Malignant Mesothelioma: 189 (Recent Results in Cancer Research)
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The epidemiological studies suggested that both the cumulative exposure and the time since the first exposure to asbestos remain detrimental risk factors for development of malignant mesothelioma [ 4 ]. The epidemiological studies indeed reported on a long latency period of around 20 to 40 years between the exposure to asbestos and the disease manifestation [ 5 , 6 ].
Malignant pleural mesothelioma in general has poor prognosis with studies suggesting that without treatment the median survival is between 4 to 12 months [ 7 ].
Overall, the median life expectancy in patients with malignant pleural mesothelioma in the UK has been reported between 12 to 21 months [ 8 ]. As based on the recent guidelines recommendations, surgical intervention may only be appropriate for consideration in a relatively small proportion of patients with malignant mesothelioma [ 5 , 7 ]. In fact, in many patients the only intervention would be surgical or medical thoracoscopy, which is aimed to provide histological confirmation, drain the pleural effusion and allow for the pleurodesis to be performed [ 9 , 10 ].
A recent MesoVATS study showed that there was no difference in overall survival between patients with malignant mesothelioma undergoing medical pleurodesis or surgical Videoassisted thoracoscopic surgery VATS partial pleurectomy with the former having shorter hospital stay and fewer complications [ 9 ].
A proportion of patients mainly those with good performance status may be offered systemic treatment in the form of chemotherapy. The studies showed that this palliative chemotherapy approach might result in a median increase in survival in malignant mesothelioma in order of around 3 months [ 11 ]. The current approach to chemotherapy involves the use of Cisplatin and folate drug analogues [ 7 , 12 ].
A recommended combination of Pemetrexed and Cisplatin has been used as the first line chemotherapy for patients with malignant mesothelioma. Other agents that can be used for management of malignant mesothelioma include Gemcitabine, Carboplatin, Vinorelbine and Doxorubicin [ 13 - 15 ]. Carboplatin, which is a platinum based drug like Cisplatin and can also be used in combination with Pemetrexed for treatment of malignant mesothelioma [ 16 , 17 ].
Gemcitabine can be used as a second line chemotherapy or if Cisplatin or Carboplatin are not tolerated [ 16 , 18 ]. Another option may be to consider a re-treatment with Pemetrexed based chemotherapy [ 19 ]. There are studies that assessed other agents such as tyrosine kinase inhibitor Axitinib in combination with Cisplatin and Pemetrexed but unfortunately did not show any clinical benefits [ 21 ].
In another study, Amatuximab, which is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma, in combination with Pemetrexed and Cisplatin was assessed in patients with malignant mesothelioma and was shown to be well tolerated but the progression free survival was no different with historical data with median overall survival of One such strategy would be through the targeted treatments that work on the programmed cell death pathway that incorporates Programmed Death 1 PD-1 and Programmed Death Ligand 1 PD-L1 , which is an immune check point required for protecting the normal tissue from the immune attack by inhibiting the T-cell responses [ 23 , 24 ].
It has also an important role in tumor pathway and tumor response to the immune system. PD-1 receptor is present on the T lymphocytes and is a negative regulator by inhibiting and preventing overactive immune response. PD-L1 is a cell surface glycoprotein, which is mainly expressed by the antigen presenting cells of the immune system such as the activated T-cells.
Thus PD-L1 regulates the cellular response. PD-L1 is also expressed by a number of tumors such as non-small cell lung cancer, gastric or colorectal cancers. The PD-L1 has also been shown to be expressed in malignant mesothelioma [ 25 - 27 ]. For example, in a recent report Cedres, et al. In this particular study, PD-L1 was more commonly detected in non-epithelioid malignant mesothelioma and was associated with a poorer prognosis.
In another study, Nguyen, et al. The authors found that A simplified way of explaining these concepts would be that the PDL1 is a protein that assists cancer cells including malignant mesothelioma to avoid being detected by the immune system and by doing so it prevents the immune system from destroying malignant mesothelioma cells. Therefore, if malignant mesothelioma cells express the PD-L1 it is more likely to grow unchecked by the immune system hence leading to poorer outcomes and response to treatment. Malignant mesothelioma cells may take advantage of this immune check point by interacting with the PD-1 on the T-cells and blocking its cytolytic activity by inhibition of its proliferation.
In fact, this approach is considered to be very promising in the context of improving long-term survival outcomes for a number of cancer types. In general, these agents are called the immune checkpoint inhibitors. Their role has increasingly been assessed in the context of managing malignant mesothelioma. One example of such an agent is Pembrolizumab, which is a highly selective humanised monoclonal IgG4 anti-body directed against the PD-1 receptor on the cell surface [ 23 , 24 ].
As a result Pembrolizumab prevents binding and subsequent activation of the PD-L1, which in turn causes activation of the T-cell mediated immune response against the tumor. Patients received Pembrolizumab for up to 2 years or until there was confirmed progression of the disease or unacceptable toxicity. More importantly the response was durable with the median response duration of 12 months. The authors concluded that overall Pembrolizumab was well tolerated and might confer anti-tumor activity in patients with PD-L1 positive malignant pleural mesothelioma.
In addition, to Pembrolizumab there are other immunotherapy agents currently under investigation for the potential future treatment options for patients with malignant mesothelioma [ 30 , 31 ]. Preclinical studies have supported the rationale for current clinical development of agents working on the Cytotoxic T lymphocyte antigen-4 CTLA-4 , which is a protein receptor that down-regulates the immune system and is a key negative regulator of T-cell activation, in the form of anti- CTLA-4 antibodies [ 32 ].
New Perspectives on Diagnosis and Therapy of Malignant Pleural Mesothelioma
Tremelimumab, which is a human monoclonal antibody against CTLA-4, has been tested in the clinical trials as novel therapeutic agents to augment anti-tumor immunity in cancer. Recently, Maio, et al. Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of Tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors.
In addition, there are ongoing investigations into whether immunotherapy combination regimens can provide greater efficacy than mono-therapies in malignant mesotheliom [ 30 , 31 , 34 , 35 ]. The patients with combined treatments showed better response rates but had more frequent adverse events. These studies together with other ongoing trials into the role of immunotherapy in malignant mesothelioma will provide hopefully more information into timing, efficacy and toxicity profile of the immunotherapy agents [ 30 , 31 ].
In conclusion, malignant mesothelioma is a very aggressive form of cancer. The conventional chemotherapy regimens seem to have some survival advantage. J Clin Respir Dis Care 4: DOI: MPM is one of a few cancers that harbor mutations in Hippo pathway genes [ 33 ]. NF2 is an upstream regulator of the Hippo pathway. This leads to the YAP shuttling into the cell nucleus, favouring an unregulated interaction with TEAD family transcription factors; thereby promoting tumorigenesis [ 33 , 41 , 42 ].
Filipendula hexapetala Gilib dropwort, syn. Filipendula vulgaris Moench belongs to genus Filipendula Rosaceae.
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It is known for its analgesic, antirheumatic, anti-inflammatory and diuretic effects [ 47 , 48 ]. Several evidences have reported other properties of the plant as antimicrobial, antigenotoxic, antioxidant [ 49 , 50 ] and hepatoprotective effects [ 51 ]. We also show that a standardized extract from Dropwort Filipendula vulgaris , Fil.
At the end of the extraction time, flowers are removed from the obtained rich hydroalcoholic solution by filtration. The obtained solution is concentrated by Thin-Film evaporation until the ethanol is removed. Concentrated aqueous solution is dried in a freeze-drier equipment until a solid cake is obtained. Freeze-dried cake is reduced to a powder using a hammer mill and blended to obtain a homogeneous freeze-dried extract powder. A homogeneous sample of each single lot is taken for Quality Control testing.
The freeze-dried extract is submitted to a complete characterization of their composition by means of metabolomic analysis MS-HPLC and by quantitative analysis of the main chemical classes of compounds phenols, phenolic acids, flavonoids, lignins, tannins, pheylpropanoid derivatives, salicilates, fat, proteins, amino acids, minerals, polysaccharides together with the most important single chemical compounds [ 52 ].
Each plate was evaluated immediately on a microplate reader Expire Technology, Perkin Elmer. Calcusyn software was used to calculate combination index CI [ 53 ]. Sixteen hours later, cells were detached and seeded at cells per 6 well into six-well dishes Corning-Costar, Tewksbury, MA, USA in drug-free media. Cells were suspended in 0. Migrated cells that attached to the outside of the filter were visualized by staining with DAPI Thermo Fisher and counted. The average number of cells per field was expressed as percentage of the control after normalizing for cell number.
PBS washing was used to remove loosely attached cells.
Malignant Pleural Mesothelioma (references)
The progression of migration was photographed at different under a light microscope. The number of cells migrated into the scratched area was calculated. In the co-immunoprecipitation the lysis buffer was modified accordingly the protein isoelectric point. All the indicated antibodies were used at the minimum dilutions suggested by the manufacturer.
Secondary horseradish peroxidase-conjugated was purchased from Santa Cruz. The Uvitec Alliance software Eppendorf was used to quantify the obtained data. A number of 1. Protein extracts were immunoprecipitated as described and subjected to Western Blotting. Georg Halder. Cells were incubated overnight with the indicated antibody.
Each free induction decay FID was Fourier transformed after a multiplication with sine-bell window functions in both dimensions. The exported p-JRES were aligned, corrected for baseline offset and then reduced into spectral bins with widths ranging from 0. This method sets the bucket divisions at local minima within the spectra to ensure that each resonance is in the same bin throughout all spectra. The area within each spectral bin was integrated and, to compare the spectra, the integrals derived from the bucketing procedure were normalized to the total integral region.
Metabolites were identified using an in-house NMR database and literature data and confirmed by 2D homo- and hetero-nuclear NMR spectroscopy. The 1D skyline projections exported were aligned and then reduced into spectral bins with ranging from 0. To compare the spectra, the integrals derived from the binning procedure were normalized to the total integral region, following exclusion of bins representing the residual water peak 4. Sunnyvale, CA , contains antibodies.
Each of the antibodies has two replicates that are printed on a coated glass microscope slide, along with multiple positive and negative controls. The antibody array experiment was performed using Full Moon Biosystems, according to their established protocol. The antibody microarray slides were first blocked with a blocking solution Full Moon Biosystems, Inc.
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The slides were then incubated with the biotin-labeled cell lysates in coupling solution Full Moon Biosystems, Inc. The fluorescence signal of each antibody was obtained from the fluorescence intensity of this antibody spot after subtraction of the blank signal spot in the absence of antibody [ 55 ].