. BLU was re-expressed in NPC-derived HNE1 cells by recombinant adenoviral infection and the cells were challenged with recombinant TRAIL. The growth inhibition of BLU was assayed and apoptosis was examined by flow cytometry-based tetramethylrhodamine ethyl ester (TMRE) and annexin V staining, cleavage of pro-caspase-8 and poly ADP ribose polymerase (PARP). The modulation of NF-κB pathway by BLU was evaluated by the reporter activity and estimation of the level of the molecules involved such as IKKalpha, p65 NF-κB, as well as NF-κB induced anti-apoptotic factors cFLIPL and cIAP2. The expression of BLU exerted in vitro and in vivo growth inhibitory effect and promoted TRAIL-induced apoptosis. This phenomenon was validated by FACS-based assays of mitochondrial membrane potential (BLU vs. Vector 87.8% ± 7.7% and 72.1%±6.7% at 6h exposure to TRAIL) and phosphatidylserine turnover (BLU vs. vector: 28.7%±2.9% and 22.6%±2.5%), as well as, enhanced caspapse-8 cleavage. Similar with the findings that BLU promotes chemotherapeutic agent-induced apoptosis, it also augmented death receptor-induced pathway through NF-κB pathway inhibition. In conclusion, BLU suppressed tumor formation by strengthening the antitumor immunity.
The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4
Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would allow for systematic identification of best practices to improve reproducibility. We therefore constructed three very large gene expression meta-analyses from clinical samples, and then examined meta-analyses of subsets of the datasets (all combinations of datasets with up to N/2 samples and K/2 datasets) compared to a 'silver standard' of differentially expressed genes found in the entire cohort. We tested three random-effects meta-analysis models using this procedure. We showed relatively greater reproducibility with more-stringent effect size thresholds with relaxed significance thresholds; relatively lower reproducibility when imposing extraneous constraints on residual heterogeneity; and an underestimation of actual false positive rate by Benjamini-Hochberg correction. In addition, multivariate regression showed that the accuracy of a meta-analysis increased significantly with more included datasets even when controlling for sample size.
Turtle CJ, Hanafi LA, Berger C, et al.Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells.
Sci Transl Med. 2016; 8(355):355ra116 [PubMed
] Free Access to Full Article Related Publications
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4(+)/CD8(+) ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.
Hu L, Lin Z, Wu Y, et al.Comprehensive profiling of EBV gene expression in nasopharyngeal carcinoma through paired-end transcriptome sequencing.
Front Med. 2016; 10(1):61-75 [PubMed
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The latent expression pattern of Epstein-Barr Virus (EBV) genes in nasopharyngeal carcinoma (NPC) has been extensively investigated, and the expression of several lytic genes in NPC has been reported. However, comprehensive information through EBV transcriptome analysis in NPC is limited. We performed paired-end RNA-seq to systematically and comprehensively characterize the expression of EBV genes in NPC tissue and C666-1 NPC cell line, which consistently carries EBV. In addition to the transcripts restricted to type II latency infection, the type III latency EBNA3s genes and a substantial number of lytic genes, such as BZLF1, BRLF1, and BMRF1, were detected through RNA-seq and were further verified in C666-1 cells and NPC tissue through realtime PCR.We also performed clustering analysis to classify NPC patient groups in terms of EBV gene expression, which presented two subtypes of NPC samples. Results revealed interesting patterns of EBV gene expression in NPC patients. This clustering was correlated with many signaling pathways, such as those related to heterotrimeric G-protein signaling, inflammation mediated by chemokine and cytokine signaling, ribosomes, protein metabolism, influenza infection, and ECM-receptor interaction. Our combined findings suggested that the expression of EBV genes in NPC is restricted not only to type II latency genes but also to type III latency and lytic genes. This study provided further insights into the potential role of EBV in the development of NPC.
Kiseleva LN, Kartashev AV, Vartanyan NL, et al.CHARACTERISTICS OF A172 AND T98G CELL LINES.
Tsitologiia. 2016; 58(5):349-55 [PubMed
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During continuous cultivation cell lines can lose a number of innate characteristics or acquire new ones. In this work we compared growth and phenotypic characteristics of human glioblastoma À172 and Ò98G lines from cell culture collection of Research Institute of Influenza of Ministry of Health of Russian Federation (St. Petersburg). The activity of genes encoding intracellular proteins that determine cell lines belonging to mesenchymal type, as well as several growth factor genes and extracellular matrix genes were estimated. Cell lines A172 and T98G varied in morphology and surface markers expression. A172 cells were characterized by higher expression of mesenchymal markers CD90, CD105, fibroblast activation protein, and tenascin C. Both cell lines showed high level of a2 smooth muscle actin expression. The obtained data indicating high activity of genes encoding major inductors of angiogenesis (VEGF, FGF2 (b), TGFb1) and thrombospondin-1 in foregoing cell lines are in agreement with published data. Reduction of fetal serum in culture medium from 10 to 5 % in both cell lines resulted in the increase of proportion of cells with surface antigens CD73 and CD105. Both A172 and T98G cell lines sustain the main features of glioblastomas and therefore can serve as research objects in investigation of this kind of neoplasms.
The α-Gal epitope (Galα1,3Galα1,4GlcNAc‑R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti‑Gal antibody with the α‑Gal epitope, humans have a distinct anti‑α‑gal reactivity, which is responsible for hyperacute rejection of organs transplanted from α‑gal donors. In addition, the α1,3 galactosyltransferases (α1,3GT) can catalyze the synthesis of the α‑Gal epitope. Therefore, the α1,3GT gene, which encodes the α1,3GT, is developed profoundly. The distributions of the α‑Gal epitope and anti‑Gal antibody, and the activation of α1,3GT, reveal that the enzyme of α1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human α1,3‑GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the α1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the α‑Gal epitope and anti‑Gal antibody, they can be applied to clinical exploitation. Knocking out the α1,3GT gene will eliminate the xenoantigen, Gal(α1,3)Gal, so that the transplantation of α1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the α‑Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti‑Gal‑mediated autologous tumor vaccines, which express α‑Gal epitope to antigen‑presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, α‑Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues.
Immunotherapy treatments for cancer are becoming increasingly successful, however to further improve our understanding of the T-cell recognition involved in effective responses and to encourage moves towards the development of personalised treatments for leukaemia immunotherapy, precise antigenic targets in individual patients have been identified. Cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen specific T-cell populations naturally circulating in patients and normal donors. We have developed the pMHC array to detect CD8+ T-cell populations in leukaemia patients that recognise epitopes within viral antigens (cytomegalovirus (CMV) and influenza (Flu)) and leukaemia antigens (including Per Arnt Sim domain 1 (PASD1), MelanA, Wilms' Tumour (WT1) and tyrosinase). We show that the pMHC array is at least as sensitive as flow cytometry and has the potential to rapidly identify more than 40 specific T-cell populations in a small sample of T-cells (0.8-1.4 x 10(6)). Fourteen of the twenty-six acute myeloid leukaemia (AML) patients analysed had T cells that recognised tumour antigen epitopes, and eight of these recognised PASD1 epitopes. Other tumour epitopes recognised were MelanA (n = 3), tyrosinase (n = 3) and WT1(126-134) (n = 1). One of the seven acute lymphocytic leukaemia (ALL) patients analysed had T cells that recognised the MUC1(950-958) epitope. In the future the pMHC array may be used provide point of care T-cell analyses, predict patient response to conventional therapy and direct personalised immunotherapy for patients.
H5N1 influenza A virus (IAV) causes severe respiratory diseases and high mortality rates in animals and humans. MicroRNAs are being increasingly studied to evaluate their potential as therapeutic entities to combat viral infection. However, mechanistic studies delineating the roles of microRNAs in regulating host-H5N1 virus interactions remain scarce. Here, we performed microRNA microarray analysis using A549 human lung epithelial cells infected with a highly pathogenic avian influenza virus. The microRNA expression profile of infected cells identified a small number of microRNAs being dysregulated upon H5N1 influenza A virus infection. Of the differentially expressed microRNAs, miR-136 was up-regulated 5-fold and exhibited potent antiviral activity in vitro against H5N1 influenza A virus, as well as vesicular stomatitis virus. On the one hand, 3'-untranslated region (UTR) reporter analysis revealed a miR-136 binding site in the 3' UTR of IL-6. However, on the other hand, we subsequently determined that miR-136 meanwhile acts as an immune agonist of retinoic acid-inducible gene 1 (RIG-I), thereby causing IL-6 and IFN-β accumulation in A549 cells. Overall, this study implicates the dual role of miRNA-136 in the regulation of host antiviral innate immunity and suggests an important role for the microRNA-activated pathway in viral infection via pattern recognition receptors.
Small nucleolar RNAs (snoRNAs) are appreciable players in gene expression regulation in human cells. The canonical function of box C/D and box H/ACA snoRNAs is posttranscriptional modification of ribosomal RNAs (rRNAs), namely, 2'-O-methylation and pseudouridylation, respectively. A series of independent studies demonstrated that snoRNAs, as well as other noncoding RNAs, serve as the source of various short regulatory RNAs. Some snoRNAs and their fragments can also participate in the regulation of alternative splicing and posttranscriptional modification of mRNA. Alterations in snoRNA expression in human cells can affect numerous vital cellular processes. SnoRNA level in human cells, blood serum, and plasma presents a promising target for diagnostics and treatment of human pathologies. Here we discuss the relation between snoRNAs and oncological, neurodegenerative, and viral diseases and also describe changes in snoRNA level in response to artificial stress and some drugs.
Kato T, Yui M, Deo VK, Park EYDevelopment of Rous sarcoma Virus-like Particles Displaying hCC49 scFv for Specific Targeted Drug Delivery to Human Colon Carcinoma Cells.
Pharm Res. 2015; 32(11):3699-707 [PubMed
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PURPOSE: Virus-like particles (VLPs) have been used as drug carriers for drug delivery systems. In this study, hCC49 single chain fragment variable (scFv)-displaying Rous sarcoma virus-like particles (RSV VLPs) were produced in silkworm larvae to be a specific carrier of an anti-cancer drug.
METHOD: RSV VLPs displaying hCC49 scFv were created by the fusion of the transmembrane and cytoplasmic domains of hemagglutinin from influenza A (H1N1) virus and produced in silkworm larvae. The display of hCC49 scFv on the surface of RSV VLPs was confirmed by enzyme-linked immunosorbent assay using tumor-associated glycoprotein-72 (TAG-72), fluorescent microscopy, and immunoelectron microscopy. Fluorescein isothiocyanate (FITC) or doxorubicin (DOX) was incorporated into hCC49 scFv-displaying RSV VLPs by electroporation and specific targeting of these VLPs was investigated by fluorescent microscopy and cytotoxicity assay using LS174T cells.
RESULTS: FITC was delivered to LS174T human colon adenocarcinoma cells by hCC49 scFv-displaying RSV VLPs, but not by RSV VLPs. This indicated that hCC49 scFv allowed FITC-loaded RSV VLPs to be delivered to LS174T cells. DOX, which is an anti-cancer drug with intrinsic red fluorescence, was also loaded into hCC49 scFv-displaying RSV VLPs by electroporation; the DOX-loaded hCC49 scFv-displaying RSV VLPs killed LS174T cells via the specific delivery of DOX that was mediated by hCC49 scFv. HEK293 cells were alive even though in the presence of DOX-loaded hCC49 scFv-displaying RSV VLPs.
CONCLUSION: These results showed that hCC49 scFv-displaying RSV VLPs from silkworm larvae offered specific drug delivery to colon carcinoma cells in vitro. This scFv-displaying enveloped VLP system could be applied to drug and gene delivery to other target cells.
Xiao K, Yu Z, Shi DT, et al.Inactivation of BLU is associated with methylation of Sp1-binding site of BLU promoter in gastric cancer.
Int J Oncol. 2015; 47(2):621-31 [PubMed
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BLU is a candidate tumor suppressor gene, which is epigenetically inactivated in many human malignancies. However, the expression and biological functions of BLU in gastric cancer has not yet been reported. In the present study, we identified a functional BLU promoter which was regulated by the transcription activator Sp1. Bisulfite sequencing and qRT-PCR assays indicated that the silence of BLU expression in gastric cancer was significantly associated with DNA hypermethylation of BLU promoter including -39 CpG site located in the Sp1 transcription element. The expression of BLU was notably restored in AGS and SGC7901 cells following the demethylation-treatment with 5'-Aza-2'-deoxycytidine. Moreover, the results from ChIP, EMSA and luciferase reporter gene showed that -39 CpG methylation could prevent Sp1 from binding to the promoter of BLU and decreased transcription activity of the BLU gene by ~70%. In addition, knockdown of BLU significantly promoted cellular proliferation and colony formation in gastric cancer cells. In conclusion, we identified a novel functional BLU promoter and proved that BLU promoter activity was regulated by Sp1. Furthermore, we found that hypermethylated -39 CpG in BLU proximal promoter directly reduced its binding with Sp1, which may be one of the mechanisms accounting for the inactivation of BLU in gastric cancer.
Nalwa HSA special issue on reviews in nanomedicine, drug delivery and vaccine development.
J Biomed Nanotechnol. 2014; 10(9):1635-40 [PubMed
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This thematic special issue of the Journal of Biomedical Nanotechnology focused on the "Reviews in Nanomedicine, Drug Delivery and Vaccine Development" contains 30 state-of-the-art review articles covering recent advances, trends and future directions emphasized on nanoparticle-based new strategies for diagnosis and cancer phototherapies, nanomedicine, nucleic acid-based nanocarriers, gene and drug delivery systems, tuberculosis mucosal and H5N1 influenza vaccines, drug-loaded electrospun polymer nanofibers, microneedle technology for insulin delivery for the treatment of insulin-dependent diabetes mellitus, RNA-based therapies, nanotoxicity and biosafety of nanomaterials to environment and human health.
Liu H, Lei C, Long K, et al.Mutant GNAQ promotes cell viability and migration of uveal melanoma cells through the activation of Notch signaling.
Oncol Rep. 2015; 34(1):295-301 [PubMed
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The occurrence of guanine nucleotide binding protein (G protein), q polypeptide (GNAQ) mutations has been found to be high in the majority of uveal melanomas. However, the underlying molecular mechanism of GNAQ mutations in modulating uveal melanoma is poorly understood. The aim of the present study was to investigate the role and underlying mechanism of mutant GNAQ in the regulation of cell viability and migration of uveal melanoma cells. Uveal melanoma cells containing mutant GNAQ were transfected with scrambled or GNAQ small-interfering RNA. Compared with the control, GNAQ knockdown markedly inhibited cell viability and migration. However, tumor cells without GNAQ mutations exhibited enhanced viability and migration following transfection with HA-GαqQL. Additionally, GNAQ knockdown significantly downregulated the expression of Jag-1 (Notch ligand), Notch intracellular domain and Hes-1 (Notch target gene) in uveal melanoma cells. Conversely, the GNAQ overexpression promoted their expression. Cell viability and migration induced by GNAQ was significantly inhibited following treatment with 5 µmol/l MRK003, a Notch signaling inhibitor. Furthermore, the transfection of human influenza hemagglutinin A epitope (HA)-GαqQL into tumor cells caused Yes-associated protein (YAP) dephosphorylation and nuclear translocation, which stimulated the expression of Jag-1 and Hes-1. Positive correlations were observed between the GNAQ and Jag-1 mRNA levels and between the GNAQ and Hes-1 mRNA levels. However, no positive correlation was observed between the GNAQ and YAP mRNA levels. The results suggested that GNAQ mutation induced viability and migration of uveal melanoma cells via Notch signaling activation, which is mediated by YAP dephosphorylation and nuclear translocation.
RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and pro-inflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced anticancer activity by suppressing apoptosis via TRAIL and anti-apoptotic genes. Collectively, our study shows that IPS-1 induces anticancer activity through upregulation of pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE via IRF3 and IRF7 in type I IFN-dependent and -independent manners.