A Glimpse in the Future of Malignant Mesothelioma Treatment

Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The landscape of effective therapy for this disease remained unchanged in the last two decades. Recently, however, the introduction of Immune Checkpoint Inhibitors (ICIs) led to small, but nevertheless, promising improvements. However, many efforts are still needed to radically improve the prognosis of MMe. In this review, we analyze all those therapeutic strategies for MMe that are still in a preclinical or early clinical phase of development. In particular, we focus on novel antiangiogenic drugs and their possible combination with immunotherapy. Furthermore, we describe also more complex strategies such as microRNA-loaded vectors, oncolytic viruses, and engineered lymphocytes

Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of malignant pleural mesothelioma (brief report)

Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease. Methods: We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan-Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients' overall survival (OS). Results: We detected positive staining of basigin, MCT1, and MCT4 in most MPM specimens. In particular, MCT4 was always positive in malignant tissues but undetectable in the 4 normal pleural specimens incorporated within the tissue microarray. This was confirmed in the additional series of 15 normal pleural samples. Moreover, MCT4 expression was significantly associated with reduced OS. Conclusion: In this study, the tissue expression of basigin did not prove to be exploitable as a diagnostic or prognostic marker for MPM patients. The expression of MCT1 was not informative either, being tightly correlated with that of basigin. However, the expression of MCT4 showed promise as a diagnostic/therapeutic and prognostic biomarker

Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state

Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER‑mitochondria communication and the balance between pro‑survival and pro‑death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA‑G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro‑apoptotic effects in estrogen receptor (ERα)‑positive breast cancer MCF‑7 and pro‑survival in triple negative breast cancer (TNBC) MDA‑MB‑231 cells. ATP generation was upregulated in PDIA1‑silenced MCF‑7 cells and downregulated in PDIA1‑silenced MDA‑MB‑231 cells in a manner dependent on the cellular redox status. Furthermore, MCF‑7 and MDA‑MB‑231 cells in the presence of PDIA1 expressed higher surface levels of the non‑classical human leukocyte antigen (HLA‑G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA‑G mRNA expression levels correlated with longer survival in both ERα‑positive and ERα‑negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA‑G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA‑G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA‑G mRNA and occurred predominantly in ERα‑positive breast cancer patients whereas in the same subgroup of the ERα‑negative breast cancer mainly this ratio was low PDIA1 and high HLA‑G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition

Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases.

Exposure to asbestos fibers is a major risk factor for malignant pleuralmesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on a1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes

Development of an RNA Interference Tool, Characterization of Its Target, and an Ecological Test of Caste Differentiation in the Eusocial Wasp Polistes

Recent advancements in genomics provide new tools for evolutionary ecological research. The paper wasp genus Polistes is a model for social insect evolution and behavioral ecology. We developed RNA interference (RNAi)-mediated gene silencing to explore proposed connections between expression of hexameric storage proteins and worker vs. gyne (potential future foundress) castes in naturally-founded colonies of P. metricus. We extended four fragments of putative hexamerin-encoding P. metricus transcripts acquired from a previous study and fully sequenced a gene that encodes Hexamerin 2, one of two proposed hexameric storage proteins of P. metricus. MALDI-TOF/TOF, LC-MSMS, deglycosylation, and detection of phosphorylation assays showed that the two putative hexamerins diverge in peptide sequence and biochemistry. We targeted the hexamerin 2 gene in 5th (last)-instar larvae by feeding RNAi-inducing double-stranded hexamerin 2 RNA directly to larvae in naturally-founded colonies in the field. Larval development and adult traits were not significantly altered in hexamerin 2 knockdowns, but there were suggestive trends toward increased developmental time and less developed ovaries, which are gyne characteristics. By demonstrating how data acquisition from 454/Roche pyrosequencing can be combined with biochemical and proteomics assays and how RNAi can be deployed successfully in field experiments on Polistes, our results pave the way for functional genomic research that can contribute significantly to learning the interactions of environment, development, and the roles they play in paper wasp evolution and behavioral ecology

An evaluation of the Wii Nunchuk as an alternative assistive device for people with intellectual and physical disabilities using switch controlled software

Many people with intellectual disabilities also have physical difficulties which prevent them from using standard computer control devices. Custom made alternative devices for those with special needs can be expensive and the low unit turnover makes the prospect unattractive to potential manufacturers. One solution is to explore the potential of devices used in contemporary gaming technology, such as the Nintendo Wii. The Wii Nunchuk has the potential to replace joystick functions with the advantages of not being surface bound and easier for some individuals to grasp. This study evaluated the feasibility of using the Nunchuk by comparing its performance as a switch with the participant's usual switch. Twenty three volunteers aged between 17 and 21 with intellectual and physical disabilities completed a Single Switch Performance Test using the new device and their familiar device. For most functions of the switch, there was no significant difference between the participants' performance using the Nunchuck and their familiar device. Additional analysis found that some participants' performance did improve whilst using the Nunchuck, but this was not significantly related to physical or cognitive ability. Those whose performance was better with the Nunchuk were more likely to hold it in the conventional way than were those who had better performance with their familiar device. This merits it being offered as a possible alternative to currently available switches for those with physical difficulties affecting their grip

Precision Measurement of the 29Si, 33S, and 36Cl Binding Energies

The binding energies of 29Si, 33S, and 36Cl have been measured with a relative uncertainty $< 0.59 \times 10^{-6}$ using a flat-crystal spectrometer. The unique features of these measurements are 1) nearly perfect crystals whose lattice spacing is known in meters, 2) a highly precise angle scale that is derived from first principles, and 3) a gamma-ray measurement facility that is coupled to a high flux reactor with near-core source capability. The binding energy is obtained by measuring all gamma-rays in a cascade scheme connecting the capture and ground states. The measurements require the extension of precision flat-crystal diffraction techniques to the 5 to 6 MeV energy region, a significant precision measurement challenge. The binding energies determined from these gamma-ray measurements are consistent with recent highly accurate atomic mass measurements within a relative uncertainty of $4.3 \times 10^{-7}$. The gamma-ray measurement uncertainties are the dominant contributors to the uncertainty of this consistency test. The measured gamma-ray energies are in agreement with earlier precision gamma-ray measurements.Comment: 13 pages, 4 figure

Diagnóstico molecular de huanglongbing dos citros, via qPCR, em mudas de valência sobre Swingle.

O HLB é, sem dúvidas, a grande ameaça da citricultura no país, por ser uma doença severa e destrutiva, com prejuízos no desenvolvimento da planta e na produção de frutos. Os agentes causais da doença são espécies da bactéria Candidatus Liberibacter spp., que se alojam em vasos do floema. Três espécies de Liberibacter estão associadas ao HLB dos citros: Ca. Liberibacter africanus, Ca. L. asiaticus e Ca. L. americanus, sendo as duas últimas de ocorrência no Brasil. A doença pode se propagar através de seu vetor, o psilídeo Diaphorina citri, e/ou por enxertia de tecidos infectados (Bové, 2006). O HLB não provoca a morte das plantas, mas, com o passar dos anos, elas se tornam debilitadas e improdutivas. Pomares inteiros podem ficar inviáveis economicamente dentro de sete a dez anos após o aparecimento da primeira planta sintomática se as medidas de controle não forem tomadas (Gottwald et al., 2007).O período de incubação do HLB depende de vários fatores, variando geralmente de seis a doze meses (Bové, 2006). Diante disso, a inspeção visual do pomar não representa o controle da doença, visto que plantas assintomáticas, porém infectadas, podem permanecer como fontes de inóculo para plantas ainda sadias. Como discutido por Bové (2006) e Gottwald et al. (2007), o conhecimento da proporção de plantas sintomáticas e assintomáticas é importante e deve ser utilizado na decisão da eliminação de pomares inteiros altamente infestados. Assim, a detecção de Ca. Liberibacter sp. precocemente é de extrema importância, pois minimiza, dentro do possível, o impacto financeiro aos citricultores com a erradicação das plantas.Hoje o método mais confiável para o diagnóstico do HLB é o PCR quantitativo em tempo real (qPCR), que amplifica e detecta o DNA bacteriano presente no tecido. O método visual é também utilizado, porém o diagnóstico é impreciso e pode levar a falsos negativos (plantas infectadas e ainda assintomáticas) ou falsos positivos, uma vez que os sintomas da doença podem ser facilmente confundidos com deficiência nutricional.pdf 186

Spectroscopic investigation of quantum confinement effects in ion implanted silicon-on-sapphire films

Crystalline Silicon-on-Sapphire (SOS) films were implanted with boron (B$^+$) and phosphorous (P$^+$) ions. Different samples, prepared by varying the ion dose in the range $10^{14}$ to 5 x $10^{15}$ and ion energy in the range 150-350 keV, were investigated by the Raman spectroscopy, photoluminescence (PL) spectroscopy and glancing angle x-ray diffraction (GAXRD). The Raman results from dose dependent B$^+$ implanted samples show red-shifted and asymmetrically broadened Raman line-shape for B$^+$ dose greater than $10^{14}$ ions cm$^{-2}$. The asymmetry and red shift in the Raman line-shape is explained in terms of quantum confinement of phonons in silicon nanostructures formed as a result of ion implantation. PL spectra shows size dependent visible luminescence at $\sim$ 1.9 eV at room temperature, which confirms the presence of silicon nanostructures. Raman studies on P$^+$ implanted samples were also done as a function of ion energy. The Raman results show an amorphous top SOS surface for sample implanted with 150 keV P$^+$ ions of dose 5 x $10^{15}$ ions cm$^{-2}$. The nanostructures are formed when the P$^+$ energy is increased to 350 keV by keeping the ion dose fixed. The GAXRD results show consistency with the Raman results.Comment: 9 Pages, 6 Figures and 1 Table, \LaTex format To appear in SILICON(SPRINGER

A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma

Simple Summary Malignant pleural mesothelioma (MPM) is a disease of the pleura related to asbestos exposure. Despite the advancements in new therapeutic frontiers, it has a dismal prognosis and very limited treatment options. To find novel weapons in the care of MPM, we undertook a drug-repurposing approach that consists of evaluating existing drugs already approved for other human diseases. We screened 1170 drugs, and we observed that cephalomannine, a taxane; ouabain, a cardiac glycoside; thonzonium bromide, an antifungal surfactant; and emetine, an emetic alkaloid, had marked activity against immortalized and patient-derived primary MPM cell lines. These compounds were shown to be promising, and they will be evaluated in further studies, both in vitro and in vivo. We believe that drug repurposing is a valuable strategy to facilitate and accelerate the definition of novel treatment options for the management of MPM. The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activation in all cancer lines tested. The proliferation was inhibited also on an extended panel of cell lines, including primary MPM cells. Thus, we suggest that cephalomannine, ouabain, thonzonium bromide, and emetine could represent novel candidates to be repurposed for improving the arsenal of therapeutic weapons in the fight against MPM