Clonal evolution through loss of chromosomes and subsequent polyploidization in chondrosarcoma

Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events.     

Enhanced platelet activation mediates the accelerated angiogenic switch in mice lacking histidine-rich glycoprotein

Background

The heparin-binding plasma protein histidine-rich glycoprotein (HRG; alternatively, HRGP/HPRG) can suppress tumor angiogenesis and growth in vitro and in vivo. Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times. In addition, the angiogenic switch is significantly enhanced in HRG-deficient mice.

Methodology/Principal Findings

To address whether HRG deficiency affects tumor development, we have crossed HRG knockout mice with the RIP1-Tag2 mouse, a well established orthotopic model of multistage carcinogenesis. RIP1-Tag2 HRG^−/− mice display significantly larger tumor volume compared to their RIP1-Tag2 HRG^+/+ littermates, supporting a role for HRG as an endogenous regulator of tumor growth. In the present study we also demonstrate that platelet activation is increased in mice lacking HRG. To address whether this elevated platelet activation contributes to the increased pathological angiogenesis in HRG-deficient mice, they were rendered thrombocytopenic before the onset of the angiogenic switch by injection of the anti-platelet antibody GP1bα. Interestingly, this treatment suppressed the increase in angiogenic neoplasias seen in HRG knockout mice. However, if GP1bα treatment was initiated at a later stage, after the onset of the angiogenic switch, no suppression of tumor growth was detected in HRG-deficient mice.

Conclusions

Our data show that increased platelet activation mediates the accelerated angiogenic switch in HRG-deficient mice. Moreover, we conclude that platelets play a crucial role in the early stages of tumor development but are of less significance for tumor growth once angiogenesis has been initiated.     

Morphology of the cranial skeleton and musculature in the obligate carnivorous tadpole of Lepidobatrachus laevis (Anura: Ceratophryidae)

Ziermann, J.M., Infante, C., Hanken, J. and Olsson, L. 2011. Morphology of the cranial skeleton and musculature in the obligate carnivorous tadpole of Lepidobatrachus laevis (Anura: Ceratophryidae). —Acta Zoologica (Stockholm) 00 :1–12. Lepidobatrachus laevis (Ceratophryidae: Ceratophryinae) is a bizarre frog endemic to the Chacoan desert of central South America. Its tadpole is an obligate carnivore that can catch and consume live prey nearly its own size. Morphological adaptations associated with this unique feeding mode, including the larval skull anatomy and associated cranial musculature, have only been partly described. We studied the head of Stages 26–27 larvae using gross dissection, immunohistochemistry, and standard histology. Derived features of this tadpole compared to the microphagous, herbivorous larvae of most other anurans include simplified chondrocranial cartilages and very robust jaw muscles. The mm. suspensorio‐ et quadratoangularis do not take their origin from the processus muscularis of the palatoquadrate, as in most other tadpoles, but instead originate from the corpus of the palatoquadrate caudal to this process. The jaw levators are unusually large. The tadpole of Ceratophrys, another member of the ceratophryine clade, also consumes large animal prey, but its morphology is very different. It probably has evolved independently from a generalized, mainly herbivorous tadpole similar to the larva of Chacophrys, the third ceratophryine genus. Most specialized features of the larval head of Lepidobatrachus laevis are adaptations for ‘megalophagy’—ingestion of whole, very large animal prey.     

Monoclonal antibodies selective for α‐synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α‐synuclein transgenic mice with the disease‐causing A30P mutation

Inclusions of intraneuronal alpha‐synuclein (α‐synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of α‐synuclein is a central feature of the disease pathogenesis. Among the different α‐synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large α‐synuclein oligomers were generated. These antibodies, which do not bind amyloid‐beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in α‐synuclein transgenic mice than linear epitope antibodies. An oligomer‐selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of α‐synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of α‐synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer‐selective α‐synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.     

Steady-state generation of hydrogen peroxide: kinetics and stability of alcohol oxidase immobilized on nanoporous alumina

Alcohol oxidase from Pichia pastoris was immobilized on nanoporous aluminium oxide membranes by silanization and activation by carbonyldiimidazole to create a flow-through enzyme reactor. Kinetic analysis of the hydrogen peroxide generation was carried out for a number of alcohols using a subsequent reaction with horseradish peroxidase and ABTS. The activity data for the immobilized enzyme showed a general similarity with literature data in solution, and the reactor could generate 80 mmol H₂O₂/h per litre reactor volume. Horseradish peroxidase was immobilized by the same technique to construct bienzymatic modular reactors. These were used in both single pass mode and circulating mode. Pulsed injections of methanol resulted in a linear relation between response and concentration, allowing quantitative concentration measurement. The immobilized alcohol oxidase retained 58 % of initial activity after 3 weeks of storage and repeated use.     

Distribution and Variation in the Treeboa Corallus annulatus (Serpentes: Boidae)

The arboreal boid Corallus annulatus has a disjunct distribution in tropical wet forests from extreme southeastern Guatemala to southwestern Ecuador (west of the Andes). The characters upon which subspecies (C. a. blombergi and C. a. colombianus) were described are shown to be of no diagnostic value. Based on a suite of characters (scale, pattern, osteological), Corallus a. blombergi is elevated to species status and Corallus a. colombianus is placed in the synonymy of C. annulatus. Corallus annulatus and C. blombergi are considered to be species that are genuinely uncommon, although not necessarily rare. Resumen La boa arbórea Corallus annulatus tiene una distribución alopatrica en bosques húmedos tropicales desde el extremo sudeste de Guatemala hasta el sudoeste de Ecuador (oeste de los Andes). Demostramos que los carácteres usados para describir las subespecies C. a. blombergi y C. a. colombianus no tienen valor diagnóstico. Basado en carácteres de escamas, patrones, y osteológicos, Corallus a. blombergi es elevado al nivel de especie y Corallus a. colombianus es puesto en sinonimia con C. annulatus. Corallus annulatus y Corallus blombergi son consideradas como especies no verdaderamente comunes, pero no son necesariamente raras.