KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.

Stimulating immune responses to fight cancer: Basic biology and mechanisms

Chronic inflammation is now recognized as a major cause of malignant disease. In concert with various mechanisms (including DNA instability), hypoxia and activation of inflammatory bioactive lipid pathways and pro-inflammatory cytokines open the doorway to malignant transformation and proliferation, angiogenesis, and metastasis in many cancers. A balance between stimulatory and inhibitory signals regulates the immune response to cancer. These include inhibitory checkpoints that modulate the extent and duration of the immune response and may be activated by tumor cells. This contributes to immune resistance, especially against tumor antigen-specific T-cells. Targeting these checkpoints is an evolving approach to cancer immunotherapy, designed to foster an immune response. The current focus of these trials is on the programmed cell death protein 1 (PD-1) receptor and its ligands (PD-L1, PD-L2) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Researchers have developed anti-PD-1 and anti-PDL-1 antibodies that interfere with the ligands and receptor and allow the tumor cell to be recognized and attacked by tumor-infiltrating T-cells. These are currently being studied in lung cancer. Likewise, CTLA-4 inhibitors, which have had success treating advanced melanoma, are being studied in lung cancer with encouraging results.

HER2 positive gastric and gastroesophageal adenocarcinoma; An Irish tertiary center experience

Background: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2) over expression and gene amplification metastatic gastric cancer. Here we present the prevalence of HER2 positive gastric cancer in an Irish population, the use of Trastuzumab in first line and beyond progression. Methods: The study was conducted in St James's Hospital, Dublin. A retrospective analysis of the date of patients with HER2 positive gastric cancer over a period of 3 years was carried out. Her2 positive was defined as immunohistochemistry (IHC) score of +3, of IHC score of +2 and increased gene copy number by fluorescence in situ hybridization (FISH). Overall survival was calculated from the day of initiation of treatment with Trastuzumab until death. Results: During the study period 140 patients with gastric and gastro-esophageal junction adenocarcinoma were treated. Out of those, 30 (21.4%) had HER2 positive disease. Among HER2 positive disease patients 18 (12.8%) were treated with first line Trastuzumab containing regimen with a median overall survival of 13 months. Nine (50%) developed progressive disease while on Trastuzumab and of those, 4 (22.2%) patients continued on Trastuzumab beyond progression, two (11.1%) of whom achieved stable disease and a prolonged survival. Conclusion: HER2 positivity rate in an Irish population with advanced gastric and gastro-esophageal junction adenocarcinoma is 21.4%. Treatment with Trastuzumab in the first line in combination with chemotherapy is a reasonable approach. Continuation of Trastuzumab beyond progression is a feasible strategy that requires further exploration.

Epigenetic therapy in lung cancer and mesothelioma

Thoracic malignancies present a considerable global health burden with the incidence and mortality of both lung cancer and malignant pleural mesothelioma (MPM) increasing year on year. Survival rates are poor and treatment options are limited in these cancers. Several epigenetic modifications have been associated with the development of both of these diseases with alterations discriminating between MPM and adenocarcinoma (AC) of the lung. In addition, studies have suggested that epigenetic agents are effective in altering the cellular characteristics of lung and MPM cells in terms of proliferation and migration. Furthermore, it has been demonstrated that epigenetic therapy can alter a pathologically relevant gene expression profile, with one that is more associated with comparative normal tissue. Therefore agents, which target the epi-genomes of lung cancer and MPM, may provide a substantial therapeutic improvement when used in combination with current therapy or indeed benefit when used as a single treatment modality.

Targeting the fibroblast growth factor receptor family in cancer

Fibroblast growth factors (FGFs) regulate a plethora of biological functions, in both the embryonic and adult stages of development, binding their cognate receptors and thus activating a variety of downstream signalling pathways. Deregulation of the FGF/FGFR signalling axis, observed in multifarious tumor types including squamous non-small cell lung cancer, occurs through genomic FGFR alterations that drive ligand-independent receptor signalling or alterations that support ligand-dependent activation. Mutations are not restricted to the tyrosine kinase domain and aberrations appear to be tumor type dependent. As well as its complementarity and synergy with VEGF of particular interest is the interplay between FGFR and EGFR and the ability of these pathways to offer a compensatory signalling escape mechanism when either is inhibited. Hence there exists a rationale for a combinatorial approach to inhibition of these dysregulated pathways to reverse drug resistance. To date, several multi-target tyrosine kinase inhibitors as well as FGFR specific tyrosine kinase inhibitors (TKIs), monoclonal antibodies and FGF ligand traps have been developed. Promising preclinical data has resulted in several drugs entering clinical trials. This review explores aberrant FGFR and its potential as a therapeutic target in solid tumors.

VEGF-mediated cell survival in non-small-cell lung cancer: implications for epigenetic targeting of VEGF receptors as a therapeutic approach

Aims: To evaluate the potential therapeutic utility of histone deacetylase inhibitors (HDACi) in targeting VEGF receptors in non-small-cell lung cancer. Materials & methods: Non-small-cell lung cancer cells were screened for the VEGF receptors at the mRNA and protein levels, while cellular responses to various HDACi were examined. Results: Significant effects on the regulation of the VEGF receptors were observed in response to HDACi. These were associated with decreased secretion of VEGF, decreased cellular proliferation and increased apoptosis which could not be rescued by addition of exogenous recombinant VEGF. Direct remodeling of the VEGFR1 and VEGFR2 promoters was observed. In contrast, HDACi treatments resulted in significant downregulation of the Neuropilin receptors. Conclusion: Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for lung cancer patients in the clinical setting.

Metabolomic and proteomic analysis of breast cancer patient samples suggests that glutamate and 12-HETE in combination with CA15-3 may be useful biomarkers reflecting tumour burden

Evaluation of protein and metabolite expression patterns in blood using mass spectrometry and high-throughput antibody-based screening platforms has potential for the discovery of new biomarkers for managing breast cancer patient treatment. Previously identified blood-based breast cancer biomarkers, including cancer antigen 15.3 (CA15-3) are useful in combination with imaging (computed tomography scans, magnetic resonance imaging, X-rays) and physical examination for monitoring tumour burden in advanced breast cancer patients. However, these biomarkers suffer from insufficient levels of accuracy and with new therapies available for the treatment of breast cancer, there is an urgent need for reliable, non-invasive biomarkers that measure tumour burden with high sensitivity and specificity so as to provide early warning of the need to switch to an alternative treatment. The aim of this study was to identify a biomarker signature of tumour burden using cancer and non-cancer (healthy controls/non-malignant breast disease) patient samples. Results demonstrate that combinations of three candidate biomarkers from Glutamate, 12-Hydroxyeicosatetraenoic acid, Beta-hydroxybutyrate, Factor V and Matrix metalloproteinase-1 with CA15-3, an established biomarker for breast cancer, were found to mirror tumour burden, with AUC values ranging from 0.71 to 0.98 when comparing non-malignant breast disease to the different stages of breast cancer. Further validation of these biomarker panels could potentially facilitate the management of breast cancer patients, especially to assess changes in tumour burden in combination with imaging and physical examination.

Mutational analysis of the insulin‑like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

The insulin‑like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non‑small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well‑documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single‑nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16‑21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease‑free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.

Abnormal levels of heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) in tumour tissue and blood samples from patients diagnosed with lung cancer

Lung cancer is the second most common type of cancer in the world and is the most common cause of cancer-related death in both men and women. Research into causes, prevention and treatment of lung cancer is ongoing and much progress has been made recently in these areas, however survival rates have not significantly improved. Therefore, it is essential to develop biomarkers for early diagnosis of lung cancer, prediction of metastasis and evaluation of treatment efficiency, as well as using these molecules to provide some understanding about tumour biology and translate highly promising findings in basic science research to clinical application. In this investigation, two-dimensional difference gel electrophoresis and mass spectrometry were initially used to analyse conditioned media from a panel of lung cancer and normal bronchial epithelial cell lines. Significant proteins were identified with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), pyruvate kinase M2 isoform (PKM2), Hsc-70 interacting protein and lactate dehydrogenase A (LDHA) selected for analysis in serum from healthy individuals and lung cancer patients. hnRNPA2B1, PKM2 and LDHA were found to be statistically significant in all comparisons. Tissue analysis and knockdown of hnRNPA2B1 using siRNA subsequently demonstrated both the overexpression and potential role for this molecule in lung tumorigenesis. The data presented highlights a number of in vitro derived candidate biomarkers subsequently verified in patient samples and also provides some insight into their roles in the complex intracellular mechanisms associated with tumour progression.

Revisiting Coptotermes (Isoptera: Rhinotermitidae): a global taxonomic road map for species validity and distribution of an economically important subterranean termite genus

Coptotermes Wasmann (Isoptera: Rhinotermitidae) is one of the most economically important subterranean termite genera and some species are successful invaders. However, despite its important pest status, the taxonomic validity of many named Coptotermes species remains unclear. In this study, we reviewed all named species within the genus and investigated evidence supporting the validity of each named species. Species were systematically scrutinized according to the region of their original description: Southeast Asia, India, China, Africa, the Neotropics, and Australia. We estimate that of the currently 69 named species described by accepted nomenclatural rules, only 21 taxa have solid evidence for validity, 44 names have uncertain status, and the remaining species names should be synonymized or were made unavailable. Species with high degrees of invasiveness may be known under additional junior synonyms due to independent parochial descriptions. Molecular data for a vast majority of species are scarce and significant effort is needed to complete the taxonomic and phylogenetic revision of the genus. Because of the wide distribution of Coptotermes, we advocate for an integrative taxonomic effort to establish the distribution of each putative species, provide specimens and corresponding molecular data, check original descriptions and type specimens (if available), and provide evidence for a more robust phylogenetic position of each species. This study embodies both consensus and contention of those studying Coptotermes and thus pinpoints the current uncertainty of many species. This project is intended to be a roadmap for identifying those Coptotermes species names that need to be more thoroughly investigated, as an incentive to complete a necessary revision process.

Measurements of the top-quark mass using charged particle tracking

We present three measurements of the top-quark mass in the lepton plus jets channel with approximately 1.9 fb-1 of integrated luminosity collected with the CDF II detector using quantities with minimal dependence on the jet energy scale. One measurement exploits the transverse decay length of b-tagged jets to determine a top-quark mass of 166.9+9.5-8.5 (stat) +/- 2.9 (syst) GeV/c2, and another the transverse momentum of electrons and muons from W-boson decays to determine a top-quark mass of 173.5+8.8-8.9 (stat) +/- 3.8 (syst) GeV/c2. These quantities are combined in a third, simultaneous mass measurement to determine a top-quark mass of 170.7 +/- 6.3 (stat) +/- 2.6 (syst) GeV/c2.

Measurement of $d\sigma/dy$ of Drell-Yan $e^+e^-$ pairs in the $Z$ Mass Region from $p\bar{p}$ Collisions at $\sqrt{s}=1.96$ TeV

We report on a CDF measurement of the total cross section and rapidity distribution, $d\sigma/dy$, for $q\bar{q}\to \gamma^{*}/Z\to e^{+}e^{-}$ events in the $Z$ boson mass region ($66M_{ee}

Measurement of Particle Production and Inclusive Differential Cross Sections in pbar{p} Collisions at sqrt{s}=1.96 TeV

We report a set of measurements of particle production in inelastic pbar{p} collisions collected with a minimum-bias trigger at the Tevatron Collider with the CDF II experiment. The inclusive charged particle transverse momentum differential cross section is measured, with improved precision, over a range about ten times wider than in previous measurements. The former modeling of the spectrum appears to be incompatible with the high particle momenta observed. The dependence of the charged particle transverse momentum on the event particle multiplicity is analyzed to study the various components of hadron interactions. This is one of the observable variables most poorly reproduced by the available Monte Carlo generators. A first measurement of the event transverse energy sum differential cross section is also reported. A comparison with a Pythia prediction at the hadron level is performed. The inclusive charged particle differential production cross section is fairly well reproduced only in the transverse momentum range available from previous measurements. At higher momentum the agreement is poor. The transverse energy sum is poorly reproduced over the whole spectrum. The dependence of the charged particle transverse momentum on the particle multiplicity needs the introduction of more sophisticated particle production mechanisms, such as multiple parton interactions, in order to be better explained.

Measurement of particle production and inclusive differential cross sections in pp̅ collisions at √s=1.96 TeV

We report a set of measurements of particle production in inelastic pbar{p} collisions collected with a minimum-bias trigger at the Tevatron Collider with the CDF II experiment. The inclusive charged particle transverse momentum differential cross section is measured, with improved precision, over a range about ten times wider than in previous measurements. The former modeling of the spectrum appears to be incompatible with the high particle momenta observed. The dependence of the charged particle transverse momentum on the event particle multiplicity is analyzed to study the various components of hadron interactions. This is one of the observable variables most poorly reproduced by the available Monte Carlo generators. A first measurement of the event transverse energy sum differential cross section is also reported. A comparison with a Pythia prediction at the hadron level is performed. The inclusive charged particle differential production cross section is fairly well reproduced only in the transverse momentum range available from previous measurements. At higher momentum the agreement is poor. The transverse energy sum is poorly reproduced over the whole spectrum. The dependence of the charged particle transverse momentum on the particle multiplicity needs the introduction of more sophisticated particle production mechanisms, such as multiple parton interactions, in order to be better explained.