The interaction between agricultural production and wildlife can shape, and even condition, the f... more The interaction between agricultural production and wildlife can shape, and even condition, the functioning of both systems. In this study, we i) explored the degree to which a widespread European bat, namely the common bent-wing bat Miniopterus schreibersii, consumes crop-damaging insects at a continental scale, and ii) tested whether its dietary niche is shaped by the extension and type of agricultural fields. We employed a dual-primer DNA metabarcoding approach to characterize arthropod 16S and COI DNA sequences within bat faecal pellets collected across 16 Southern European localities, to first characterize the bat species' dietary niche, second measure the incidence of agricultural pests across their ranges and third assess whether geographical dietary variation responds to climatic, landscape diversity, agriculture type and vegetation productivity factors. We detected 12 arthropod orders, among which lepidopterans were predominant. We identified >200 species, 44 of whic...
BACKGROUND: The EGFR deletion mutation, EGFRvIII, is expressed in ~30% of glioblastomas (GBM). Th... more BACKGROUND: The EGFR deletion mutation, EGFRvIII, is expressed in ~30% of glioblastomas (GBM). The EGFRvIII-targeted vaccine rindopepimut consists of EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH). A survival benefit was observed in a randomized phase 2 trial of recurrent GBM (ReACT; n=73). In three phase 2 studies of 105 total patients with newly diagnosed, EGFRvIII+ GBM and minimal residual disease (MRD), the median overall survival (mOS) was 20-22 months, as compared to ~16 months for two matched contemporary datasets (n=16, n=29). METHODS: Patients with newly diagnosed, resected, EGFRvIII+ GBM were, after standard chemoradiation, stratified by RPA class, MGMT promoter methylation, and geographic region, and randomized (1:1) to double-blind rindopepimut or control (KLH) concurrent with standard maintenance temozolomide. Primary endpoint is OS for MRD patients (enhancing tumor <2 cm2 post-chemoradiation by central review) aiming to detect hazard ratio (HR) ≤0.71 with 80% power and alpha=0.05 (log-rank test). Interim analyses were preplanned at 50% and 75% of events. Secondary analyses included patients with ≥2 cm2 of residual tumor (non-MRD). RESULTS: 745 patients (405 MRD) were enrolled at 165 centers. The study was terminated for futility after the 2nd interim analysis (MRD OS HR=0.99). At final analysis, mOS for rindopepimut vs. control was 20.1 vs. 20.0 (HR=1.01; p=0.93) in the MRD cohort, and 14.8 vs. 14.1 (HR=0.79; p=0.066) with 2-year OS 30% vs. 19% in the non-MRD cohort. There were no substantial differences in progression-free survival. Rindopepimut was well tolerated (chief toxicity: injection site reaction) with robust anti-EGFRvIII immune response. CONCLUSIONS: The study failed to demonstrate a survival benefit for patients treated with rindopepimut and standard chemotherapy. Rindopepimut OS is comparable to prior studies, however, patients in the control arm fared better than historical controls. A trend for long-term survival benefit in non-MRD patients suggests a preferential effect in bulkier disease.
We have developed retroviral replicating vectors (RRV) derived from Moloney murine gammaretroviru... more We have developed retroviral replicating vectors (RRV) derived from Moloney murine gammaretrovirus with an amphotropic envelope and an encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES)-transgene cassette downstream of the env gene. During long-term (180 days) replication of the vector in animals, a bulge of 7 adenosine residues (A's) in the J-K bifurcation domain sometimes serially added A's. Therefore, vectors with 4-12 A's in the A bulge in the J-K bifurcation domain were generated, and the impact of the variants on transgene protein expression, vector stability, and IRES sequence upon multiple infection cycles was assessed in RRV encoding yeast-derived cytosine deaminase and green fluorescent protein in vitro. For transgene protein expression, after multiple infection cycles, RRV-IRES with 5-7 A's gave roughly comparable levels, 4 and 8 A's were within about 4-5-fold of the 6 A's, whereas 10 and 12 A's were marked lower. In terms of...
Introduction: The sinus lifting floor using bone grafts is a predictable procedure for the treatm... more Introduction: The sinus lifting floor using bone grafts is a predictable procedure for the treatment of the atrophic posterior maxilla. The graft material must possess mechanical and biological properties which promote osteoconduction and a good stability of the implants. Purpose: The purpose of this study was to evaluate the effect of anorganic bovine xenograft natural macroporous hydroxyapatite particle´s size (small 0.25-1 mm or large 1-2 mm) for human maxillary sinus lifting on implant stability quotient using Resonance Frequency Analysis (RFA). Material and Methods: The stability quotient of 30 implants placed in 15 patients (8 males and 7 females) treated with sinus lifting procedures, using as anorganic bovine xenograft (Bio-Oss®) material 's large or small particles (11 and 7 respectively) was measured. The measurements were made at the time of surgery implant placement through resonance frequency analysis. The healing time for the lifting procedure was 8 to 9 month. Data was analyzed using non-parametric statistics. Results: No significant differences in ISQ values of implants placed in sinus filled with small or large particles (P< 0.05) were detected. Standard deviation values of RFA were higher in large particles (±13.46 ISQ) than in small ones (±5.23 ISQ). Conclusion: Within the limitations of this study performed in human maxillary sinuses, it was concluded that the anorganic bovine xenograft particle´s size (0.25-1mm or 1-2 mm) did not produce different effect in the RFA values of the implants placed.
This paper focuses on the important problem of semanticaware search in textual (structured, semi-... more This paper focuses on the important problem of semanticaware search in textual (structured, semi-structured, NoSQL) databases. This problem has emerged as a required extension of the standard containment keyword based query to meet user needs in textual databases and IR applications. We provide here a new approach, called SemIndex, that extends the standard inverted index by constructing a tight coupling inverted index graph that combines two main resources: a general purpose semantic network, and a standard inverted index on a collection of textual data. We also provide an extended query model and related processing algorithms with the help of SemIndex. To investigate its effectiveness, we set up experiments to test the performance of SemIndex. Preliminary results have demonstrated the effectiveness, scalability and optimality of our approach.
We present a secure deterministic cipher and decipher mechanism based on the well-known Lorenz dy... more We present a secure deterministic cipher and decipher mechanism based on the well-known Lorenz dynamic system. The ciphering process is performed by the combination of the message to be ciphered and the states of the Lorenz dynamic system, which act as the ciphering key. The deciphering process is implemented by the reconstruction of the key, which is generated using a
Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activ... more Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75 NTR), but the mechanism of receptor activation has remained elusive. Here we show that p75 NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys 257 in its transmembrane domain. Mutation of Cys 257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75 NTR /NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75 NTR. FRET experiments revealed a close association of p75 NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys 257 did not alter the oligomeric state of p75 NTR , the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75 NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.
A Trypanosoma cruzi antigen which is shed into the culture medium by the trypomastigote stage of ... more A Trypanosoma cruzi antigen which is shed into the culture medium by the trypomastigote stage of the parasite and detected in blood of acutely infected mice was cloned and characterized. We designate this antigen shed acute phase antigen (SAPA). Five protein bands with apparent molecular masses ranging from 160 to 200 kDa were detected by immunoblotting of plasma from infected mice and in supernatants of cultured trypomastigotes upon reaction with antibodies against SAPA. A serum obtained from a patient acutely infected with Chagas&#39; disease revealed a similar set of polypeptides in supernatants of cultured trypomastigotes when tested by immunoblotting. SAPA seems thus to be a major shed protein during the acute period of the disease. Twenty-six of 28 sera from human acute cases of Chagas&#39; disease tested reacted with SAPA. Conversely, only 8-10% of sera from chronic cases of the disease contained detectable levels of antibody against SAPA. Sera from rabbits infected with six different parasite strains all contained antibodies against SAPA. Antibodies against SAPA are detectable 15 days after the manifestation of acute Chagas&#39; disease symptoms in humans and 15 days post-infection in sera from mice and rabbits. The nucleotide sequence of a genomic clone encoding the 3&#39; end of the SAPA gene revealed the presence of 14 tandemly arranged 12-amino acid-long repeats. A 39-amino acid-long region that is very hydrophobic precedes the stop codon. Due to its early appearance it might be possible to design diagnostic assays which are based on SAPA for identification of recently infected cases of Chagas&#39; disease.
Taylor & Francis makes every effort to ensure the accuracy of all the information (the "Content")... more Taylor & Francis makes every effort to ensure the accuracy of all the information (the "Content") contained in the publications on our platform. Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor & Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV)... more Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.
We used an integrative approach combining cranio-dental characters, mitochondrial and nuclear dat... more We used an integrative approach combining cranio-dental characters, mitochondrial and nuclear data and acoustic data to show the presence in the genus Miniopterus of a cryptic species from the Maghreb region. This species was previously recognised as Miniopterus schreibersii (Kuhl, 1817). Miniopterus maghrebensis sp. nov. can be differentiated from M. schreibersii sensu stricto on the basis of cranial characters and from mitochondrial DNA and microsatellite evidence. Although slight external morphological and acoustic differences were noted between the two species, these criteria alone did not allow reliable species identification from live animals. Based on the specimens identified morphologically and/or genetically, the distribution range of M. maghrebensis sp. nov. extends from northern Morocco to south of the High Atlas Mountains and northern Tunisia. The new cryptic species is found in sympatry with M. schreibersii s.str. near coastal regions of North Africa.
The demographic history of Rhinolophus hipposideros (lesser horseshoe bat) was reconstructed acro... more The demographic history of Rhinolophus hipposideros (lesser horseshoe bat) was reconstructed across its European, North African and Middle-Eastern distribution prior to, during and following the most recent glaciations by generating and analysing a multimarker data set. This data set consisted of an X-linked nuclear intron (Bgn; 543 bp), mitochondrial DNA (cytb-tRNA-control region; 1630 bp) and eight variable microsatellite loci for up to 373 individuals from 86 localities. Using this data set of diverse markers, it was possible to determine the species' demography at three temporal stages. Nuclear intron data revealed early colonization into Europe from the east, which pre-dates the Quaternary glaciations. The mtDNA data supported multiple glacial refugia across the Mediterranean, the largest of which were found in the Ibero-Maghreb region and an eastern location (Anatolia/Middle East)-that were used by R. hipposideros during the most recent glacial cycles. Finally, microsatellites provided the most recent information on these species' movements since the Last Glacial Maximum and suggested that lineages that had diverged into glacial refugia, such as in the Ibero-Maghreb region, have remained isolated. These findings should be used to inform future conservation management strategies for R. hipposideros and show the power of using a multimarker data set for phylogeographic studies.
Chromosomal DNA from Trypanosoma cruzi, the agent of the American trypanosomiasis (Chagas&#39... more Chromosomal DNA from Trypanosoma cruzi, the agent of the American trypanosomiasis (Chagas&#39; disease), was used for construction of a DNA library, employing the expression vector lambda gt11. Nine clones encoding different parasite antigens were isolated from this library by screening with an antiserum from a Chagasic patient. Nucleotide sequence analysis showed that seven out of the nine isolated clones code for antigens which contain tandemly repeated amino acid sequence motifs. Each of the seven antigens contains a unique repeat, ranging in length between 5 and 68 amino acids. The length of the repeats is highly conserved within each clone. Fusion proteins, expressed from two of the clones, reacted with a large proportion of sera collected from Chagasic patients in Argentina, Brazil and Chile. These clones appear thus to encode antigens which are shared between different strains of T. cruzi. Immunofluorescence experiments with live parasites showed that three of the antigens were detectable on the surface of trypanosomes.
The interaction between agricultural production and wildlife can shape, and even condition, the f... more The interaction between agricultural production and wildlife can shape, and even condition, the functioning of both systems. In this study, we i) explored the degree to which a widespread European bat, namely the common bent-wing bat Miniopterus schreibersii, consumes crop-damaging insects at a continental scale, and ii) tested whether its dietary niche is shaped by the extension and type of agricultural fields. We employed a dual-primer DNA metabarcoding approach to characterize arthropod 16S and COI DNA sequences within bat faecal pellets collected across 16 Southern European localities, to first characterize the bat species' dietary niche, second measure the incidence of agricultural pests across their ranges and third assess whether geographical dietary variation responds to climatic, landscape diversity, agriculture type and vegetation productivity factors. We detected 12 arthropod orders, among which lepidopterans were predominant. We identified >200 species, 44 of whic...
BACKGROUND: The EGFR deletion mutation, EGFRvIII, is expressed in ~30% of glioblastomas (GBM). Th... more BACKGROUND: The EGFR deletion mutation, EGFRvIII, is expressed in ~30% of glioblastomas (GBM). The EGFRvIII-targeted vaccine rindopepimut consists of EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH). A survival benefit was observed in a randomized phase 2 trial of recurrent GBM (ReACT; n=73). In three phase 2 studies of 105 total patients with newly diagnosed, EGFRvIII+ GBM and minimal residual disease (MRD), the median overall survival (mOS) was 20-22 months, as compared to ~16 months for two matched contemporary datasets (n=16, n=29). METHODS: Patients with newly diagnosed, resected, EGFRvIII+ GBM were, after standard chemoradiation, stratified by RPA class, MGMT promoter methylation, and geographic region, and randomized (1:1) to double-blind rindopepimut or control (KLH) concurrent with standard maintenance temozolomide. Primary endpoint is OS for MRD patients (enhancing tumor <2 cm2 post-chemoradiation by central review) aiming to detect hazard ratio (HR) ≤0.71 with 80% power and alpha=0.05 (log-rank test). Interim analyses were preplanned at 50% and 75% of events. Secondary analyses included patients with ≥2 cm2 of residual tumor (non-MRD). RESULTS: 745 patients (405 MRD) were enrolled at 165 centers. The study was terminated for futility after the 2nd interim analysis (MRD OS HR=0.99). At final analysis, mOS for rindopepimut vs. control was 20.1 vs. 20.0 (HR=1.01; p=0.93) in the MRD cohort, and 14.8 vs. 14.1 (HR=0.79; p=0.066) with 2-year OS 30% vs. 19% in the non-MRD cohort. There were no substantial differences in progression-free survival. Rindopepimut was well tolerated (chief toxicity: injection site reaction) with robust anti-EGFRvIII immune response. CONCLUSIONS: The study failed to demonstrate a survival benefit for patients treated with rindopepimut and standard chemotherapy. Rindopepimut OS is comparable to prior studies, however, patients in the control arm fared better than historical controls. A trend for long-term survival benefit in non-MRD patients suggests a preferential effect in bulkier disease.
We have developed retroviral replicating vectors (RRV) derived from Moloney murine gammaretroviru... more We have developed retroviral replicating vectors (RRV) derived from Moloney murine gammaretrovirus with an amphotropic envelope and an encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES)-transgene cassette downstream of the env gene. During long-term (180 days) replication of the vector in animals, a bulge of 7 adenosine residues (A's) in the J-K bifurcation domain sometimes serially added A's. Therefore, vectors with 4-12 A's in the A bulge in the J-K bifurcation domain were generated, and the impact of the variants on transgene protein expression, vector stability, and IRES sequence upon multiple infection cycles was assessed in RRV encoding yeast-derived cytosine deaminase and green fluorescent protein in vitro. For transgene protein expression, after multiple infection cycles, RRV-IRES with 5-7 A's gave roughly comparable levels, 4 and 8 A's were within about 4-5-fold of the 6 A's, whereas 10 and 12 A's were marked lower. In terms of...
Introduction: The sinus lifting floor using bone grafts is a predictable procedure for the treatm... more Introduction: The sinus lifting floor using bone grafts is a predictable procedure for the treatment of the atrophic posterior maxilla. The graft material must possess mechanical and biological properties which promote osteoconduction and a good stability of the implants. Purpose: The purpose of this study was to evaluate the effect of anorganic bovine xenograft natural macroporous hydroxyapatite particle´s size (small 0.25-1 mm or large 1-2 mm) for human maxillary sinus lifting on implant stability quotient using Resonance Frequency Analysis (RFA). Material and Methods: The stability quotient of 30 implants placed in 15 patients (8 males and 7 females) treated with sinus lifting procedures, using as anorganic bovine xenograft (Bio-Oss®) material 's large or small particles (11 and 7 respectively) was measured. The measurements were made at the time of surgery implant placement through resonance frequency analysis. The healing time for the lifting procedure was 8 to 9 month. Data was analyzed using non-parametric statistics. Results: No significant differences in ISQ values of implants placed in sinus filled with small or large particles (P< 0.05) were detected. Standard deviation values of RFA were higher in large particles (±13.46 ISQ) than in small ones (±5.23 ISQ). Conclusion: Within the limitations of this study performed in human maxillary sinuses, it was concluded that the anorganic bovine xenograft particle´s size (0.25-1mm or 1-2 mm) did not produce different effect in the RFA values of the implants placed.
This paper focuses on the important problem of semanticaware search in textual (structured, semi-... more This paper focuses on the important problem of semanticaware search in textual (structured, semi-structured, NoSQL) databases. This problem has emerged as a required extension of the standard containment keyword based query to meet user needs in textual databases and IR applications. We provide here a new approach, called SemIndex, that extends the standard inverted index by constructing a tight coupling inverted index graph that combines two main resources: a general purpose semantic network, and a standard inverted index on a collection of textual data. We also provide an extended query model and related processing algorithms with the help of SemIndex. To investigate its effectiveness, we set up experiments to test the performance of SemIndex. Preliminary results have demonstrated the effectiveness, scalability and optimality of our approach.
We present a secure deterministic cipher and decipher mechanism based on the well-known Lorenz dy... more We present a secure deterministic cipher and decipher mechanism based on the well-known Lorenz dynamic system. The ciphering process is performed by the combination of the message to be ciphered and the states of the Lorenz dynamic system, which act as the ciphering key. The deciphering process is implemented by the reconstruction of the key, which is generated using a
Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activ... more Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75 NTR), but the mechanism of receptor activation has remained elusive. Here we show that p75 NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys 257 in its transmembrane domain. Mutation of Cys 257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75 NTR /NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75 NTR. FRET experiments revealed a close association of p75 NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys 257 did not alter the oligomeric state of p75 NTR , the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75 NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.
A Trypanosoma cruzi antigen which is shed into the culture medium by the trypomastigote stage of ... more A Trypanosoma cruzi antigen which is shed into the culture medium by the trypomastigote stage of the parasite and detected in blood of acutely infected mice was cloned and characterized. We designate this antigen shed acute phase antigen (SAPA). Five protein bands with apparent molecular masses ranging from 160 to 200 kDa were detected by immunoblotting of plasma from infected mice and in supernatants of cultured trypomastigotes upon reaction with antibodies against SAPA. A serum obtained from a patient acutely infected with Chagas&#39; disease revealed a similar set of polypeptides in supernatants of cultured trypomastigotes when tested by immunoblotting. SAPA seems thus to be a major shed protein during the acute period of the disease. Twenty-six of 28 sera from human acute cases of Chagas&#39; disease tested reacted with SAPA. Conversely, only 8-10% of sera from chronic cases of the disease contained detectable levels of antibody against SAPA. Sera from rabbits infected with six different parasite strains all contained antibodies against SAPA. Antibodies against SAPA are detectable 15 days after the manifestation of acute Chagas&#39; disease symptoms in humans and 15 days post-infection in sera from mice and rabbits. The nucleotide sequence of a genomic clone encoding the 3&#39; end of the SAPA gene revealed the presence of 14 tandemly arranged 12-amino acid-long repeats. A 39-amino acid-long region that is very hydrophobic precedes the stop codon. Due to its early appearance it might be possible to design diagnostic assays which are based on SAPA for identification of recently infected cases of Chagas&#39; disease.
Taylor & Francis makes every effort to ensure the accuracy of all the information (the "Content")... more Taylor & Francis makes every effort to ensure the accuracy of all the information (the "Content") contained in the publications on our platform. Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor & Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV)... more Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.
We used an integrative approach combining cranio-dental characters, mitochondrial and nuclear dat... more We used an integrative approach combining cranio-dental characters, mitochondrial and nuclear data and acoustic data to show the presence in the genus Miniopterus of a cryptic species from the Maghreb region. This species was previously recognised as Miniopterus schreibersii (Kuhl, 1817). Miniopterus maghrebensis sp. nov. can be differentiated from M. schreibersii sensu stricto on the basis of cranial characters and from mitochondrial DNA and microsatellite evidence. Although slight external morphological and acoustic differences were noted between the two species, these criteria alone did not allow reliable species identification from live animals. Based on the specimens identified morphologically and/or genetically, the distribution range of M. maghrebensis sp. nov. extends from northern Morocco to south of the High Atlas Mountains and northern Tunisia. The new cryptic species is found in sympatry with M. schreibersii s.str. near coastal regions of North Africa.
The demographic history of Rhinolophus hipposideros (lesser horseshoe bat) was reconstructed acro... more The demographic history of Rhinolophus hipposideros (lesser horseshoe bat) was reconstructed across its European, North African and Middle-Eastern distribution prior to, during and following the most recent glaciations by generating and analysing a multimarker data set. This data set consisted of an X-linked nuclear intron (Bgn; 543 bp), mitochondrial DNA (cytb-tRNA-control region; 1630 bp) and eight variable microsatellite loci for up to 373 individuals from 86 localities. Using this data set of diverse markers, it was possible to determine the species' demography at three temporal stages. Nuclear intron data revealed early colonization into Europe from the east, which pre-dates the Quaternary glaciations. The mtDNA data supported multiple glacial refugia across the Mediterranean, the largest of which were found in the Ibero-Maghreb region and an eastern location (Anatolia/Middle East)-that were used by R. hipposideros during the most recent glacial cycles. Finally, microsatellites provided the most recent information on these species' movements since the Last Glacial Maximum and suggested that lineages that had diverged into glacial refugia, such as in the Ibero-Maghreb region, have remained isolated. These findings should be used to inform future conservation management strategies for R. hipposideros and show the power of using a multimarker data set for phylogeographic studies.
Chromosomal DNA from Trypanosoma cruzi, the agent of the American trypanosomiasis (Chagas&#39... more Chromosomal DNA from Trypanosoma cruzi, the agent of the American trypanosomiasis (Chagas&#39; disease), was used for construction of a DNA library, employing the expression vector lambda gt11. Nine clones encoding different parasite antigens were isolated from this library by screening with an antiserum from a Chagasic patient. Nucleotide sequence analysis showed that seven out of the nine isolated clones code for antigens which contain tandemly repeated amino acid sequence motifs. Each of the seven antigens contains a unique repeat, ranging in length between 5 and 68 amino acids. The length of the repeats is highly conserved within each clone. Fusion proteins, expressed from two of the clones, reacted with a large proportion of sera collected from Chagasic patients in Argentina, Brazil and Chile. These clones appear thus to encode antigens which are shared between different strains of T. cruzi. Immunofluorescence experiments with live parasites showed that three of the antigens were detectable on the surface of trypanosomes.
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