Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma

Tumor-associated macrophages (TAMs) derived from peripheral blood monocytes recruited into the renal cell carcinoma (RCC) microenvironment. In response to inflammatory stimuli, macrophages undergo M1 (classical) or M2 (alternative) activation. M1 cells produce high levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-12, IL-23 and IL-6, while M2 cells produce anti-inflammatory cytokines, such as IL-10, thus contributing to RCC-related immune dysfunction. The presence of extensive TAM infiltration in RCC microenvironment contributes to cancer progression and metastasis by stimulating angiogenesis, tumor growth, and cellular migration and invasion. Moreover, TAMs are involved in epithelial–mesenchymal transition of RCC cancer cells and in the development of tumor resistance to targeted agents. Interestingly, macrophage autophagy seems to play an important role in RCC. Based on this scenario, TAMs represent a promising and effective target for cancer therapy in RCC. Several strategies have been proposed to suppress TAM recruitment, to deplete their number, to switch M2 TAMs into antitumor M1 phenotype and to inhibit TAM-associated molecules. In this review, we summarize current data on the essential role of TAMs in RCC angiogenesis, invasion, impaired anti-tumor immune response and development of drug resistance, thus describing the emerging TAM-centered therapies for RCC patients.     

Localization of Mitochondrial Carnitine/Acylcarnitine Translocase in Sensory Neurons from Rat Dorsal Root Ganglia

The carnitine/acylcarnitine transporter is a transport system whose function is essential for the mitochondrial β-oxidation of fatty acids. Here, the presence of carnitine/acylcarnitine carrier (CACT) in nervous tissue and its sub-cellular localization in dorsal root ganglia (DRG) neurons have been investigated. Western blot analysis using a polyclonal anti-CACT antibody produced in our laboratory revealed the presence of CACT in all the nervous tissue extracts analyzed. Confocal microscopy experiments performed on fixed and permeabilized DRG neurons co-stained with the anti-CACT antibody and the mitochondrial marker MitoTracker Red clearly showed a mitochondrial localization for the carnitine/acylcarnitine transporter. The transport activity of CACT from DRG extracts reconstituted into liposomes was about 50 % in respect to liver extracts. The experimental data here reported represent the first direct evidence of the expression of the carnitine/acylcarnitine transporter in sensory neurons, thus supporting the existence of the β-oxidation pathway in these cells.     

Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features,psychomotor delay,microcephaly and no history of seizures

Mutations in neuronal voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A may play an important role in the etiology of neurological diseases and psychiatric disorders, besides various types of epilepsy. Here we describe a 3-year-old boy with autistic features, language delay, microcephaly and no history of seizures. Array-CGH analysis revealed an interstitial deletion of ~ 291.9 kB at band 2q24.3 disrupting the entire SCN2A gene and part of SCN3A. We discuss the effects of haploinsufficiency of SCN2A and SCN3A on the genetic basis of neurodevelopmental and neurobehavioral disorders and we propose that this haploinsufficiency may be associated not only with epilepsy, but also with autistic features.     

DNA Topological Context Affects Access to Eukaryotic DNA Topoisomerase I

Abstract

We have analyzed the reactivity of a 217 base pair segment of the intrinsically curved Crithidia fasciculata kinetoplast DNA towards eukaryotic DNA topoisomerase I. The substrates were open [linear fragment and nicked circle] and closed minidomains [closed relaxed circle and circles with linking differences of ?1 and ?2], We interpreted the results with the aid of a model that was used to predict the structures of the topoisomers. The modelling shows that the ΔLk(?l) form is unusually compact because of the curvature in the DNA. To determine the role of sequence-directed curvature in both the experimental and modeling studies, controls were examined in which the curved Crithidia sequence was replaced by an uncurved sequence obtained from the plasmid pBR322.

Reactivity of the Crithidia DNA [as analyzed both by the cleavage and the topoisomerization reactions] markedly varied among the DNA forms: (i) the hierarchy of overall reactivity observed is: linear fragment > nicked circular, closed circular [ΔLk(O)], interwound [ΔLk(?2)] > bent interwound [ΔLk(?l)]; (ii) the intensity of several cleavage positions differs among DNA forms.

The results show that eukaryotic DNA topoisomerase I is very sensitive to the conformation of the substrates and that its reactivity is modulated by the variation of the compactness of the DNA molecule. The C. fasciculata sequence contains a highly curved segment that determines the conformation of the closed circle in a complex way.     

Involvement of Microorganisms in the Formation of Carbonate Speleothems in the Cervo Cave (L'Aquila-Italy)

Much is known about the bacterial precipitation of carbonate rocks, but comparatively little is known about the involvement of microbes in the formation of secondary mineral structures in caves. We hypothesized that bacteria isolated from calcareous stalactites, which are able to mediate CaCO₃ precipitation in vitro, play a role in the formation of carbonate speleothems. We collected numerous cultivable calcifying bacteria from calcareous speleothems from Cervo cave, implying that their presence was not occasional. The relative abundance of calcifying bacteria among total cultivable microflora was found to be related to the calcifying activity in the stalactites. We also determined the δ ¹³C and δ ¹⁸ O values of the Cervo cave speleothems from which bacteria were isolated and of the carbonates obtained in vitro to determine whether bacteria were indeed involved in the formation of secondary mineral structures. We identified three groups of biological carbonates produced in vitro at 11°C on the basis of their carbon isotopic composition: carbonates with δ ¹³C values (a) slightly more positive, (b) more negative, and (c) much more negative than those of the stalactite carbonates. The carbonates belonging to the first group, characterized by the most similar δ ¹³C values to stalactites, were produced by the most abundant strains. Most of calcifying isolates belonged to the genus Kocuria. Scanning electron microscopy showed that dominant morphologies of the bioliths were sherulithic with fibrous radiated interiors. We suggest a mechanism of carbonate crystal formation by bacteria.     

Long‐term effects of climatic–hydrological drivers on macroinvertebrate richness and composition in two Mediterranean streams

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Individual tooth macrowear pattern guides the reconstruction of Sts 52 (Australopithecus africanus) dental arches

The functional restoration of the occlusal relationship between maxillary and mandibular tooth rows is a major challenge in modern dentistry and maxillofacial surgery. Similar technical challenges are present in paleoanthropology when considering fragmented and deformed mandibular and maxillary fossils. Sts 52, an Australopithecus africanus specimen from Sterkfontein Member 4, represents a typical case where the original shape of the dental arches is no longer preserved. It includes a partial lower face (Sts 52a) and a fragmented mandible (Sts 52b), both incomplete and damaged to such an extent to thwart attempts at matching upper and lower dentitions. We show how the preserved macrowear pattern of the tooth crowns can be used to functionally reconstruct Sts 52's dental arches. High‐resolutiondental stone casts of Sts 52 maxillary and mandibular dentition were mounted and repositioned in a dental articulator. The occlusal relationship between antagonists was restored based on the analysis of the occlusal wear pattern of each preserved tooth, considering all dental contact movements represented in the occlusal compass. The reconstructed dental arches were three‐dimensional surface scanned and their occlusal kinematics tested in a simulation. The outcome of this contribution is the first functional restoration of A. africanus dental arches providing new morphometric data for specimen Sts 52. It is noteworthy that the method described in this case study might be applied to several other fossilspecimens. Am J Phys Anthropol, 2013. © 2013 Wiley Periodicals, Inc.