1,721,009 research outputs found
Anastasiadou, Eleni: Die Klavierballaden von Frédéric Chopin
No full textGraz, Univ. für Musik und darstellende Kunst, Wiss. Masterarb., 201
Malicious exosomes
No full textNanovesicles known as exosomes are secreted from a variety of cell types and circulate in biological fluids such as urine and plasma. These exosomes “hijack” membrane components and cytoplasmic contents of these cells and play an important role in intercellular communication, often inducing physiological changes in recipient cells by transferring bioactive lipids, nucleic acids, and proteins. These tiny vesicles also have been implicated in a number of human diseases, including cancer, and are becoming an appreciated fundamental aspect of tumor progression and metastasis. Recently, Melo et al. showed that exosomes from breast cancer cells transfer microRNAs (miRNAs) to normal cells and stimulate them to become cancerous. This potentially expands the mechanisms by which cancer spreads and may provide opportunities to develop exosome-based diagnostics and therapies
RNA-aided immunotherapeutics
No full textSUMMARY
[0006] Immunotherapy of cancers is a desirable therapeutic alternative in lieu of or in addition to the standard chemotherapy and radiation therapy protocols. Immune checkpoint inhibitors have been satisfactory in overall response rate for several different tumors and in particular EBV-associated tumors. In the context of EBV-associated tumors, viral proteins like EBNA2 and LMP1 affect immune checkpoint genes, such as, PD-L1 and ICOSL expression by altering miRNAs. Thus, a combination of miRNA, their mimics or chemically modified antisense oligonucleotides targeting miRNAs (i.e., a locked nucleic acid (LNA)), and immune checkpoints inhibitors on nanoparticles, provide a unique method for silencing immune checkpoints both from outside and within the tumor cell.
[0007] In one aspect, the present disclosure provides a method for treating an EBV-related cancer in a subject in need thereof, comprising administering an effective amount of one or more of (a) an agent that increases an amount of miR-34a in the subject and (b) an agent that decreases an amount of miR-l29 in the subject, wherein: the subject is undergoing treatment with an immune checkpoint immunotherapy selected from an agent that modulates one or more of programmed cell death protein-l (PD-l), programmed death-ligand 1 (PD-L1), programmed death-ligand 2 (PD-L2), inducible T-cell costimulator (ICOS), inducible T-cell costimulator ligand (ICOSL), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
[0008] In some embodiments, the EBV-related cancer is selected from one or more of Non-Hodgkin lymphoma (NHL), B- cell Lymphoma (BL), Burkitt lymphoma, Hodgkin lymphoma (HL), nasopharyngeal carcinoma, gastric carcinoma, human T-lymphotropic virus 1 (HTLV-1), and adult T-cell leukemia (ATL)/lymphoma.
[0009] In some embodiments, the agent that increases an amount of miR-34a is selected from one or more of miR-34a and a miR-34a mimetic. In some embodiments, the agent that increases an amount of miR-34a is an inhibitor of Early B-cell factor (EBF1).
[0010] In some embodiments, the agent that decreases an amount of miR-l29 is selected from one or more of an antisense oligonucleotide, an antagomir and a construct expressing a miRNA inhibitor. In some embodiments, the antisense oligonucleotide comprises a sequence that is at least partially complementary to a mature sequence of miR-l29. In some embodiments, the agent is chemically modified. In some embodiments, the chemical modification is selected from locked nucleic acid (LNA), phosphorothioate, 2'-0-Methyl, 2'-0-Methoxyethyl, 2'-0-alkyl-RNA unit, 2'-OMe-RNA unit, 2'-amino-DNA unit, 2'-fluoro-DNA unit, peptide nucleic
acid (PNA) unit, hexitol nucleic acids (HNA) unit, INA unit, and a 2'-0-(2-Methoxyethyl)-RNA (2' MOE RNA) unit.
[0011] In some embodiments, the agent that modulates PD-l is an antibody or antibody format specific for PD-l. In some embodiments, the antibody or antibody format specific for PD-l is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody. In some embodiments, the antibody or antibody format specific for PD-l is selected from Nivolumab, Pembrolizumab, Pidilizumab, BMS-936559, Atezolizumab, or Avelumab.
[0012] In some embodiments, the agent that modulates PD-L1 is an antibody or antibody format specific for PD-L1. In some embodiments, the antibody or antibody format specific for PD-L1 is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody. In some embodiments, the antibody or antibody format specific for PD-L1 is selected from Nivolumab, Pembrolizumab, Pidilizumab, BMS-936559, Atezolizumab, Avelumab or Durvalumab.
[0013] In some embodiments, the agent that modulates PD-L2 is an antibody or antibody format specific for PD-L2. In some embodiments, the antibody or antibody format specific for PD-L2 is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody.
[0014] In some embodiments, the agent that modulates ICOS is an antibody or antibody format specific for ICOS. In some embodiments, the antibody or antibody format specific for ICOS is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody. In some embodiments, the antibody or antibody format specific for ICOS comprises JTX-2011.
[0015] In some embodiments, the agent that modulates ICOSL is an antibody or antibody
format specific for ICOSL. In some embodiments, the antibody or antibody format specific for ICOSL is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody.
[0016] In some embodiments, the agent that modulates CTLA-4 is an antibody or antibody format specific for CTLA-4. In some embodiments, the antibody or antibody format specific for CTLA-4 is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody. In some embodiments, the antibody or antibody format specific for CTLA-4 is selected from tremelimumab or Ipilimumab.
[0017] In some embodiments, administration is by intratumoral, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection, or direct injection into cancer tissue.
[0018] In one aspect, the disclosure provides a method for treating an EBV-related cancer in a subject in need thereof, comprising administering (i) an effective amount of one or more of (a) an agent that increases an amount of miR-34a in the subject and (b) an agent that decreases an amount of miR-l29 in the subject, and (ii) an effective amount of an immune checkpoint immunotherapy selected from an agent that modulates one or more of PD-l, PD-L1, PD-L2, ICOS, ICOSL, and CTLA-4.
[0019] In one aspect, the disclosure provides a method for potentiating an immune checkpoint immunotherapy of an EBV-related cancer in a subject in need thereof, comprising administering an agent that increases an amount of miR-34a in the subject, wherein: the immune checkpoint immunotherapy is an agent that modulates one or more of PD-l, PD-L1, and PD-L2 and the subject is predicted to be poorly responsive or non-responsive to the immune checkpoint immunotherapy or has presented as poorly responsive or non-responsive to the immune checkpoint immunotherapy.
[0020] In one aspect, the disclosure provides a method for potentiating immune checkpoint immunotherapy of an EBV-related cancer in a subject in need thereof, comprising administering an agent that decreases an amount of miR-l29 in the subject, wherein the immune checkpoint immunotherapy is an agent that modulates one or more of ICOS, ICOSL,
and CTLA-4 and the subject is predicted to be poorly responsive or non-responsive to the immune checkpoint immunotherapy or has presented as poorly responsive or non-responsive to the immune checkpoint immunotherapy.
[0021] In some embodiments, the method reduces and/or mitigates one or more side effects of the immune checkpoint immunotherapy. In some embodiments, the side effect is selected from decreased appetite, rashes, fatigue, pneumonia, pleural effusion, pneumonitis, pyrexia, nausea, dyspnea, cough, constipation, diarrhea, immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, hypophysitis, iridocyclitis, and nephritis.
[0022] In some embodiments, the method reduces the dose of immune checkpoint immunotherapy. In some embodiments, method reduces number of administrations of the immune checkpoint immunotherapy. In some embodiments, the method increases a therapeutic window of the immune checkpoint immunotherapy.
[0023] In some embodiments, the method elicits a potent immune response in less-immunogenic tumors. In some embodiments, the method converts a tumor with reduced inflammation (“cold tumor”) to a responsive, inflamed tumor (“hot tumor”).
[0024] In some embodiments, the method makes the cancer responsive or more responsive to a combination therapy of the immune checkpoint immunotherapy and one or more chemotherapeutic agents and/or radiotherapy. In some embodiments, the subject is predicted to be poorly responsive or non-responsive to the immune checkpoint immunotherapy based on expression of one or more of PD-l, PD-L1, PD-L2, ICOS, ICOSL, and CTLA-4 in a tumor specimen. In some embodiments, the subject is predicted to be poorly responsive or non-responsive to an agent that modulates one or more of PD-l, PD-L1, and PD-L2 based on low on expression of PD-l, PD-L1, and PD-L2 in a tumor specimen.
[0025] In some embodiments, the subject is predicted to be poorly responsive or non-responsive to an agent that modulates one or more of PD-l, PD-L1, and PD-L2 tumor proportion score (TPS) of less than about 49% for PD-L1 staining.
[0026] In one aspect, the disclosure provides a method for treating an EBV-related cancer in a subject in need thereof, comprising administering (i) an effective amount of one or more of (a) an agent that increases an amount of miR-34a in the subject and (b) an agent that decreases an amount of miR-l29 in the subject, and (ii) an effective amount of an immune checkpoint immunotherapy selected from an agent that modulates one or more of PD-l, PD-L1, PD-L2, ICOS, ICOSL, and CTLA-4.
[0027] In one aspect, the disclosure provides a method for evaluating an EBV-related cancer subject’s likelihood of response to an immune checkpoint immunotherapy, comprising evaluating a level of one or more of miR-34a and miR-l29 in a biological sample from the subject, wherein a low level of miR-34a and/or high level of miR-l29 is indicative of a cancer that is suitable for immune checkpoint immunotherapy.
[0028] In one aspect, the disclosure provides a method for treating an EBV-related cancer, comprising: (a) evaluating a subject’s likelihood of response to an immune checkpoint immunotherapy, comprising evaluating a level of one or more of miR-34a and miR-l29 in a biological sample from the subject, wherein a low level of miR-34a and/or high level of miR-129 is indicative of a cancer that is suitable for immune checkpoint immunotherapy and (b) administering an immune checkpoint immunotherapy selected from an agent that modulates one or more of PD-l, PD-L1, and PD-L2 based on low on expression of PD-l, PD-L1, and PD-L2 to the subject having a low level of miR-34a and/or high level of miR-l29
Immunomodulatory effect of adipose-derived stem cells: the cutting edge of clinical application
Get PDFAdipose-derived stem cells (ASCs) represent a promising tool for soft tissue engineering as well as for clinical treatment of inflammatory and autoimmune pathologies. The well-characterized multi-differentiation potential and self-renewal properties of ASCs are coupled with their immunomodulatory ability in providing therapeutic efficacy. Yet, their impact in immune or inflammatory disorders might rely both on cell contact-dependent mechanisms and paracrine effects, resulting in the release of various soluble factors that regulate immune cells functions. Despite the widespread use of ASCs in clinical trials addressing several pathologies, the pathophysiological mechanisms at the basis of their clinical use have been not yet fully investigated. In particular, a thorough analysis of ASC immunomodulatory potential is mandatory. Here we explore such molecular mechanisms involved in ASC immunomodulatory properties, emphasizing the relevance of the milieu composition. We review the potential clinical use of ASC secretome as a mediator for immunomodulation, with a focus on in vitro and in vivo environmental conditions affecting clinical outcome. We describe some potential strategies for optimization of ASCs immunomodulatory capacity in clinical settings, which act either on adult stem cells gene expression and local microenvironment. Finally, we discuss the limitations of both allogeneic and autologous ASC use, highlighting the issues to be fixed in order to significantly improve the efficacy of ASC-based cell therapy
Non-coding RNA networks in cancer
No full textThousands of unique non-coding RNA (ncRNA) sequences exist within cells. Work from the past decade has altered our perception of ncRNAs from 'junk' transcriptional products to functional regulatory molecules that mediate cellular processes including chromatin remodelling, transcription, post-transcriptional modifications and signal transduction. The networks in which ncRNAs engage can influence numerous molecular targets to drive specific cell biological responses and fates. Consequently, ncRNAs act as key regulators of physiological programmes in developmental and disease contexts. Particularly relevant in cancer, ncRNAs have been identified as oncogenic drivers and tumour suppressors in every major cancer type. Thus, a deeper understanding of the complex networks of interactions that ncRNAs coordinate would provide a unique opportunity to design better therapeutic interventions
The Inescapable Influence of Noncoding RNAs in Cancer
No full textThis report summarizes information presented at the 2015 Keystone Symposium on "MicroRNAs and Noncoding RNAs in Cancer." Nearly two decades after the discovery of the first miRNA, the role of noncoding RNAs in developmental processes and the mechanisms behind their dysregulation in cancer has been steadily elucidated. Excitingly, miRNAs have begun making their way into the clinic to combat diseases such as hepatitis C and various forms of cancer. Therefore, at this Keystone meeting, novel findings were presented that enhance our view on how small and long noncoding RNAs control developmental timing and oncogenic processes. Recurring themes included (i) how miRNAs can be differentially processed, degraded, and regulated by ribonucleoprotein complexes, (ii) how particular miRNA genetic networks that control developmental process, when disrupted, can result in cancer disease, (iii) the technologies available to therapeutically deliver RNA to combat diseases such as cancer, and (iv) the elucidation of the mechanism of actions for long noncoding RNAs, currently a poorly understood class of noncoding RNA. During the meeting, there was an emphasis on presenting unpublished findings, and the breadth of topics covered reflected how inescapable the influence of noncoding RNAs is in development and cancer
Revisiting the physiological role of androgens in women
No full textIntroduction: Extensive research underlines the critical functions of androgens in females. Nevertheless, the precise mechanisms of their action are poorly understood. Here, we review the existing literature regarding the physiological role of androgens in women throughout life.
Areas covered: Several studies show that androgen receptors (ARs) are broadly expressed in numerous female tissues. They are essential for many physiological processes, including reproductive, sexual, cardiovascular, bone, muscle, and brain health. They are also involved in adipose tissue and liver function. Androgen levels change with the menstrual cycle and decrease in the first decades of life, independently of menopause.
Expert opinion: To date, studies are limited by including small numbers of women, the difficulty of dosing androgens, and their cyclical variations. In particular, whether androgens play any significant role in regulating the establishment of pregnancy is poorly understood. The neural functions of ARs have also been investigated less thoroughly, although it is expressed at high levels in brain structures. Moreover, the mechanism underlying the decline of dehydroepiandrosterone (DHEA) and dehydroe piandrosterone sulfate (DHEAS) with age is unclear. Other factors, including estrogen’s effect on adrenal androgen production, reciprocal regulation of ARs, and non-classical effects of androgens, remain to be determined
Epstein-Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b
No full textEpstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR-29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response. Oncogene (2010) 29, 1316-1328; doi:10.1038/onc.2009.439; published online 7 December 200
Hydrophobically Modified let-7b miRNA Enhances Biodistribution to NSCLC and Downregulates HMGA2 In Vivo
Get PDFMicroRNAs (miRNAs) have increasingly been shown to be involved in human cancer, and interest has grown about the potential use of miRNAs for cancer therapy. miRNA levels are known to be altered in cancer cells, including in non-small cell lung cancer (NSCLC), a subtype of lung cancer that is the most prevalent form of cancer worldwide and that lacks effective therapies. The let-7 miRNA is involved in the regulation of oncogene expression in cells and directly represses cancer growth in the lung. let-7 is therefore a potential molecular target for tumor therapy. However, applications of RNA interference for cancer research have been limited by a lack of simple and efficient methods to deliver oligonucleotides (ONs) to cancer cells. In this study, we have used in vitro and in vivo approaches to show that HCC827 cells internalize hydrophobically modified let-7b miRNAs (hmiRNAs) added directly to the culture medium without the need for lipid formulation. We identified functional let-7b hmiRNAs targeting the HMGA2 mRNA, one of the let-7 target genes upregulated in NSCLC, and show that direct uptake in HCC827 cells induced potent and specific gene silencing in vitro and in vivo. Thus, hmiRNAs constitute a novel class of ONs that enable functional studies of genes involved in cancer biology and are potentially therapeutic molecules
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