In Vivo Application of beta Amyloid Oligomers: A Simple Tool to Evaluate Mechanisms of Action and New Therapeutic Approaches

Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4–6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor responsein vivo.

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An Overview of Long Non-Coding (lnc)RNAs in Neuroblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms22084234 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4234

Author(s):

Francesca Baldini ◽

Matilde Calderoni ◽

Laura Vergani ◽

Paola Modesto ◽

Tullio Florio ◽

...

Keyword(s):

Recent Progress ◽

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Biological Functions ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Definitive Therapy ◽

Sporadic Cases ◽

Non Coding Rnas

Neuroblastoma (NB) is a heterogeneous developmental tumor occurring in childhood, which arises from the embryonic sympathoadrenal cells of the neural crest. Although the recent progress that has been done on this tumor, the mechanisms involved in NB are still partially unknown. Despite some genetic aberrations having been identified, the sporadic cases represent the majority. Due to its wide heterogeneity in clinical behavior and etiology, NB represents a challenge in terms of prevention and treatment. Since a definitive therapy is lacking so far, there is an urgent necessity to unveil the molecular mechanisms behind NB onset and progression to develop new therapeutic approaches. Long non-coding RNAs (lncRNAs) are a group of RNAs longer than 200 nucleotides. Whether lncRNAs are destined to become a protein or not, they exert multiple biological functions such as regulating gene expression and functions. In recent decades, different research has highlighted the possible role of lncRNAs in the pathogenesis of many diseases, including cancer. Moreover, lncRNAs may represent potential markers or targets for diagnosis and treatment of diseases. This mini-review aimed to briefly summarize the most recent findings on the involvement of some lncRNAs in NB disease by focusing on their mechanisms of action and possible role in unveiling NB onset and progression.

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Beta-amyloid oligomers: recent developments

BioMolecular Concepts ◽

10.1515/bmc.2011.019 ◽

2011 ◽

Vol 2 (3) ◽

pp. 211-222 ◽

Cited By ~ 6

Author(s):

Vilmante Borutaite ◽

Ramune Morkuniene ◽

Gintaras Valincius

Keyword(s):

Critical Role ◽

Chemical Properties ◽

Amyloid Β ◽

Neuronal Loss ◽

Beta Amyloid ◽

Amyloid Oligomers ◽

Recent Developments ◽

Β Amyloid

AbstractRecent studies point to a critical role of soluble β-amyloid oligomers in the pathogenesis of one of the most common neurodegenerative diseases, Alzheimer's disease (AD). Beta-amyloid peptides are cleavage products of a ubiquitously expressed protein, the amyloid precursor protein. Early studies suggested that accumulation of extracellular β-amyloid aggregates are the most toxic species causing synaptic dysfunction and neuronal loss in particular regions of the brain (neurobiological features underlying cognitive decline of the AD patients). In recent years, a shift of pardigm occurred, and now there is accumulating evidence that soluble oligomeric forms of the peptide are the most toxic to neuronal cells. In this review, we discuss recent findings on the toxic effects of amyloid-β oligomers, their physico-chemical properties and the possible pathways of their formation in vitro and in vivo.

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Pleiotropic Effects of Statins: New Therapeutic Approaches to Chronic, Recurrent Infection by Staphylococcus aureus

Pharmaceutics ◽

10.3390/pharmaceutics13122047 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2047

Author(s):

Melissa D. Evans ◽

Susan A. McDowell

Keyword(s):

Staphylococcus Aureus ◽

Recurrent Infection ◽

Opportunistic Pathogen ◽

Pleiotropic Effects ◽

In Vivo Studies ◽

Therapeutic Approaches ◽

Risk Of Death ◽

New Therapeutic Approaches

An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection.

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Adrenal glands stem cells: general signaling pathways

Problems of Endocrinology ◽

10.14341/probl12819 ◽

2021 ◽

Vol 67 (6) ◽

pp. 90-97

Author(s):

O. V. Glazova ◽

M. V. Vorontsova ◽

L. V. Shevkova ◽

N. Sakr ◽

N. A. Onyanov ◽

...

Keyword(s):

Stem Cells ◽

Adrenal Gland ◽

Signaling Pathways ◽

Cell Types ◽

Patient Specific ◽

Therapeutic Approaches ◽

Adult Type ◽

New Therapeutic Approaches ◽

Induced Pluripotent

Nowadays stem cells of adult type are attractive in case of active development of cell and genome technologies. They are the target of new therapeutic approaches, which are based on correction of mutations or replenishment of organs, that were damaged by autoimmune reactions, aging or other pathological processes. Also stem cells, including patient-specific (induced Pluripotent Stem Cells, iPSCs), and obtained by differentiation from them tissue cultures and organoids are the closest models to in vivo researches on humans, which gives an opportunity to get more relevant data while testing different therapeutic approaches and pharmacological drugs. The main molecular pathways, that are essential for homeostasis of a cortex of a adrenal gland — compound, structurally and functionally heterogeneous organ, is described the presented review. The adrenal cortex is renewing during the organism’s ontogenesis at the expense of the pool of stem and progenitors cells, which are in tight junctions with differentiated steroidogenic cells and which are under constant control of endocrine and paracrine signals. The understanding of signaling pathways and interactions of different cell types will give an opportunity to develop the most suitable protocols for obtaining cells of adrenal gland cortex in a different stages of differentiation to use them in scientific and medical purposes.

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Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms222010996 ◽

2021 ◽

Vol 22 (20) ◽

pp. 10996

Author(s):

Maria Giovanna Francipane ◽

Bruno Douradinha ◽

Cinzia Maria Chinnici ◽

Giovanna Russelli ◽

Pier Giulio Conaldi ◽

...

Keyword(s):

Zika Virus ◽

Therapy Resistance ◽

Mechanisms Of Action ◽

Therapeutic Approaches ◽

Term Outcome ◽

Long Term Outcome ◽

New Therapeutic Approaches ◽

Neural Stem Progenitor Cells ◽

Cns Malformations

Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32–36 weeks of initial treatment. The recent discovery that Zika virus (ZIKV) has an oncolytic action against GBM has brought hope for the development of new therapeutic approaches. ZIKV is an arbovirus of the Flaviviridae family, and its infection during development has been associated with central nervous system (CNS) malformations, including microcephaly, through the targeting of neural stem/progenitor cells (NSCs/NPCs). This finding has led various groups to evaluate ZIKV’s effects against glioblastoma stem cells (GSCs), supposedly responsible for GBM onset, progression, and therapy resistance. While preliminary data support ZIKV tropism toward GSCs, a more accurate study of ZIKV mechanisms of action is fundamental in order to launch ZIKV-based clinical trials for GBM patients.

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Precision-Cut Bovine Udder Slices (PCBUS) as an in-vitro-model of an early phase of infection of bovine mastitis

10.21203/rs.3.rs-51086/v1 ◽

2020 ◽

Author(s):

Viviane Filor ◽

Monique Petry ◽

Jessica Meißner ◽

Manfred Kietzmann

Keyword(s):

Infectious Diseases ◽

Early Phase ◽

Antimicrobial Agents ◽

Bovine Mastitis ◽

Therapeutic Approaches ◽

Tissue Slices ◽

New Therapeutic Approaches ◽

Pharmacological Interactions

Abstract Background The aim of this study was the establishment of precision-cut bovine udder slices (PCBUS) as an in-vitro-model to investigate pathophysiological processes in the early phase of mastitis in order to have the possibility to investigate new therapeutic approaches for the treatment of such udder inflammation in later studies. Furthermore, this model should contribute to substitute in-vivo-experiments. Bovine mastitis is one of the most common and costly infectious diseases in the dairy industry, which is largely associated with the use of antimicrobial agents. Given this problem of antimicrobial resistance, it is essential to step up research into bacterial infectious diseases. Thus, the transfer of the in-vitro-model of precision-cut tissue slices to the bovine udder enables broad research into new therapeutic approaches in this area and can also be used to address issues in basic research or the characterization of complex pathophysiological processes. Results A stimulation with LPS, PGN or the combination of both substances (LPS:PGN) demonstrated the ability of the PCBUS to react with a significant secretion of IL-1ß, TNF-α and PGE2. Conclusion The slices represent an instrument for investigating pharmacological interactions with udder tissue, which can be useful for studies on pharmacological questions and the understanding of complex pathophysiological processes of infection and inflammation.

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Treating Bladder Cancer: Engineering of Current and Next Generation Antibody-, Fusion Protein-, mRNA-, Cell- and Viral-Based Therapeutics

Frontiers in Oncology ◽

10.3389/fonc.2021.672262 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jan P. Bogen ◽

Julius Grzeschik ◽

Joern Jakobsen ◽

Alexandra Bähre ◽

Björn Hock ◽

...

Keyword(s):

Gene Therapy ◽

Bladder Cancer ◽

Mechanisms Of Action ◽

Next Generation ◽

Therapeutic Approaches ◽

Preclinical Development ◽

New Therapeutic Approaches ◽

Car T ◽

Mrna Gene ◽

Shed Light

Bladder cancer is a frequent malignancy and has a clinical need for new therapeutic approaches. Antibody and protein technologies came a long way in recent years and new engineering approaches were applied to generate innovative therapeutic entities with novel mechanisms of action. Furthermore, mRNA-based pharmaceuticals recently reached the market and CAR-T cells and viral-based gene therapy remain a major focus of biomedical research. This review focuses on the engineering of biologics, particularly therapeutic antibodies and their application in preclinical development and clinical trials, as well as approved monoclonal antibodies for the treatment of bladder cancer. Besides, newly emerging entities in the realm of bladder cancer like mRNA, gene therapy or cell-based therapeutics are discussed and evaluated. As many discussed molecules exhibit unique mechanisms of action based on innovative protein engineering, they reflect the next generation of cancer drugs. This review will shed light on the engineering strategies applied to develop these next generation treatments and provides deeper insights into their preclinical profiles, clinical stages, and ongoing trials. Furthermore, the distribution and expression of the targeted antigens and the intended mechanisms of action are elucidated.

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Nonsteroidal sulfamate derivatives as new therapeutic approaches for Neurofibromatosis 2 (NF2)

BMC Pharmacology and Toxicology ◽

10.1186/s40360-019-0369-8 ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Yu-chi Shen ◽

Caroline Arellano-Garcia ◽

Rosa E. Menjivar ◽

Ethan M. Jewett ◽

Wolfgang Dohle ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Lines ◽

Tumour Cell ◽

Mechanisms Of Action ◽

Neurofibromatosis 1 ◽

Tumour Suppressor ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Tumour Cell Lines

Abstract Background Neurofibromatosis 1 and 2, although involving two different tumour suppressor genes (neurofibromin and merlin, respectively), are both cancer predisposition syndromes that disproportionately affect cells of neural crest origin. New therapeutic approaches for both NF1 and NF2 are badly needed. In promising previous work we demonstrated that two non-steroidal analogues of 2-methoxy-oestradiol (2ME2), STX3451(2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), and STX2895 (7-Ethyl-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline) reduced tumour cell growth and induced apoptosis in malignant and benign human Neurofibromatosis 1 (NF1) tumour cells. In earlier NF1 mechanism of action studies we found that in addition to their effects on non-classical hormone-sensitive pathways, STX agents acted on the actin- and myosin-cytoskeleton, as well as PI3Kinase and MTOR signaling pathways. Tumour growth in NF2 cells is affected by different inhibitors from those affecting NF1 growth pathways: specifically, NF2 cells are affected by merlin-downstream pathway inhibitors. Because Merlin, the affected tumour suppressor gene in NF2, is also known to be involved in stabilizing membrane-cytoskeletal complexes, as well as in cell proliferation, and apoptosis, we looked for potentially common mechanisms of action in the agents’ effects on NF1 and NF2. We set out to determine whether STX agents could therefore also provide a prospective avenue for treatment of NF2. Methods STX3451 and STX2895 were tested in dose-dependent studies for their effects on growth parameters of malignant and benign NF2 human tumour cell lines in vitro. The mechanisms of action of STX3451 and STX2895 were also analysed. Results Although neither of the agents tested affected cell growth or apoptosis in the NF2 tumour cell lines tested through the same mechanisms by which they affect these parameters in NF1 tumour cell lines, both agents disrupted actin- and myosin-based cytoskeletal structures in NF2 cell lines, with subsequent effects on growth and cell death. Conclusions Both STX3451 and STX2895 provide new approaches for inducing cell death and lowering tumour burden in NF2 as well as in NF1, which both have limited treatment options.

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