Emerging Avenues Immunotherapy for the Management of Malignant Pleural Mesothelioma

Background: The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Main text: While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/ PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may afect the clinical outcomes of such therapies in this cancer. Conclusions: The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term beneft to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratifcation, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer

The eyes have it?-intra- and inter-observer reproducibility of the PD-L1 companion diagnostic assay

No abstract available

Pre-clinical models of small cell lung cancer and the validation of therapeutic targets

Introduction: Small-cell lung cancer (SCLC) is an aggressive form of lung cancer that has a dismal prognosis. One of the factors hindering therapeutic developments for SCLC is that most SCLC is not surgically resected resulting in a paucity of material for analysis. To address this, significant efforts have been made by investigators to develop pre-clinical models of SCLC allowing for downstream target identification in this difficult to treat cancer. Areas covered: In this review, we describe the current pre-clinical models that have been developed to interrogate SCLC, and outline the benefits and limitations associated with each. Using examples we show how each has been used to (i) improve our knowledge of this intractable cancer, and (ii) identify and validate potential therapeutic targets that (iii) are currently under development and testing within the clinic. Expert opinion: The large numbers of preclinical models that have been developed have dramatically improved the ways in which we can examine SCLC and test therapeutic targets/interventions. The newer models are rapidly providing novel avenues for the design and testing of new therapeutics. Despite this many of these models have inherent flaws that limit the possibility of their use for individualized therapy decision-making for SCLC

Epigenetics Underpinning the Regulation of the CXC (ELR+) Chemokines in Non-Small Cell Lung Cancer

Background: Angiogenesis may play a role in the pathogenesis of Non-Small Cell Lung cancer (NSCLC). The CXC (ELR+) chemokine family are powerful promoters of the angiogenic response. Methods: The expression of the CXC (ELR+) family members (CXCL1-3/GROα-γ, CXCL8/IL-8, CXCR1/2) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of these chemokines was examined in normal bronchial epithelial and NSCLC cell lines. Results: Overall, expression of the chemokine ligands (CXCL1, 2, 8) and their receptors (CXCR1/2) were down regulated in tumour samples compared with normal, with the exception of CXCL3. CXCL8 and CXCR1/2 were found to be epigenetically regulated by histone post-translational modifications. Recombinant CXCL8 did not stimulate cell growth in either a normal bronchial epithelial or a squamous carcinoma cell line (SKMES-1). However, an increase was observed at 72 hours post treatment in an adenocarcinoma cell line. Conclusions: CXC (ELR+) chemokines are dysregulated in NSCLC. The balance of these chemokines may be critical in the tumour microenvironment and requires further elucidation. It remains to be seen if epigenetic targeting of these pathways is a viable therapeutic option in lung cancer treatment. © 2011 Baird et al

Long noncoding RNAs in liver cancer: what we know in 2014.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with an estimated over half a million new cases diagnosed annually. Due to the difficulty in early diagnosis and lack of effective treatment options, HCC is currently ranked as the second highest neoplastic-related mortality in the world, with an extremely low 5-year survival rate of between 6 and 11%. Long noncoding RNAs (lncRNAs), are genes lacking protein coding ability, have recently emerged as pivotal participants in biological processes, often dysregulated in a range of cancers, including HCC. AREAS COVERED: In this review, we highlight the recent findings of lncRNAs in HCC pathogenesis, with particular attention on epigenetic events. In silico analysis was utilized to emphasize intrinsic linkages within the ncRNA families associated with hepatocarcinogenesis. EXPERT OPINION: While our understanding of lncRNAs in the onset and progression of HCC is still in its infancy, there is no doubt that understanding the activities of ncRNAs will certainly secure strong biomarkers and improve treatment options for HCC patients

Sinapinic and protocatechuic acids found in rapeseed: isolation, characterisation and potential benefits for human health as functional food ingredients

peer-reviewedRapeseed is one of the world’s major oilseeds, and rapeseed oil is produced by pressing of the seeds. This process results in the production of a low-economic-value by-product, rapeseed meal, which is commonly used as animal feed. Rapeseed meal is rich in bioactive phenolic compounds, including sinapinic acid (SA) and protocatechuic acid (PCA). Isolation of these bioactive compounds from a by-product of rapeseed oil production is largely in agreement with the current concept of the circular economy and total utilisation of crop harvest using a biorefinery approach. In this review, current information concerning traditional and novel methods to isolate phenolic compounds – including SA and PCA – from rapeseed meal, along with in vitro and in vivo studies concerning the bioactivity of SA and PCA and their associated health effects, is collated. These health effects include anti-inflammatory, anti-cancer, anti-diabetes activities, along with histone deacetylase inhibition and protective cardiovascular, neurological and hepatic effects. The traditional extraction methods include use of solvents and/or enzymes. However, a need for simpler, more efficient methodologies has led to the development of novel extraction processes, including microwave-assisted, ultrasound-assisted, pulsed electric field and high-voltage electrical discharge extraction processes

Carcinogenesis in Prostate Cancer: The role of Long Non-Coding RNAs

LncRNAs appear to play a considerable role in tumourigenesis through regulating key processes in cancer cells such as proliferative signalling, replicative immortality, invasion and metastasis, evasion of growth suppressors, induction of angiogenesis and resistance to apoptosis. LncRNAs have been reported to play a role in prostate cancer, particularly in regulating the androgen receptor signalling pathway. In this review article, we summarise the role of 34 lncRNAs in prostate cancer with a particular focus on their role in the androgen receptor signalling pathway and the epithelial to mesenchymal transition pathway

First determination of the strange and light quark masses from full lattice QCD

We compute the strange quark mass $m_s$ and the average of the $u$ and $d$ quark masses $\hat m$ using full lattice QCD with three dynamical quarks combined with experimental values for the pion and kaon masses. The simulations have degenerate $u$ and $d$ quarks with masses $m_u=m_d\equiv \hat m$ as low as $m_s/8$, and two different values of the lattice spacing. The bare lattice quark masses obtained are converted to the \msbar scheme using perturbation theory at $O(alpha_s)$. Our results are: m_s^\msbar(2 GeV) = 76(0)(3)(7)(0) MeV, \hat m^\msbar(2 GeV) = 2.8(0)(1)(3)(0) MeV and $m_s/\hat m$ = 27.4(1)(4)(0)(1), where the errors are from statistics, simulation, perturbation theory, and electromagnetic effects, respectively.Comment: 5 pages, revtex, 2 figures. v2: New ms/hat(m) discussion and reference, v3: slight change in discussion of referenc

Diesel exhaust particulate induces pulmonary and systemic inflammation in rats without impairing endothelial function ex vivo or in vivo

<p>Abstract</p> <p>Background</p> <p>Inhalation of diesel exhaust impairs vascular function in man, by a mechanism that has yet to be fully established. We hypothesised that pulmonary exposure to diesel exhaust particles (DEP) would cause endothelial dysfunction in rats as a consequence of pulmonary and systemic inflammation.</p> <p>Methods</p> <p>Wistar rats were exposed to DEP (0.5 mg) or saline vehicle by intratracheal instillation and hind-limb blood flow, blood pressure and heart rate were monitored <it>in situ </it>6 or 24 h after exposure. Vascular function was tested by administration of the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) <it>in vivo </it>and <it>ex vivo </it>in isolated rings of thoracic aorta, femoral and mesenteric artery from DEP exposed rats. Bronchoalveolar lavage fluid (BALF) and blood plasma were collected to assess pulmonary (cell differentials, protein levels & interleukin-6 (IL-6)) and systemic (IL-6), tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP)) inflammation, respectively.</p> <p>Results</p> <p>DEP instillation increased cell counts, total protein and IL-6 in BALF 6 h after exposure, while levels of IL-6 and TNFα were only raised in blood 24 h after DEP exposure. DEP had no effect on the increased hind-limb blood flow induced by ACh <it>in vivo </it>at 6 or 24 h. However, responses to SNP were impaired at both time points. In contrast, <it>ex vivo </it>responses to ACh and SNP were unaltered in arteries isolated from rats exposed to DEP.</p> <p>Conclusions</p> <p>Exposure of rats to DEP induces both pulmonary and systemic inflammation, but does not modify endothelium-dependent vasodilatation. Other mechanisms <it>in vivo </it>limit dilator responses to SNP and these require further investigation.</p