TMEFF2 Is a PDGF-AA Binding Protein with Methylation-Associated Gene Silencing in Multiple Cancer Types Including Glioma

BACKGROUND: TMEFF2 is a protein containing a single EGF-like domain and two follistatin-like modules. The biological function of TMEFF2 remains unclear with conflicting reports suggesting both a positive and a negative association between TMEFF2 expression and human cancers. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that the extracellular domain of TMEFF2 interacts with PDGF-AA. This interaction requires the amino terminal region of the extracellular domain containing the follistatin modules and cannot be mediated by the EGF-like domain alone. Furthermore, the extracellular domain of TMEFF2 interferes with PDGF-AA-stimulated fibroblast proliferation in a dose-dependent manner. TMEFF2 expression is downregulated in human brain cancers and is negatively correlated with PDGF-AA expression. Suppressed expression of TMEFF2 is associated with its hypermethylation in several human tumor types, including glioblastoma and cancers of ovarian, rectal, colon and lung origins. Analysis of glioma subtypes indicates that TMEFF2 hypermethylation and decreased expression are associated with a subset of non-Proneural gliomas that do not display CpG island methylator phentoype. CONCLUSIONS/SIGNIFICANCE: These data provide the first evidence that TMEFF2 can function to regulate PDGF signaling and that it is hypermethylated and downregulated in glioma and several other cancers, thereby suggesting an important role for this protein in the etiology of human cancers

Synergistic Anticancer Effects of the 9.2.27PE Immunotoxin and ABT-737 in Melanoma

In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE) - based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA) enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination

Mechanisms of decadal variability in the Labrador Sea and the wider North Atlantic in a high-resolution climate model

A necessary step before assessing the performance of decadal predictions is the evaluation of the processes that bring memory to the climate system, both in climate models and observations. These mechanisms are particularly relevant in the North Atlantic, where the ocean circulation, related to both the Subpolar Gyre and the Meridional Overturning Circulation (AMOC), is thought to be important for driving significant heat content anomalies. Recently, a rapid decline in observed densities in the deep Labrador Sea has pointed to an ongoing slowdown of the AMOC strength taking place since the mid 90s, a decline also hinted by in-situ observations from the RAPID array. This study explores the use of Labrador Sea densities as a precursor of the ocean circulation changes, by analysing a 300-year long simulation with the state-of-the-art coupled model HadGEM3-GC2. The major drivers of Labrador Sea density variability are investigated, and are characterised by three major contributions. First, the integrated effect of local surface heat fluxes, mainly driven by year-to-year changes in the North Atlantic Oscillation, which accounts for 62% of the total variance. Additionally, two multidecadal-to-centennial contributions from the Greenland-Scotland Ridge outflows are quantified; the first associated with freshwater exports via the East Greenland Current, and the second with density changes in the Denmark Strait Overflow. Finally, evidence is shown that decadal trends in Labrador Sea densities are followed by important atmospheric impacts. In particular, a negative winter NAO response appears to follow the positive Labrador Sea density trends, and provides a phase reversal mechanism

Nanoparticles

Ultrafine particles featuring a size distribution in the nanometer rang

Morphometric, anatomic and radiographic study of the scapula in the white‐footed tamarin (Saguinus leucopus): report of scapular cartilage and one variation in cranial (superior) transverse scapular ligament

The white-footed tamarin (Saguinus leucopus) is an endangered endemic primate of Colombia, mainly due to the deforestation of its habitat and illegal trade, which generates a high incidence of these animals in wildlife care centres. Musculoskeletal system disorders in S. leucopus are one of the most common diseases and therefore the aim of this study was to contribute to the morphologic studies with a morphometric, anatomic and radiographic description of the scapula in this species to provide a basis for medical interventions, surgical approaches, radiologic diagnoses and comparative functions of this bone. Gross dissections of each scapular region were made in eight specimens without a diagnosis of osteomuscular disease. These specimens died from natural cases in the wildlife care centres of the Corporación Autónoma Regional de Caldas (CORPORCALDAS); after necropsy their carcasses were fixed with 10% formaldehyde, 5% mineral oil and 1% phenic acid in these centres over the course of at least 1 week. X-rays of the scapula were taken in the small animal clinic of the Universidad del Tolima, and morphometric data of the scapulae were obtained with a digital calliper. The scapula of the white-footed tamarin was a flat triangular bone with a deep scapular notch in its cranial margin, where there was a cranial transverse scapular ligament that was absent in two specimens. The coracoid process was highly developed, medially covering the humeral joint. The dorsal margin was covered by the scapular cartilage, which was highly developed in the caudal angle. In the dorsal fourth of the caudal margin, there was a surface from which the m. teres major originated. The lateral surface had a scapular spine with a long hamatus process of the acromion until the lateral part of the humeral joint. The infraspinatus fossa was wider than the supraspinous fossa. On the costal surface, the subscapular fossa was formed by three subscapular lines and one subscapular ridge, the latter helping to form the surface for the m. teres major. In the two radiographic views, caudocranial to the scapula and dorsoventral to the thorax, the scapular spine, acromion, coracoid process, scapular incisura, supraglenoid tubercle, caudal margin, subscapular ridge, and the joints with the clavicle and the humerus could be observed. The scapula of the white-footed tamarin presented bony reliefs that share characteristics with other primates but also with domestic mammals due to its quadrupedal locomotion, which allowed us to correlate its morphologic adaptation with its quadrupedal arboreal displacement