Publications by authors named "José Luis Ramírez"

98 Publications

Natural malaria infection in anophelines vectors and their incrimination in local malaria transmission in Darién, Panama.

PLoS One 2021 3;16(5):e0250059. Epub 2021 May 3.

Departamento de Investigación en Entomología Médica, Instituto Conmemorativo Gorgas de Estudios de la Salud (ICGES), Panam, Repblica de Panam.

Background: More than 85% of the malaria cases in Panama occur in poor, rural and indigenous regions like Darien Province. Vector diversity, infection rate and spatial distribution are important entomological parameters of malaria transmission dynamics. Their understanding is crucial for the development of effective disease control strategies. The objective of this study was to determine the composition of Anopheles species, their natural infection rate and their geographic distribution to better understand the malaria transmission dynamics in Darién, Panama.

Methods: Anophelines mosquitoes were captured during the rainy and dry season of 2016. We selected five communities where adult anophelines were collected using CDC light-traps, and through protective human-baited traps. Detection of natural infection and Plasmodium genotype were detected via nested PCR through the amplification of ssrRNA and the circumsporozoite protein gene (csp), respectively.

Results: A total of 1,063 mosquitoes were collected mosquitoes were collected for the detection of natural infection with Plasmodium spp. Nine Anophelines species were identified, with the predominant species being: An. (Nys.) darlingi (45.0%) and An. (Nys.) albimanus (42.6%). Natural infection in An. (Nys.) albimanus with P. vivax was detected in one mosquito pool from the community Pueblo Tortuga (0.6%), three from Marraganti (1.7%), two from Bajo Chiquito (1.1%) and three pools from Alto Playona 3 (1.7%). For An. (Nys.) darlingi mosquitoes, we detected seven positive pools from the community Bajo Chiquito (4.0%), two pools from Marraganti (1.1%) and two pools from Alto Playona (1.1%). The P. vivax allelic variant VK210 was detected in infected mosquitoes.

Conclusion: The results from this study provide new information on the transmission dynamics associated with anophelines vectors in the Darién region. This is the first report of natural P. vivax infection in An. (Nys.) darlingi and its incrimination as a potential malaria vector in this region of Panama. Additional studies are necessary to expand our knowledge and determine crucial parameters in malaria transmission in Darién, which in turn will aid the National Malaria Program in attaining an adequate malaria control strategy towards malaria elimination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250059PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092770PMC
May 2021

Transcriptional Responses of Blastospores Cultured Under Varying Glucose Concentrations.

Front Cell Infect Microbiol 2021 24;11:644372. Epub 2021 Mar 24.

Crop Bioprotection Research Unit, National Center for Agricultural Utilization Research, United States Department of Agriculture, Agriculture Research Service, Peoria, IL, United States.

Culturing the entomopathogenic fungus, , under high glucose concentrations coupled with high aeration results in a fungal developmental shift from hyphal growth to mostly blastospores (yeast-like cells). The underlying molecular mechanisms involved in this shift remain elusive. A systematic transcriptome analysis of the differential gene expression was preformed to uncover the fungal transcriptomic response to osmotic and oxidative stresses associated with the resulting high blastospore yield. Differential gene expression was compared under moderate (10% w/v) and high (20% w/v) glucose concentrations daily for three days. The RNAseq-based transcriptomic results depicted a higher proportion of downregulated genes when the fungus was grown under 20% glucose than 10%. Additional experiments explored a broader glucose range (4, 8, 12, 16, 20% w/v) with phenotype assessment and qRT-PCR transcript abundance measurements of selected genes. Antioxidant, calcium transport, conidiation, and osmosensor-related genes were highly upregulated in higher glucose titers (16-20%) compared to growth in lower glucose (4-6%) concentrations. The class 1 hydrophobin gene () was highly expressed throughout the culturing. is known to be involved in spore coat rodlet layer assembly, and indicates that blastospores or another cell type containing hydrophobin 1 is expressed in the haemocoel during the infection process. Furthermore, we found implications of the HOG signaling pathway with upregulation of homologous genes and for all fermentation time points under hyperosmotic medium (20% glucose). These findings expand our knowledge of the molecular mechanisms behind blastospore development and may help facilitate large-scale industrial production of blastospores for pest control applications.
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http://dx.doi.org/10.3389/fcimb.2021.644372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024584PMC
March 2021

Assessment of scattered radiation from hand-held dental X-ray equipment using the Monte Carlo method.

J Radiol Prot 2021 Mar 31. Epub 2021 Mar 31.

Metrologia das Radiações, Instituto de Pesquisas Energeticas e Nucleares, Sao Paulo, SP, BRAZIL.

The objective of the present study was to evaluate the intensity and spatial distribution of scattered radiation caused by the use of hand-held x-ray equipment in the zone occupied by the operator using the Monte Carlo simulation for radiographic views of the upper and lower incisor teeth and the consequent evaluation of the equivalent dose in the lens. In order to carry out this evaluation, the geometry of a typical dental facility with plaster walls containing the scattering object was used for the computational scenario implemented for the Monte Carlo method simulation. The PENELOPE code for Monte Carlo simulation of electron and photon transport was used with the radiation beam represented by a 60 kV spectrum; 1.5 mm Al and tungsten target. The simulations were carried out with typical parameters for workload and the number of radiographs/week. The results demonstrated that the exposure levels varied significantly according to the angle of the x-ray beam and with the distance to the scattering object. It is concluded that the incorporation of hand-held equipment in dental radiology must be accompanied by surveillance of occupational exposure levels and a review of the training structure of professionals in dental radiology regarding aspects of radiological protection and the particularities of using this type of equipment.
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http://dx.doi.org/10.1088/1361-6498/abf3cdDOI Listing
March 2021

Wolbachia in mosquitoes from the Central Valley of California, USA.

Parasit Vectors 2020 Nov 10;13(1):558. Epub 2020 Nov 10.

Public Health, University of California, 5200 North Lake Road, Merced, CA, 95343, USA.

Background: Wolbachia bacteria are widely distributed throughout terrestrial arthropod species. These bacteria can manipulate reproduction and influence the vector competence of their hosts. Recently, Wolbachia have been integrated into vector control programmes for mosquito management. A number of supergroups and strains exist for Wolbachia, and they have yet to be characterized for many mosquito species. In this study, we examined Wolbachia prevalence and their phylogenetic relationship to other Wolbachia, using mosquitoes collected in Merced County in the Central Valley of California.

Methods: Adult mosquitoes were collected from 85 sites in Merced County, California in 2017 and 2018. Traditional and quantitative PCR were used to investigate the presence or absence and the density of Wolbachia, using Wolbachia-specific 16S rRNA and Wolbachia-surface protein (wsp) genes. The supergroup of Wolbachia was determined, and Multilocus Sequence Typing (MLST) by sequencing five housekeeping genes (coxA, gatB, ftsZ, hcpA and fbpA) was also used to determine Wolbachia supergroup as well as strain.

Results: Over 7100 mosquitoes of 12 species were collected: Aedes melanimon, Ae. nigromaculis, Ae. vexans, Ae. aegypti, Culex pipiens, Cx. stigmatosoma, Cx. tarsalis, Anopheles franciscanus, An. freeborni, An. punctipennis, Culiseta incidens and Cs. inornata. Eight showed evidence of Wolbachia. To our knowledge, this study is the first to report detection of Wolbachia in five of these species (Ae. melanimon, Cx. stigmatosoma, Cx. tarsalis, Cs. incidens and Cs. inornata). Culex pipiens and Cx. stigmatosoma had a high frequency and density of Wolbachia infection, which grouped into supergroup B; Cs. inornata clustered with supergroup A. MLST comparisons identified Cx. pipiens and Cx. stigmatosoma as wPip strain type 9 supergroup B. Six species had moderate to low (< 14%) frequencies of Wolbachia. Four species were negative, Ae. nigromaculis, An. franciscanus, An. freeborni and Ae. aegypti.

Conclusions: New records of Wolbachia detection were found in mosquitoes from Merced County, California. Culex stigmatosoma and Cs. inornata were new records for Wolbachia supergroup B and A, respectively. Other species with Wolbachia occurred with low frequency and low density. Detection of Wolbachia in mosquitoes can be used to inform potential vector control applications. Future study of Wolbachia within Cx. stigmatosoma and Cs. inornata in California and through the range of these species could further explore Wolbachia infection in these two species.
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http://dx.doi.org/10.1186/s13071-020-04429-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653878PMC
November 2020

Genomic Organization and Generation of Genetic Variability in the RHS (Retrotransposon Hot Spot) Protein Multigene Family in .

Genes (Basel) 2020 09 17;11(9). Epub 2020 Sep 17.

Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, SP, Brazil.

Retrotransposon Hot Spot (RHS) is the most abundant gene family in with unknown function in this parasite. The aim of this work was to shed light on the organization and expression of RHS in The diversity of the RHS protein family in was demonstrated by phylogenetic and recombination analyses. Transcribed sequences carrying the RHS domain were classified into ten distinct groups of monophyletic origin. We identified numerous recombination events among the RHS and traced the origins of the donors and target sequences. The transcribed RHS genes have a mosaic structure that may contain fragments of different RHS inserted in the target sequence. About 30% of RHS sequences are located in the subtelomere, a region very susceptible to recombination. The evolution of the RHS family has been marked by many events, including gene duplication by unequal mitotic crossing-over, homologous, as well as ectopic recombination, and gene conversion. The expression of RHS was analyzed by immunofluorescence and immunoblotting using anti-RHS antibodies. RHS proteins are evenly distributed in the nuclear region of replicative forms (amastigote and epimastigote), suggesting that they could be involved in the control of the chromatin structure and gene expression, as has been proposed for .
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http://dx.doi.org/10.3390/genes11091085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563717PMC
September 2020

Mosquito cellular immunity at single-cell resolution.

Science 2020 08;369(6507):1128-1132

Wellcome Sanger Institute, Hinxton, Cambridge CB10 2AZ, UK.

Hemocytes limit the capacity of mosquitoes to transmit human pathogens. Here we profile the transcriptomes of 8506 hemocytes of and mosquito vectors. Our data reveal the functional diversity of hemocytes, with different subtypes of granulocytes expressing distinct and evolutionarily conserved subsets of effector genes. A previously unidentified cell type in , which we term "megacyte," is defined by a specific transmembrane protein marker (TM7318) and high expression of lipopolysaccharide-induced tumor necrosis factor-α transcription factor 3 (LL3). Knockdown experiments indicate that LL3 mediates hemocyte differentiation during immune priming. We identify and validate two main hemocyte lineages and find evidence of proliferating granulocyte populations. This atlas of medically relevant invertebrate immune cells at single-cell resolution identifies cellular events that underpin mosquito immunity to malaria infection.
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http://dx.doi.org/10.1126/science.abc0322DOI Listing
August 2020

Genome 15 Years Later: What Has Been Accomplished?

Trop Med Infect Dis 2020 Aug 6;5(3). Epub 2020 Aug 6.

Instituto de Estudios Avanzados, Caracas, Venezuela and Universidad Central de Venezuela, Caracas 1080, Venezuela.

On 15 July 2020 was the 15th anniversary of the Magazine issue that reported three trypanosomatid genomes, namely , , and . That publication was a milestone for the research community working with trypanosomatids, even more so, when considering that the first draft of the human genome was published only four years earlier after 15 years of research. Although nowadays, genome sequencing has become commonplace, the work done by researchers before that publication represented a huge challenge and a good example of international cooperation. Research in neglected diseases often faces obstacles, not only because of the unique characteristics of each biological model but also due to the lower funds the research projects receive. In the case of the etiologic agent of Chagas disease, the first genome draft published in 2005 was not complete, and even after the implementation of more advanced sequencing strategies, to this date no final chromosomal map is available. However, the first genome draft enabled researchers to pick genes a la carte, produce proteins in vitro for immunological studies, and predict drug targets for the treatment of the disease or to be used in PCR diagnostic protocols. Besides, the analysis of the genome is revealing unique features about its organization and dynamics. In this work, I briefly summarize the actions of Latin American researchers that contributed to the first publication of the genome and discuss some features of the genome that may help to understand the parasite's robustness and adaptive capabilities.
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http://dx.doi.org/10.3390/tropicalmed5030129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559697PMC
August 2020

Nifurtimox response of isolates from an outbreak of Chagas disease in Caracas, Venezuela.

J Vector Borne Dis 2019 Jul-Sep;56(3):237-243

Sección de Inmunología, Instituto de Medicina Tropical, Facultad de Medicina, Universidad Central de Venezuela (IMT-FM-UCV), Caracas, Venezuela.

Background & Objectives: In Venezuela, Chagas disease (ChD) is considered a serious health problem, with about 6 million people at risk; and acute outbreaks due to oral transmission of Chagas Disease (OChD) are becoming increasingly important. In 2007 there was a major outbreak of OChD and although patients from this episode were treated with nifurtimox (Lampit®-Bayer), about 70% therapeutic failure was registered. These results led us to examine whether parasite's drug susceptibility was related to this therapeutic failure.

Methods: The Trypanosoma cruzi parasites were isolated by haemoculture of the peripheral blood drawn from the pre- and post-nifurtimox treated patients infected in the 2007 OChD outbreak at Caracas, Venezuela. The in vitro assays for drug testing were performed by the MTT methodology followed by calculation of inhibitory concentration-50 (IC) values.

Results: Parasite isolates obtained from the infected patients prior and after nifurtimox treatment when subjected to variable concentrations of the drug showed great heterogeneity in susceptibility with IC values ranging from 4.07 ± 1.82 to 94.92 ± 7.24 μM.

Interpretation & Conclusion: The high heterogeneity in nifurtimox IC values in the isolates and clones from the OChD patients, suggests that the therapeutic failure to nifurtimox could be due in part to a phenotypic variability that existed in the wild parasite population at the original source of contamination. Though, further pharmacological studies are needed to confirm the existence of natural nifurtimox resistance in the parasite.
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http://dx.doi.org/10.4103/0972-9062.289397DOI Listing
August 2020

An Evolutionary View of Telomeres.

Front Cell Infect Microbiol 2019 10;9:439. Epub 2020 Jan 10.

Fundación Instituto de Estudios Avanzados and United Nations University UNU-BIOLAC, Caracas, Venezuela.

Like in most eukaryotes, the linear chromosomes of end in a nucleoprotein structure called the telomere, which is preceded by regions of variable length called subtelomeres. Together telomeres and subtelomeres are dynamic sites where DNA sequence rearrangements can occur without compromising essential interstitial genes or chromosomal synteny. Good examples of subtelomeres involvement are the expansion of human olfactory receptors genes, variant surface antigens in , and mating types. telomeres are made of long stretches of the hexameric repeat 5'-TTAGGG-OH-3', and its subtelomeres are enriched in genes and pseudogenes from the large gene families RHS, TS and DGF1, DEAD/H-RNA helicase and N-acetyltransferase, intermingled with sequences of retrotransposons elements. In particular, members of the Trans-sialidase type II family appear to have played a role in shaping the current telomere structure. Although the structure and function of telomeric and subtelomeric regions have been documented, recent experiments are providing new insights into 's telomere-subtelomere dynamics. In this review, I discuss the co-evolution of telomere, subtelomeres and the TS gene family, and the role that these regions may have played in shaping 's genome.
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http://dx.doi.org/10.3389/fcimb.2019.00439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967402PMC
September 2020

Performance of Flexible Chemoresistive Gas Sensors after Having Undergone Automated Bending Tests.

Sensors (Basel) 2019 Nov 27;19(23). Epub 2019 Nov 27.

Departament d'Enginyeria Electrònica, Elèctrica i Automàtica, ETSE, Universitat Rovira i Virgili, Av. Països Catalans 26, 43007 Tarragona, Spain.

Many sensors are developed over flexible substrates to be used as wearables, which does not guarantee that they will actually withstand being bent. This work evaluates the gas sensing performance of metal oxide devices of three different types, before and after having undergone automated, repetitive bending tests. These tests were aimed at demonstrating that the fabricated sensors were actually flexible, which cannot be taken for granted beforehand. The active layer in these sensors consisted of WO nanowires (NWs) grown directly over a Kapton foil by means of the aerosol-assisted chemical vapor deposition. Their response to different H concentrations was measured at first. Then, they were cyclically bent, and finally, their response to H was measured again. Sensors based on pristine WO-NWs over Ag electrodes and on Pd-decorated NWs over Au electrodes maintained their performance after having been bent. Ag electrodes covered with Pd-decorated NWs became fragile and lost their usefulness. To summarize, two different types of truly flexible metal oxide gas sensor were fabricated, whereas a third one was not flexible, despite being grown over a flexible substrate following the same method. Finally, we recommend that one standard bending test procedure should be established to clearly determine the flexibility of a sensor considering its intended application.
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http://dx.doi.org/10.3390/s19235190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928898PMC
November 2019

Pyrosequencing versus methylation-specific PCR for assessment of MGMT methylation in tumor and blood samples of glioblastoma patients.

Sci Rep 2019 07 31;9(1):11125. Epub 2019 Jul 31.

Medical Oncology Service, Catalan Institute of Oncology Badalona, Hospital Germans Trias i Pujol, Applied Research Group in Oncology (B-ARGO Group), Badalona, Spain.

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.
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http://dx.doi.org/10.1038/s41598-019-47642-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668570PMC
July 2019

Mosquito Midgut Prostaglandin Release Establishes Systemic Immune Priming.

iScience 2019 Sep 12;19:54-62. Epub 2019 Jul 12.

Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA. Electronic address:

Anopheles gambiae mosquitoes that have been infected with Plasmodium mount a more effective immune response to a subsequent infection. Priming is established when Plasmodium invasion of the mosquito midgut allows contact of the gut microbiota with epithelial cells. This event is followed by a systemic release of a hemocyte differentiation factor (HDF) consisting of Lipoxin A4 bound to Evokin, a lipocalin carrier, which increases the proportion of circulating hemocytes. We show that mosquito midgut cells produce and release prostaglandin E2 (PGE2), which attracts hemocytes to the midgut surface and enhances their patrolling activity. Systemic injection of prostaglandins (PGs) recapitulates the priming response and enhances antiplasmodial immunity by triggering HDF production. Although insects lack cyclooxygenases, two heme peroxidases, HPX7 and HPX8, catalyze essential steps in PG biosynthesis in mosquitoes. Mosquito midgut PGE2 release attracts hemocytes and establishes a long-lasting enhanced systemic cellular immune response to Plasmodium infection.
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http://dx.doi.org/10.1016/j.isci.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661395PMC
September 2019

Correction: Monitoring -T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

Oncotarget 2019 04 2;10(26):2576. Epub 2019 Apr 2.

Molecular Biology Laboratory of Cancer Dr. Rosell, Can Ruti Campus: Institute Germans Trias i Pujol (IGTP), Catalan Institute of Oncology, Badalona, Spain.

[This corrects the article DOI: 10.18632/oncotarget.25478.].
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http://dx.doi.org/10.18632/oncotarget.26855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493461PMC
April 2019

Characterization and functionality of two members of the SPFH protein superfamily, prohibitin 1 and 2 in Leishmania major.

Parasit Vectors 2018 Dec 4;11(1):622. Epub 2018 Dec 4.

Department of Parasitology, Faculty of Science, University of Granada, Granada, Spain.

Background: Leishmaniasis, a disease caused by parasites of the genus Leishmania, infects roughly 12 million people worldwide, with about two million new cases per year. Prohibitins (PHBs) are highly conserved proteins belonging to the stomatin-prohibitin flotillin-HflC/K (SPFH) protein superfamily. In this study, we examine the potential functions of two proteins of Leishmania major, PHB1 and PHB2, as well as how they might help protect the protozoan against oxidative stress.

Results: By immunolocalization in the parasite cells, PHB1 appeared in the mitochondria and plasma membrane, whereas PHB2 was grouped in the nucleus. When Leishmania cells were under oxidative stress, PHB1 migrates towards the plasma membrane and the paraxial rod, while PHB2 remained in the nucleus and near the kinetoplast. PHB1 presented higher mRNA levels than PHB2 in the amastigotes and the infective metacyclic forms. The mRNA expression of both prohibitins was affected by the presence of the Fe ion. PHBs inhibited the Fenton reaction, where reactive oxygen species could nick DNA, implying that they play a crucial role in controlling oxidative stress.

Conclusions: Here, we propose that PHBs may help to protect membranes and DNA against superoxide ions, thus enhancing the survival capacity of the protozoan by controlling the ROS within the phagosome of the macrophages where the parasite multiplies.
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http://dx.doi.org/10.1186/s13071-018-3195-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278115PMC
December 2018

5 protein-based signature for resectable lung squamous cell carcinoma improves the prognostic performance of the TNM staging.

Thorax 2019 04 24;74(4):371-379. Epub 2018 Nov 24.

Program in Solid Tumors, CIMA, Pamplona, Spain.

Introduction: Prognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death.

Methods: Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins.

Results: We identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05).

Conclusion: We have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient's potential outcome.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212194DOI Listing
April 2019

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non-Small Cell Lung Cancer.

J Thorac Oncol 2019 02 22;14(2):304-310. Epub 2018 Nov 22.

Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain; Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain; Medical Oncology Service, Hospital General de Valencia, Valencia, Spain. Electronic address:

Introduction: Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656).

Methods: The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatin-docetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response.

Results: In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio = 0.63, 95% confidence interval: 0.42-0.83, p = 0.0080). PALB2 was also predictive of overall survival (hazard ratio = 0.68, 95% confidence interval: 0.42-0.90, p = 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive of response to cisplatin-docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared with a rate of only 23 % for those with low PALB2 mRNA expression (p = 0.0448).

Conclusions: High PALB2 mRNA expression identified patients with NSCLC who significantly benefited from cisplatin-docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy will become the standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making.
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http://dx.doi.org/10.1016/j.jtho.2018.10.168DOI Listing
February 2019

Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2.

Cancer Treat Res Commun 2018 1;15:21-31. Epub 2018 Mar 1.

Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address:

Objective: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment.

Materials And Methods: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain).

Results: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients.

Conclusion: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy.

Microabstract: A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy.
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http://dx.doi.org/10.1016/j.ctarc.2018.02.003DOI Listing
June 2019

Monitoring -T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

Oncotarget 2018 Jun 5;9(43):27074-27086. Epub 2018 Jun 5.

Molecular Biology Laboratory of Cancer Dr. Rosell, Can Ruti Campus: Institute Germans Trias i Pujol (IGTP), Catalan Institute of Oncology, Badalona, Spain.

Background: Osimertinib is efficacious in lung cancer patients with epidermal growth factor receptor () mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to -T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes.

Material And Methods: Serum/plasma from -mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment. Changes in T790M were evaluated using a peptide-nucleic acid-PCR assay, and correlated with clinical and radiographic response.

Results: Thirteen patients were included. Median time on osimertinib treatment was 10.6 months with a median progression-free survival of 13.6 months. Best response to osimertinib was partial response (PR), stable disease (SD) or progression (PD) in 46.1%, 30.8% and 23.1% of patients, respectively.Most of the patients were paucisymptomatic at baseline. Symptom improvement was reported in 66.6% of responder patients; while symptoms remained stable in 75% of patients with SD, and 66% of patients with PD had clinical deterioration.Three patterns of T790M changes during osimertinib treatment were identified. T790 remained detectable with PD or a short-lasting SD in 15.4% of the patients. T790M disappeared in 69.2% of patients with PR or SD. T790M disappeared, despite clinical and/or radiographic progression in 15.4% of the patients.

Conclusion: Changes of T790M in serum/plasma in -mutant lung cancer patients with T790M-AR might be a useful marker of symptomatic and radiographic outcome to osimertinib. Longer follow-up is needed to establish if subsequent emergence of T790M could be a marker of resistance.
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http://dx.doi.org/10.18632/oncotarget.25478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007479PMC
June 2018

Flexible Gas Sensors Employing Octahedral Indium Oxide Films.

Sensors (Basel) 2018 Mar 28;18(4). Epub 2018 Mar 28.

MINOS-EMaS, Universitat Rovira i Virgili, Avda. Països Catalans, 26, 43007 Tarragona, Spain.

Indium oxide octahedral nanopowders were obtained from an ionic precursor compound after an oxidation process conducted under a low-oxygen atmosphere. This method was found to produce contamination-free indium oxide nanomaterial with very similar morphological and crystalline properties to the one produced by vapor-phase transport, but at significantly lower temperatures and higher yield. The as-synthesized indium oxide was mixed to an organic vehicle and microdrop deposited to form a film bridging the interdigitated silver electrodes patterned on top of a flexible, polyimide (Kapton), substrate. The gas sensing properties of the flexible chemoresistors towards ammonia vapors, hydrogen, and nitrogen dioxide were investigated. It was found that these sensors were remarkably sensitive to nitrogen dioxide at a low operating temperature of 150 °C. These results are consistent with the performance of vapor-phase transport synthesized indium oxide octahedra sensors on rigid, ceramic substrates. Therefore, the results presented here pave the way for the mass production of inexpensive gas sensors onto flexible substrates via additive manufacturing.
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http://dx.doi.org/10.3390/s18040999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948632PMC
March 2018

Entomopathogen ID: a curated sequence resource for entomopathogenic fungi.

Antonie Van Leeuwenhoek 2018 Jun 23;111(6):897-904. Epub 2017 Nov 23.

Mycotoxin Prevention and Applied Microbiology Research Unit, National Center for Agricultural Utilization Research, Agricultural Research Service, United States Department of Agriculture, 1815 North University Street, Peoria, IL, 61604, USA.

We report the development of a publicly accessible, curated nucleotide sequence database of hypocrealean entomopathogenic fungi. The goal is to provide a platform for users to easily access sequence data from taxonomic reference strains. The database can be used to accurately identify unknown entomopathogenic fungi based on sequence data for a variety of phylogenetically informative loci. The database provides full multi-locus sequence alignment capabilities. The initial release contains data compiled for 525 strains covering the phylogenetic diversity of three important entomopathogenic families: Clavicipitaceae, Cordycipitaceae, and Ophiocordycipitaceae. Furthermore, Entomopathogen ID can be expanded to other fungal clades of insect pathogens, as sequence data becomes available. The database will allow isolate characterisation and evolutionary analyses. We contend that this freely available, web-accessible database will facilitate the broader community to accurately identify fungal entomopathogens, which will allow users to communicate research results more effectively.
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http://dx.doi.org/10.1007/s10482-017-0988-2DOI Listing
June 2018

Effect of naturally occurring in mosquitoes from Mali on malaria transmission.

Proc Natl Acad Sci U S A 2017 11 7;114(47):12566-12571. Epub 2017 Nov 7.

Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;

A naturally occurring strain (Anga-Mali) was identified in mosquitoes of the complex collected in the Malian villages of Dangassa and Kenieroba. Phylogenetic analysis of the nucleotide sequence of two 16S rRNA regions showed that Anga-Mali clusters with strains from supergroup A and has the highest homology to a strain isolated from cat fleas (). Anga-Mali is different from two strains previously reported in from Burkina Faso (Anga_VK5_STP and Anga_VK5_3.1a). Quantitative analysis of and sporozoite infection in field-collected mosquitoes indicates that the prevalence and intensity of sporozoite infection is significantly lower in -infected females. The presence of in females from a laboratory (, M form) colony experimentally infected with (NF54 strain) gametocyte cultures slightly enhanced oocyst infection. However, infection significantly reduced the prevalence and intensity of sporozoite infection, as observed in the field. This indicates that Anga-Mali infection does not limit early stages of infection in the mosquito, but it has a strong deleterious effect on sporozoites and reduces malaria transmission.
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http://dx.doi.org/10.1073/pnas.1716181114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703331PMC
November 2017

Plasmodium berghei P47 is essential for ookinete protection from the Anopheles gambiae complement-like response.

Sci Rep 2017 07 20;7(1):6026. Epub 2017 Jul 20.

Vector Immunogenomics and Infection Laboratory, Department of Life Sciences, Imperial College London, London, United Kingdom.

Malaria is a mosquito-borne disease affecting millions of people every year. The rodent parasite Plasmodium berghei has served as a model for human malaria transmission studies and played a pivotal role in dissecting the mosquito immune response against infection. The 6-cysteine protein P47, known to be important for P. berghei female gamete fertility, is shown to serve a different function in Plasmodium falciparum, protecting ookinetes from the mosquito immune response. Here, we investigate the function of P. berghei P47 in Anopheles gambiae mosquito infections. We show that P47 is expressed on the surface of both female gametocytes and ookinetes where it serves distinct functions in promoting gametocyte-to-ookinete development and protecting ookinetes from the mosquito complement-like response, respectively. The latter function is essential, as ookinetes lacking P47 are targeted for killing while traversing the mosquito midgut cells and eliminated upon exposure to hemolymph proteins of the complement-like system. Silencing key factors of the complement-like system restores oocyst development and disease transmission to rodent hosts. Our data establish a dual role of P. berghei P47 in vivo and reinforce the use of this parasite to study the impact of the mosquito immune response on human malaria transmission.
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http://dx.doi.org/10.1038/s41598-017-05917-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519742PMC
July 2017

Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC).

Oncotarget 2017 Jul;8(29):47305-47316

Institut d'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain.

Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory. Afatinib has great activity in gefitinib-sensitive as well as in gefitinib-resistant EGFR mutant NSCLC cell lines. However, afatinib therapy causes phosphorylation of STAT3 tyrosine 705 (pSTAT3Tyr705) and elevation of STAT3 and RANTES mRNA levels. The combination of afatinib with TPCA-1 (a STAT3 inhibitor) ablated pSTAT3Tyr705 and down-regulated STAT3 and RANTES mRNA levels with significant growth inhibitory effect in both gefitinib-sensitive and gefitinib-resistant EGFR mutant NSCLC cell lines. Aldehyde dehydrogenase positive (ALDH+) cells were still observed with the combination at the time that Hairy and Enhancer of Split 1 (HES1) mRNA expression was elevated following therapy. Although the combination of afatinib with STAT3 inhibition cannot eliminate the potential problem of a remnant cancer stem cell population, it represents a substantial advantage and opportunity to further prolong progression free survival and probably could increase the response rate in comparison to the current standard of single therapy.
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http://dx.doi.org/10.18632/oncotarget.17625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564566PMC
July 2017

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC.

J Natl Cancer Inst 2017 09;109(9)

WVU Cancer Institute, West Virginia University, Morgantown, WV, USA.

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response.

Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided.

Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort.

Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.
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http://dx.doi.org/10.1093/jnci/djx014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409000PMC
September 2017

Correlation of DNA Repair Gene Polymorphisms With Clinical Outcome in Patients With Locally Advanced Non-Small-Cell Lung Cancer Receiving Induction Chemotherapy Followed by Surgery.

Clin Lung Cancer 2017 03 9;18(2):178-188.e4. Epub 2016 Nov 9.

Cancer Biology and Precision Medicine Program, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona, Spain; Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain; Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Spain.

Objective: The aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non-small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery.

Materials And Methods: A total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (-37 C/A) polymorphisms with response and survival.

Results: The median survival was 32.14 months for carriers of XPD 312 Asp/Asp and 12.04 months for those with the variant Asn allele (P = .05). In addition, event-free survival was longer for patients with the XPD 312 Asp/Asp genotype compared with patients with Asp/Asn or Asn/Asn (P = .03). A similar but nonsignificant trend was observed for the XPD 751 genotype. In a multivariate analysis, complete resection and age emerged as prognostic factors for overall survival; in patients with incomplete resection or exploratory thoracotomy, XPD 312 was the most significant prognostic factor (P = .03).

Conclusion: The XPD 312 single nucleotide polymorphism is a prognostic factor for survival in patients with locally advanced NSCLC receiving induction chemotherapy followed by surgery. The Asn allele is associated with unfavorable outcome and could be used for better stratification of patients.
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http://dx.doi.org/10.1016/j.cllc.2016.08.007DOI Listing
March 2017

Low RAP80 mRNA expression correlates with shorter survival in sporadic high-grade serous ovarian carcinoma.

Int J Biol Markers 2017 Mar 2;32(1):e90-e95. Epub 2017 Mar 2.

 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona - Spain.

Objective: Homologous recombination (HR) is frequently impaired in sporadic high-grade serous ovarian carcinoma (sHGSOC) due to deficiencies in BRCA1/2 genes, a situation associated with hypersensitivity to platinum compounds. Alterations in other genes can also cause HR deficiency. Preclinical data show that RAP80 is an HR-pathway-related gene that influences BRCA1 activity. RAP80 has been reported to affect outcome in some solid neoplasms. This study investigates the role of RAP80 in sHGSOC survival.

Methods: mRNA expression of RAP80 was analyzed in tumor samples from 35 patients who postoperatively received standard platinum-based chemotherapy. The effects of RAP80 expression on progression-free survival (PFS) and overall survival (OS) were examined by means of Cox regressions. The clinical variables known to have prognostic value (FIGO stage, residual disease at surgery, and debulking surgery) were included as covariates in the analysis. BRCA1 was analyzed given the moderate correlations with RAP80.

Results: Median follow-up, PFS and OS were 61.3, 20.2 and 62.8 months, respectively. Low RAP80 expression levels were associated with shorter PFS (HR = 1.449, p = 0.007) and OS (HR = 1.331, p = 0.047).

Conclusions: This is the first study to show a potential prognostic role of RAP80 expression in patients with HGSOC. The results suggest that HR deficiency due to low RAP80 expression is not associated with hypersensitivity to platinum compounds in sHGSOC.
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http://dx.doi.org/10.5301/jbm.5000223DOI Listing
March 2017

Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma.

Oncotarget 2016 Dec;7(50):82254-82265

Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined (p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients (p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect (p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F (p = 0.01; HR= 0.21). The 5-year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5-year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 (p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment.
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http://dx.doi.org/10.18632/oncotarget.12672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347689PMC
December 2016

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

J Neurooncol 2016 May 3;127(3):569-79. Epub 2016 Feb 3.

Radiation Oncology Service, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.
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http://dx.doi.org/10.1007/s11060-016-2065-5DOI Listing
May 2016

The diversity and expansion of the trans-sialidase gene family is a common feature in Trypanosoma cruzi clade members.

Infect Genet Evol 2016 Jan 2;37:266-74. Epub 2015 Dec 2.

Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil.

Trans-sialidase (TS) is a polymorphic protein superfamily described in members of the protozoan genus Trypanosoma. Of the eight TS groups recently described, TS group I proteins (some of which have catalytic activity) are present in the distantly related Trypanosoma brucei and Trypanosoma cruzi phylogenetic clades, whereas other TS groups have only been described in some species belonging to the T. cruzi clade. In the present study we analyzed the repertoire, distribution and phylogenetic relationships of TS genes among species of the T. cruzi clade based on sequence similarity, multiple sequence alignment and tree-reconstruction approaches using TS sequences obtained with the aid of PCR-based strategies or retrieved from genome databases. We included the following representative isolates of the T. cruzi clade from South America: T. cruzi, T. cruzi Tcbat, Trypanosoma cruzi marinkellei, Trypanosoma dionisii, Trypanosoma rangeli and Trypanosoma conorhini. The cloned sequences encoded conserved TS protein motifs Asp-box and VTVxNVxLYNR but lacked the FRIP motif (conserved in TS group I). The T. conorhini sequences were the most divergent. The hybridization patterns of TS probes with chromosomal bands confirmed the abundance of these sequences in species in the T. cruzi clade. Divergence and relationship analysis placed most of the TS sequences in the groups defined in T. cruzi. Further examination of members of TS group II, which includes T. cruzi surface glycoproteins implicated in host cell attachment and invasion, showed that sequences of T. cruzi Tcbat grouped with those of T. cruzi genotype TcI. Our analysis indicates that different members of the T. cruzi clade, with different vertebrate hosts, vectors and pathogenicity, share the extensive expansion and sequence diversification of the TS gene family. Altogether, our results are congruent with the evolutionary history of the T. cruzi clade and represent a contribution to the understanding of the molecular evolution and role of TS proteins in trypanosomes.
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http://dx.doi.org/10.1016/j.meegid.2015.11.024DOI Listing
January 2016