ABSTRACT
A significant fraction of Earth's ecosystems undergoes periodic wet-dry alternating transitional states. These globally distributed water-driven transitional ecosystems, such as intermittent rivers and coastal shorelines, have traditionally been studied as two distinct entities, whereas they constitute a single, interconnected meta-ecosystem. This has resulted in a poor conceptual and empirical understanding of water-driven transitional ecosystems. Here, we develop a conceptual framework that places the temporal availability of water as the core driver of biodiversity and functional patterns of transitional ecosystems at the global scale. Biological covers (e.g., aquatic biofilms and biocrusts) serve as an excellent model system thriving in both aquatic and terrestrial states, where their succession underscores the intricate interplay between these two states. The duration, frequency, and rate of change of wet-dry cycles impose distinct plausible scenarios where different types of biological covers can occur depending on their desiccation/hydration resistance traits. This implies that the distinct eco-evolutionary potential of biological covers, represented by their trait profiles, would support different functions while maintaining similar multifunctionality levels. By embracing multiple alternating transitional states as interconnected entities, our approach can help to better understand and manage global change impacts on biodiversity and multifunctionality in water-driven transitional ecosystems, while providing new avenues for interdisciplinary studies.
Subject(s)
Biodiversity , Ecosystem , BiofilmsABSTRACT
Speciation and diversification patterns in angiosperms are frequently shaped by niche evolution. Centaurium Hill is a Mediterranean genus with ca. 25 species, of which 60% are polyploids (tetra- and hexaploids), distributed mainly in the Mediterranean Basin and in areas with temperate and arid climates of Asia, Europe, North-Central Africa and North America. The evolutionary history of this genus has been studied using morphological, biogeographical and molecular approaches, but its climatic niche characterization and its relation with genome evolution (chromosome number and ploidy level) has not been addressed yet. Thus, this study aims to identify the role of the evolution of climatic niche, ploidy level, life cycle and floral traits in the diversification of Centaurium. Climatic niche characterization involved estimating present climate preferences using quantitative data and reconstructing ancestral niches to evaluate climatic niche shifts. The evolution of climatic niche towards selective optima determined by ploidy level (three ploidy levels) and different binary traits (polyploidy, floral size, floral display, herkogamy and life cycle) was addressed under the Ornstein-Uhlenbeck model. Chromosome number evolution was inferred using the ChromoSSE model, testing if changes are clado- or anagenetic. Chromosome number evolution and its link with cladogenesis, life cycle and floral traits was modeled on the phylogeny. The reconstruction of the ancestral niches shows that Centaurium originated in a mild climate and diversified to both humid and cold as well as to dry and warmer climates. Niche conservatism was estimated in the climatic niche of the ancestors, while the climatic niche of the current taxa experienced transitions from their ancestors' niche. Besides, the evolution of climatic niche towards multiple selective optima determined by the studied traits was supported, life cycle optima receiving the highest support. The reconstruction of chromosome number transitions shows that the rate of speciation process resulting from chromosomal changes (chromosomal cladogenesis) is similar to that of non-chromosomal cladogenesis. Additionally, dependent evolution of floral size, floral display and herkogamy with chromosome number variation was supported. In conclusion, polyploidization is a crucial process in the Mediterranean region that assisted speciation and diversification into new areas with different climates, entailing niche shifts and evolution of reproductive strategies.
ABSTRACT
Biodiversity data records contain inaccuracies and biases. To overcome this limitation and establish robust geographic patterns, ecologists often curate records keeping those that are most suitable for their analyses. Yet, this choice is not straightforward and the outcome of the analysis may vary due to a trade-off between data quality and volume. This problem is particularly recurrent for less-studied groups with patchy sampling effort. The latitudinal pattern of mosses richness remains inconsistent across studies and these may emerge purely from sampling artefacts. Our main objective here is to assess the effect of different curation criteria on this spatial pattern in the Temperate Northern Hemisphere (above 20° latitude). We contrasted the geographical distribution of moss species records and the latitude-species richness relation obtained under different data curation scenarios. These scenarios comprehend five sources of taxonomical standardisations and eight data cleaning filters. The analyses are based on the selection of well-surveyed cells at 100 km cell resolution. The application of some 'data curation scenarios' severely affects the number of records selected for analysis and substantially changes the proportion of richness per cell. The sensitivity to data curation becomes detectable at regional and at the cell scales showing a large shift in the latitudinal richness peak in Europe, from 60° N to 45° N latitude, when only preserved specimens are selected and duplicates based on date of collection and coordinates are excluded. Our results stress the importance of justifying the criteria used for filtering biodiversity data retrieved from biodiversity databases to avoid detecting misleading patterns. Curating records under particular criteria compromises the information in some areas displaying different spatial information of mosses. This problem can be ameliorated if data filtering is combined with identifying well-surveyed cells, render relatively constant results under different combinations of filtering even for less well-known groups such as mosses.
ABSTRACT
Ecological and evolutionary studies often require high quality biodiversity data. This information is readily available through the many online databases that have compiled biodiversity data from herbaria, museums, and human observations. However, the process of preparing this information for analysis is complex and time consuming. In this study, we have developed a protocol in R language to process spatial data (download, merge, clean, and correct) and extract climatic data, using some genera of the ginseng family (Araliaceae) as an example. The protocol provides an automated way to process spatial and climatic data for numerous taxa independently and from multiple online databases. The script uses GBIF, BIEN, and WorldClim as the online data sources, but can be easily adapted to include other online databases. The script also uses genera as the sampling unit but provides a way to use species as the target. The cleaning process includes a filter to remove occurrences outside the natural range of the taxa, gardens, and other human environments, as well as erroneous locations and a spatial correction for misplaced occurrences (i.e., occurrences within a distance buffer from the coastal boundary). Additionally, each step of the protocol can be run independently. Thus, the protocol can begin with data cleaning, if the database has already been compiled, or with climatic data extraction, if the database has already been parsed. Each line of the R script is commented so that it can also be run by users with little knowledge of R.
ABSTRACT
INTRODUCTION AND OBJECTIVES: We previously published the toxicity and initial results of a prospective cohort of patients treated with 2 fractions HDR-BRT administered in a single day. In the present analysis we report the long-term cancer control results of our prospective trial and investigate the relationship between PSA nadir and biochemical control. MATERIAL AND METHODS: A total of 120 patients were treated with HDR Brachytherapy monotherapy administered in two fractions in a single day. Between November 2010 and February 2016, 84 patients with low-risk and 36 patients with intermediate-risk prostate cancer in accordance with the NCCN practice guidelines. RESULTS: Median age was 66 years (range 45-84) and median PSA was 7.5 ng/ml (range 0.01-16 ng/ml). Overall, 84.2% had Gleason score 6 and 15.8% Gleason 7. Thirty-one percent of patients received ADT.After a median follow-up of the cohort was 123 months. Actuarial rates of no biochemical evidence of disease (bNED), overall survival, local control and metastasis-free survival for all patients were 93.3%, 86.7%, 95.2% and 96.1%, respectively.The median time to achieve PSA nadir was 80.5 months. Patients who attained a PSA Nadir ≤ 0.20 ng/mL exhibited a 10-year bNED survival rate of 96.9%, whereas thosewho failed to reach this PSA level had a survival rate of only 40%. CONCLUSIONS: In patients with favorable localized prostate cancer, 2 fractions HDR-BT monotherapy is a highly curative radiation technique that attains PSA nadir levels < 0.2 ng/mL in 95% of cases.
Subject(s)
Brachytherapy , Prostatic Neoplasms , Male , Humans , Middle Aged , Aged , Aged, 80 and over , Prostate-Specific Antigen/analysis , Brachytherapy/methods , Prospective Studies , Radiotherapy Dosage , Prostatic Neoplasms/radiotherapy , Follow-Up StudiesABSTRACT
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows potent preclinical anticancer activity in pediatric solid tumors such as Ewing sarcoma, rhabdomyosarcoma and neuroblastoma, but responses in clinical trials have been modest. In this work, we aimed to discover a rational biomarker-based approach to select the right candidate patients for this treatment. We assessed the efficacy of nab-paclitaxel in 27 patient-derived xenografts (PDX), including 14 Ewing sarcomas, five rhabdomyosarcomas and several other pediatric solid tumors. Response rate (partial or complete response) was remarkable in rhabdomyosarcomas (four of five) and Ewing sarcomas (four of 14). We addressed several predictive factors of response to nab-paclitaxel such as the expression of the secreted protein acidic and rich in cysteine (SPARC), chromosomal stability of cancer cells and expression of antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of proteins such as Bcl-2, Bcl-xL, Bcl-W and Mcl-1. Protein (immunoblotting) and gene expression of SPARC correlated positively, while immunoblotting and immunohistochemistry expression of Bcl-2 correlated negatively with the efficacy of nab-paclitaxel in Ewing sarcoma PDX. The negative correlation of Bcl-2 immunoblotting signal and activity was especially robust (r = 0.8352; P = 0.0007; Pearson correlation). Consequently, we evaluated pharmacological strategies to inhibit Bcl-2 during nab-paclitaxel treatment. We observed that the Bcl-2 inhibitor venetoclax improved the activity of nab-paclitaxel in highly resistant Bcl-2-expressing Ewing sarcoma PDX. Overall, our results suggest that low Bcl-2 expression could be used to select patients with Ewing sarcoma sensitive to nab-paclitaxel, and Bcl-2 inhibitors could improve the activity of this drug in Bcl-2-expressing Ewing sarcoma.
Subject(s)
Antineoplastic Agents , Bone Neoplasms , Rhabdomyosarcoma , Sarcoma, Ewing , Child , Humans , Antineoplastic Agents/therapeutic use , Biomarkers , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Osteonectin/genetics , Osteonectin/metabolism , Osteonectin/therapeutic use , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Rhabdomyosarcoma/drug therapy , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/pathologyABSTRACT
Fundoscopy is the standard method for diagnosis and follow-up of intraocular retinoblastoma, but it is sometimes insufficient to discern whether tumors are inactivated following treatments. In this work, we hypothesized that the amount of conserved nuclear DNA sequences in the cell-free DNA (cfDNA) fraction of the aqueous humor (AH) might complement fundoscopy for retinoblastoma follow-up. To address our hypothesis, we developed highly sensitive droplet digital polymerase chain reaction (ddPCR) methods to quantify highly conserved DNA sequences of nucleus-encoded genes (GAPDH and B4GALNT1) and of a mitochondrial gene, MT-ATP6. We obtained AH samples during intravitreal treatments. We analyzed 42 AH samples from 25 patients with intraocular retinoblastoma and 11 AH from controls (non-cancer patients). According to clinical criteria, we grouped patients as having progression-free or progressive retinoblastoma. cfDNA concentration in the AH was similar in both retinoblastoma groups. Copy counts for nucleus-derived sequences of GAPDH and B4GALNT1 were significantly higher in the AH from patients with progressive disease, compared to the AH from progression-free patients and control non-cancer patients. The presence of mitochondrial DNA in the AH explained that both retinoblastoma groups had similar cfDNA concentration in AH. The optimal cut-off point for discriminating between progressive and progression-free retinoblastomas was 108 GAPDH copies per reaction. Among patients having serial AH samples analyzed during their intravitreal chemotherapy, GAPDH copies were high and decreased below the cut-off point in those patients responding to chemotherapy. In contrast, one non-responder patient remained with values above the cut-off during follow-up, until enucleation. We conclude that the measurement of conserved nuclear gene sequences in AH allows follow-up of intraocular retinoblastoma during intravitreal treatment. The method is applicable to all patients and could be relevant for those in which fundoscopy evaluation is inconclusive.
Subject(s)
Base Sequence , HumansABSTRACT
Colonization of new habitat patches is a key aspect of metacommunity dynamics, particularly for sessile organisms. Mosses can establish in new patches through fragmentation, with different vegetative structures acting as propagules. Despite the importance of these propagules for successful colonization the specific aspects that favour moss colonization by vegetative propagules remain poorly understood, including the effect of propagule size. We examine the intra- and interspecific variation of establishment and colonization success in culture of propagules of different sizes in six widespread soil moss species of contrasting growth form (Dicranum scoparium, Homalothecium aureum, Hypnum cupressiforme, Ptychostomum capillare, Syntrichia ruralis and Tortella squarrosa). We obtained three different size classes of propagules from artificially fragmented vegetative material, and assessed their establishment under controlled light and temperature conditions. We characterize the size, shape, apparent viability, morphological type and size changes due to hydration states of the propagules, all of them traits with potentially significant influence in their dispersal pattern and establishment. Then we assess the effect of these traits on moss establishment, using indicators of surface establishment (number of established shoots and colonized surface) and biomass production (viable biomass) as proxies of colonization success. The establishment indicators related to colonization surface and biomass production differ among species and propagule sizes. The magnitude of the interspecific differences of all indicators of establishment success was larger at the smaller propagule size class. T. squarrosa was the most successful species, and D. scoparium showed the lowest performance. We also found interspecific differences in the hydration dynamics of the propagules. The process of establishment by vegetative fragments operates differently among moss species. Besides, differences between hydration states in propagules of some species could be part of syndromes for both dispersal and establishment. This study unveils several functional traits relevant for moss colonization, such as wet versus dry area and length of fragments, which may improve our understanding of their spatial dynamics.
Subject(s)
Bryophyta , Bryopsida , Biomass , Phenotype , SoilABSTRACT
Diffuse intrinsic pontine gliomas (DIPG), the first cause of cerebral pediatric cancer death, will greatly benefit from specific and non-invasive biomarkers for patient follow-up and monitoring of drug efficacy. Since biopsies are challenging for brain tumors, molecular imaging may be a technique of choice to target and follow tumor evolution. So far, MR remains the imaging technique of reference for DIPG, although it often fails to define the extent of tumors, an essential parameter for therapeutic efficacy assessment. Thanks to its high sensitivity, positron emission tomography (PET) offers a unique way to target specific biomarkers in vivo. We demonstrated in a patient-derived orthotopic xenograft (PDOX) model in the rat that the translocator protein of 18 kDa (TSPO) may be a promising biomarker for monitoring DIPG tumors. We studied the distribution of 18F-DPA-714, a TSPO radioligand, in rats inoculated with HSJD-DIPG-007 cells. The primary DIPG human cell line HSJD-DIPG-007 highly represents this pediatric tumor, displaying the most prevalent DIPG mutations, H3F3A (K27M) and ACVR1 (R206H). Kinetic modeling and parametric imaging using the brain 18F-DPA-714 PET data enabled specific delineation of the DIPG tumor area, which is crucial for radiotherapy dose management.
Subject(s)
Astrocytoma , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Child , Animals , Humans , Rats , Glioma/diagnostic imaging , Glioma/genetics , Glioma/metabolism , Cell Line, Tumor , Brain Stem Neoplasms/diagnostic imaging , Brain Stem Neoplasms/genetics , Positron-Emission Tomography/methods , Carrier Proteins , Disease Models, Animal , Biomarkers , Receptors, GABA/genetics , Receptors, GABA/metabolism , Receptors, GABA-AABSTRACT
The path followed by species in the colonization of remote oceanic islands ultimately depends on their phylogenetic constraints and ecological responses. In this study, we aim to evaluate the relative role of geographical and ecological forces in the origin and evolution of the Madeiran ivy (Hedera maderensis), a single-species endemic belonging to the western polyploid clade of Hedera. To determine the phylogenetic placement of H. maderensis within the western polyploid clade, we analyzed 40 populations (92 individuals) using genotyping-by-sequencing and including Hedera helix as outgroup. Climatic niche differences among the study species were evaluated using a database with 867 records representing the entire species ranges. To test species responses to climate, 13 vegetative and reproductive functional traits were examined for 70 populations (335 individuals). Phylogenomic results revealed a nested pattern with H. maderensis embedded within the south-western Iberian H. iberica. Gradual niche differentiation from the coldest and most continental populations of H. iberica to the warm and stable coastal population sister to H. maderensis parallels the geographical pattern observed in the phylogeny. Similarity in functional traits is observed for H. maderensis and H. iberica. The two species show leaves with higher specific leaf area (SLA), lower leaf dry matter content (LDMC) and thickness and fruits with lower pulp fraction than the other western polyploid species H. hibernica. Acquisition of a Macaronesian climatic niche and the associated functional syndrome in mainland European ivies (leaves with high SLA, and low LDMC and thickness, and fruits with less pulp content) was a key step in the colonization of Madeira by the H. iberica/H. maderensis lineage, which points to climatic pre-adaptation as key in the success of island colonization (dispersal and establishment). Once in Madeira, budding speciation was driven by geographical isolation, while ecological processes are regarded as secondary forces with a putative impact in the lack of further in situ diversification.
ABSTRACT
PREMISE: There has been a great increase in using climatic data in phylogenetic studies over the past decades. However, compiling the high-quality spatial data needed to perform accurate climatic reconstructions is time-consuming and can result in poor geographical coverage. Therefore, researchers often resort to qualitative approximations. Our aim was to evaluate the climatic characterization of the genera of the Asian Palmate Group (AsPG) of Araliaceae as an exemplar lineage of plants showing tropical-temperate transitions. METHODS: We compiled a curated worldwide spatial database of the AsPG genera and created five raster layers representing bioclimatic regionalizations of the world. Then, we crossed the database with the layers to climatically characterize the AsPG genera. RESULTS: We found large disagreement in the climatic characterization of genera among regionalizations and little support for the climatic nature of the tropical-temperate distribution of the AsPG. Both results are attributed to the complexity of delimiting tropical, subtropical, and temperate climates in the world and to the distribution of the study group in regions with transitional climatic conditions. CONCLUSIONS: The complexity in the climatic classification of this example of the tropical-temperate transitions calls for a general climatic revision of other tropical-temperate lineages. In fact, we argue that, to properly evaluate tropical-temperate transitions across the tree of life, we cannot ignore the complexity of distribution ranges.
Subject(s)
Araliaceae , Biodiversity , Climate , Geography , Phylogeny , PlantsABSTRACT
Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3caH1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.
Subject(s)
Phosphatidylinositol 3-Kinases , Vascular Malformations , Aminopyridines , Animals , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Endothelial Cells/metabolism , Imidazoles , Mice , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Vascular Malformations/genetics , Vascular Malformations/metabolism , Vascular Malformations/pathologyABSTRACT
The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.
Subject(s)
Prognosis , Sarcoma, Ewing/drug therapy , Xenograft Model Antitumor Assays/methods , Adolescent , Animals , Child , Child, Preschool , Disease Models, Animal , Female , Heterografts/drug effects , Humans , Irinotecan/pharmacology , Irinotecan/therapeutic use , Male , Mice , Osteosarcoma/drug therapy , Rhabdomyosarcoma/drug therapy , Sarcoma/drug therapy , Treatment OutcomeABSTRACT
Phenotypic plasticity, within and across generations (transgenerational plasticity), allows organisms and their progeny to adapt to the environment without modification of the underlying DNA. Recent findings suggest that epigenetic modifications are important mediators of such plasticity. However, empirical studies have, so far, mainly focused on plasticity in response to abiotic factors, overlooking the response to competition. We tested for within-generation and transgenerational phenotypic plasticity triggered by plant-plant competition intensity, and we tested whether it was mediated via DNA methylation, using the perennial, apomictic herb Taraxacum brevicorniculatum in four coordinated experiments. We then tested the consequences of transgenerational plasticity affecting competitive interactions of the offspring and ecosystem processes, such as decomposition. We found that, by promoting differences in DNA methylation, offspring of plants under stronger competition developed faster and presented more resource-conservative phenotypes. Further, these adjustments associated with less degradable leaves, which have the potential to reduce nutrient turnover and might, in turn, favour plants with more conservative traits. Greater parental competition enhanced competitive abilities of the offspring, by triggering adaptive phenotypic plasticity, and decreased offspring leaf decomposability. Our results suggest that competition-induced transgenerational effects could promote rapid adaptations and species coexistence and feed back on biodiversity assembly and nutrient cycling.
Subject(s)
Adaptation, Physiological , Ecosystem , DNA Methylation , Phenotype , Plant LeavesSubject(s)
Brain Neoplasms/pathology , Neoplasms, Germ Cell and Embryonal/pathology , Pineal Gland/pathology , Pinealoma/pathology , Adolescent , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/pathology , Female , Humans , Male , Medulloblastoma/genetics , Medulloblastoma/metabolism , Medulloblastoma/pathology , Mutation, Missense/genetics , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/metabolism , Pinealoma/genetics , Pinealoma/metabolism , Wnt Proteins/metabolism , beta Catenin/geneticsABSTRACT
Ewing sarcoma is a bone and soft tissue tumor predominantly affecting adolescents and young adults. To characterize changes in anticancer drug activity and intratumor drug distribution during the evolution of Ewing sarcomas, we used immunodeficient mice to establish pairs of patient-derived xenografts (PDX) at early (initial diagnosis) and late (relapse or refractory progression) stages of the disease from three patients. Analysis of copy number alterations (CNA) in early passage PDX tissues showed that two tumor pairs established from patients which responded initially to therapy and relapsed more than one year later displayed similar CNAs at early and late stages. For these two patients, PDX established from late tumors were more resistant to chemotherapy (irinotecan) than early counterparts. In contrast, the tumor pair established at refractory progression showed highly dissimilar CNA profiles, and the pattern of response to chemotherapy was discordant with those of relapsed cases. In mice receiving irinotecan infusions, the level of SN-38 (active metabolite of irinotecan) in the intracellular tumor compartment was reduced in tumors at later stages compared to earlier tumors for those pairs bearing similar CNAs, suggesting that distribution of anticancer drug shifted toward the extracellular compartment during clonal tumor evolution. Overexpression of the drug transporter P-glycoprotein in late tumor was likely responsible for this shift in drug distribution in one of the cases.
Subject(s)
Antineoplastic Agents , Bone Neoplasms , Pharmaceutical Preparations , Sarcoma, Ewing , Adolescent , Animals , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Humans , Irinotecan , Mice , Sarcoma, Ewing/drug therapyABSTRACT
The blood-brain barrier (BBB) hinders the brain delivery of many anticancer drugs. In pediatric patients, diffuse intrinsic pontine glioma (DIPG) represents the main cause of brain cancer mortality lacking effective drug therapy. Using sham and DIPG-bearing rats, we analyzed 1) the brain distribution of 3-kDa-Texas red-dextran (TRD) or [14C]-sucrose as measures of BBB integrity, and 2) the role of major ATP-binding cassette (ABC) transporters at the BBB on the efflux of the irinotecan metabolite [3H]-SN-38. The unaffected [14C]-sucrose or TRD distribution in the cerebrum, cerebellum, and brainstem regions in DIPG-bearing animals suggests an intact BBB. Targeted proteomics retrieved no change in P-glycoprotein (P-gp), BCRP, MRP1, and MRP4 levels in the analyzed regions of DIPG rats. In vitro, DIPG cells express BCRP but not P-gp, MRP1, or MRP4. Dual inhibition of P-gp/Bcrp, or Mrp showed a significant increase on SN-38 BBB transport: Cerebrum (8.3-fold and 3-fold, respectively), cerebellum (4.2-fold and 2.8-fold), and brainstem (2.6-fold and 2.2-fold). Elacridar increased [3H]-SN-38 brain delivery beyond a P-gp/Bcrp inhibitor effect alone, emphasizing the role of another unidentified transporter in BBB efflux of SN-38. These results confirm a well-preserved BBB in DIPG-bearing rats, along with functional ABC-transporter expression. The development of chemotherapeutic strategies to circumvent ABC-mediated BBB efflux are needed to improve anticancer drug delivery against DIPG.
ABSTRACT
According to the competitive exclusion principle, species with low competitive abilities should be excluded by more efficient competitors; yet, they generally remain as rare species. Here, we describe the positive and negative spatial association networks of 326 disparate assemblages, showing a general organization pattern that simultaneously supports the primacy of competition and the persistence of rare species. Abundant species monopolize negative associations in about 90% of the assemblages. On the other hand, rare species are mostly involved in positive associations, forming small network modules. Simulations suggest that positive interactions among rare species and microhabitat preferences are the most probable mechanisms underpinning this pattern and rare species persistence. The consistent results across taxa and geography suggest a general explanation for the maintenance of biodiversity in competitive environments.
Subject(s)
Biodiversity , Ecology , GeographyABSTRACT
Communities of nonvascular cryptogams, such as mosses or lichens, are an important part of the Earth's biodiversity, contributing to the regulation of the carbon and nitrogen cycles in many ecosystems. Being poikilohydric organisms, they do not actively control their internal water content and need a humid environment to activate their metabolism. Therefore, studying water relationships of nonvascular cryptogams is crucial to understand both their diversity patterns and their functions in the ecosystems. We present the BtM datalogger, a low-cost open-source platform for the study of the water content of nonvascular cryptogams. The datalogger is designed to measure ambient temperature, humidity, and conductance from up to eight samples simultaneously. We provide a design for a printed circuit board (PCB), a detailed protocol to assemble the components, and the required source code. All this makes the assembly of the BtM datalogger accessible to any research group, even to those without previous specialized knowledge. Therefore, the design presented here has the potential to help popularize the use of this type of device among ecologists and field biologists.
Subject(s)
Bryophyta/metabolism , Costs and Cost Analysis , Electrical Equipment and Supplies/economics , Environmental Monitoring/instrumentation , Lichens/metabolism , Water/metabolism , Environmental Monitoring/economics , Humidity , TemperatureABSTRACT
Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1 VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.