Clinicopathologic Characterization of Diffuse-Large-B-Cell Lymphoma with an Associated Serum Monoclonal IgM Component

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p<.0001), non-GCB-type (p = .002) stage III-IV(p = .003), ≥2 extra nodal sites (p<.0001), bone-marrow (p = .002), central-nervous-system (CNS) involvement at disease onset or relapse (p<.0001), IPI-score 3–5 (p = .009) and failure to achieve complete remission (p = .005), were significantly more frequent. FISH analyses for BCL2, BCL6 and MYC gene rearrangements detected only two cases harboring BCL2 gene translocation and in one case a concomitant BCL6 gene translocation was also observed. None of the IgM-secreting DLBCL was found to have L265P mutation of MYD88 gene. Thirty-six month event-free (11.8% vs 66.4% p<.0001), progression-free (23.5% vs 75.7%, p<.0001) and overall (47.1% vs 74.8%, p<.0001) survivals were significantly worse in the IgM-secreting group. In multivariate analysis IgM-secreting (p = .005, expB = 0.339, CI = 0.160-0.716) and IPI-score 3–5 (p = .010, expB = 0.274, CI = 0.102–0.737) were the only significant factors for progression-free-survival. Notably, four relapsed patients, who were treated with salvage immmunochemotherapy combined with bortezomib or lenalidomide, achieved lasting remission. Our data suggests that IgM-secreting cases are a distinct subset of DLBCL, originating from activated-B-cells with terminally differentiated features, prevalent extra nodal dissemination and at high risk of CNS involvement.     

A Colloidal Singularity Reveals the Crucial Role of Colloidal Stability for Nanomaterials In-Vitro Toxicity Testing: nZVI-Microalgae Colloidal System as a Case Study

Aggregation raises attention in Nanotoxicology due to its methodological implications. Aggregation is a physical symptom of a more general physicochemical condition of colloidal particles, namely, colloidal stability. Colloidal stability is a global indicator of the tendency of a system to reduce its net surface energy, which may be achieved by homo-aggregation or hetero-aggregation, including location at bio-interfaces. However, the role of colloidal stability as a driver of ENM bioactivity has received little consideration thus far. In the present work, which focuses on the toxicity of nanoscaled Fe° nanoparticles (nZVI) towards a model microalga, we demonstrate that colloidal stability is a fundamental driver of ENM bioactivity, comprehensively accounting for otherwise inexplicable differential biological effects. The present work throws light on basic aspects of Nanotoxicology, and reveals a key factor which may reconcile contradictory results on the influence of aggregation in bioactivity of ENMs.     

Is There Still Room for Novel Viral Pathogens in Pediatric Respiratory Tract Infections?

Viruses are the most frequent cause of respiratory disease in children. However, despite the advanced diagnostic methods currently in use, in 20 to 50% of respiratory samples a specific pathogen cannot be detected. In this work, we used a metagenomic approach and deep sequencing to examine respiratory samples from children with lower and upper respiratory tract infections that had been previously found negative for 6 bacteria and 15 respiratory viruses by PCR. Nasal washings from 25 children (out of 250) hospitalized with a diagnosis of pneumonia and nasopharyngeal swabs from 46 outpatient children (out of 526) were studied. DNA reads for at least one virus commonly associated to respiratory infections was found in 20 of 25 hospitalized patients, while reads for pathogenic respiratory bacteria were detected in the remaining 5 children. For outpatients, all the samples were pooled into 25 DNA libraries for sequencing. In this case, in 22 of the 25 sequenced libraries at least one respiratory virus was identified, while in all other, but one, pathogenic bacteria were detected. In both patient groups reads for respiratory syncytial virus, coronavirus-OC43, and rhinovirus were identified. In addition, viruses less frequently associated to respiratory infections were also found. Saffold virus was detected in outpatient but not in hospitalized children. Anellovirus, rotavirus, and astrovirus, as well as several animal and plant viruses were detected in both groups. No novel viruses were identified. Adding up the deep sequencing results to the PCR data, 79.2% of 250 hospitalized and 76.6% of 526 ambulatory patients were positive for viruses, and all other children, but one, had pathogenic respiratory bacteria identified. These results suggest that at least in the type of populations studied and with the sampling methods used the odds of finding novel, clinically relevant viruses, in pediatric respiratory infections are low.     

Fasciola hepatica Kunitz Type Molecule Decreases Dendritic Cell Activation and Their Ability to Induce Inflammatory Responses

The complete repertoire of proteins with immunomodulatory activity in Fasciola hepatica (Fh) has not yet been fully described. Here, we demonstrated that Fh total extract (TE) reduced LPS-induced DC maturation, and the DC ability to induce allogeneic responses. After TE fractionating, a fraction lower than 10 kDa (F<10 kDa) was able to maintain the TE properties to modulate the DC pro- and anti-inflammatory cytokine production induced by LPS. In addition, TE or F<10 kDa treatment decreased the ability of immature DC to stimulate the allogeneic responses and induced a novo allogeneic CD4+CD25+Foxp3+ T cells. In contrast, treatment of DC with T/L or F<10 kDa plus LPS (F<10/L) induced a regulatory IL-27 dependent mechanism that diminished the proliferative and Th1 and Th17 allogeneic responses. Finally, we showed that a Kunitz type molecule (Fh-KTM), present in F<10 kDa, was responsible for suppressing pro-inflammatory cytokine production in LPS-activated DC, by printing tolerogenic features on DC that impaired their ability to induce inflammatory responses. These results suggest a modulatory role for this protein, which may be involved in the immune evasion mechanisms of the parasite.     

Morphology and function of the hyoid apparatus of fossil xenarthrans (mammalia)

The analysis of the hyoid apparatus of fossil xenarthrans provides insight on the form of the tongue and its function in food intake and intraoral processing. The hyoid apparatus of xenarthrans is notable for fusion among its elements. The presence of a V‐bone, a complex consisting of fused basihyal and thyrohyal bones, is a consistent and probably synapomorphic feature of xenarthrans. Fusion of other elements is variable in fossil xenarthrans. Most fossil sloths retain independent elements, as in living dasypodids and mammals generally. Among nothrotheriids, the elements are slender and their articular surfaces indicate considerable mobility, and the relatively long and horizontal orientation of the geniohyoid muscle suggests considerable tongue protrusion. Among mylodontines, such as Paramylodon and Glossotherium, the elements indicate relatively mobile articulations, except between the stylo‐ and epihyals. The relatively posterior placement of the apparatus and the length and alignment of the geniohyoid muscle indicate considerable capacity for tongue protrusion. Scelidotherium, however, had rigidly articulated stylohyal and epihyal, and the apparatus lies farther anteriorly, which together with the elongated, steeply inclined mandibular symphysis, indicates a relatively shorter geniohyoid muscle and thus more limited capacity for tongue protrusion. A similar situation is indicated for Megatherium, casting doubt on the classical reconstruction of this sloth as having a long prehensile tongue. Among cingulates Prozaedyus resembles living dasypodids, indicating considerable tongue protrusion important in food acquisition and intake. More extensive fusion of hyoid elements occurs in the cingulates Glyptodon and Proeutatus, in which the stylohyal and epihyal at least, are fused into a single element termed the sigmohyal. The presence of this element supports recent proposals of a sister‐group relationship between glyptodonts and eutatines. The rigidity of the apparatus suggests limited tongue protrusion, but the tongue, in glyptodonts at least, was a powerful structure important for intraoral manipulation of food. J. Morphol. 271:1119–1133, 2010. © 2010 Wiley‐Liss, Inc.     

Tyrosine Hydroxylase Is Short-Term Regulated by the Ubiquitin-Proteasome System in PC12 Cells and Hypothalamic and Brainstem Neurons from Spontaneously Hypertensive Rats: Possible Implications in Hypertension

Aberrations in the ubiquitin-proteasome system (UPS) are implicated in the pathogenesis of various diseases. Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamines biosynthesis, is involved in hypertension development. In this study we investigated whether UPS regulated TH turnover in PC12 cells and hypothalamic and brainstem neurons from spontaneously hypertensive rats (SHR) and whether this system was impaired in hypertension. PC12 cells were exposed to proteasome or lysosome inhibitors and TH protein level evaluated by Western blot. Lactacystin, a proteasome inhibitor, induced an increase of 86±15% in TH levels after 30 min of incubation, then it started to decrease up to 6 h to reach control levels and finally it rose up to 35.2±8.5% after 24 h. Bafilomycin, a lysosome inhibitor, did not alter TH protein levels during short times, but it increased TH by 92±22% above basal after 6 h treatment. Before degradation proteasome substrates are labeled by conjugation with ubiquitin. Efficacy of proteasome inhibition on TH turnover was evidenced by accumulation of ubiquitinylated TH after 30 min. Further, the inhibition of proteasome increased the quantity of TH phosphorylated at Ser40, which is essential for TH activity, by 2.7±0.3 fold above basal. TH protein level was upregulated in neurons from hypothalami and brainstem of SHR when the proteasome was inhibited during 30 min, supporting that neuronal TH is also short-term regulated by the proteasome. Since the increased TH levels reported in hypertension may result from proteasome dysfunction, we evaluate proteasme activity. Proteasome activity was significantly reduced by 67±4% in hypothalamic and brainstem neurons from SHR while its protein levels did not change. Present findings show that TH is regulated by the UPS. The impairment in proteasome activity observed in SHR neurons may be one of the causes of the increased TH protein levels reported in hypertension.     

Checklist of the helminth parasites of the genus Profundulus Hubbs, 1924 (Cyprinodontiformes,Profundulidae), an endemic family of freshwater fishes in Middle-America

From December 2012 to November 2014, 267 fish belonging to the family Profundulidae (representing nine of the 11 species of the genus Profundulus) were collected in 26 localities of Middle-America, across southern Mexico, Guatemala, and Honduras, comprising the distribution range of the genus, and analyzed for helminth parasites. Additionally, a database with all ten available published accounts of the helminth parasite fauna of this genus (the only genus within the family) was assembled. Based on both sources of information, a checklist containing all the records was compiled as a tool to address future questions in the areas of evolutionary biology, biogeography, ecology and phylogeography of this host-parasite association. The helminth parasite fauna of this fish group consists of 20 nominal species, classified in 17 genera and 14 families. It includes six species of adult digeneans, five metacercariae, two monogeneans, one adult cestode, three adult nematodes and three larval nematodes. The profundulid fishes are parasitized by a specialized group of helminth species (e.g. Paracreptotrema blancoi sensu Salgado-Maldonado et al. (2011b), Paracreptotrema profundulusi Salgado-Maldonado, Caspeta-Mandujano & Martínez Ramírez, 2011, Phyllodistomum spinopapillatum Pérez-Ponce de León, Pinacho-Pinacho, Mendoza-Garfias & García-Varela, 2015, Spinitectus humbertoi Mandujano-Caspeta & Moravec, 2000, Spinitectus mariaisabelae Caspeta-Mandujano Cabañas-Carranza & Salgado-Maldonado, 2007 and Rhabdochona salgadoi Mandujano-Caspeta & Moravec, 2000), representing the core helminth fauna that are not shared with other Middle-American fish species.     

Two new species of Euptychia Hübner, 1818 from the upper Amazon basin (Lepidoptera,Nymphalidae, Satyrinae)

Two new species of Euptychia Hübner, 1818 are described from the upper Amazon basin: Euptychia attenboroughi Neild, Nakahara, Fratello & Le Crom, sp. n. (type locality: Amazonas, Venezuela), and Euptychia sophiae Zacca, Nakahara, Dolibaina & Dias, sp. n. (type locality: Acre, Brazil). Their unusual facies prompted molecular and phylogenetic analyses of one of the species resulting in support for their classification in monophyletic Euptychia. Diagnostic characters for the two species are presented based on wing morphology, wing pattern, presence of androconial patches on the hindwing, and genitalia. Our results indicate that the projection of the tegumen above the uncus, previously considered a synapomorphy for Euptychia, is not shared by all species in the genus. The adults and their genitalia are documented, and distribution data and a map are provided.     

Are rodents a source of biotic resistance to tree invasion in Pampean grasslands? Tree seed consumption under different conditions

Biotic resistance has been invoked as a major barrier to woody species invasion, although the role of resident generalist consumers and their interaction with seed availability in a local community has received little attention. We assessed tree seed consumption by rodents under two different scenarios: (i) We documented in field spatio‐temporal patterns of seed predation by native rodents on two exotic tree species, Gleditsia triacanthos or ‘honey locust’ and Robinia pseudoacacia or ‘white locust’ (family Leguminosae), in five grassland habitats of the Inland Pampa, Argentina. (ii) We conducted laboratory feeding trials to evaluate tree seed consumption in the presence (cafeteria‐style feeding trials) and in the absence (non‐choice feeding trials) of alternative food supplies. Seed predation was generally higher for Robinia than for Gleditsia seeds, both in field and laboratory conditions. For both tree species, seed predation varied between habitats and seasons and was higher in the native tussock grassland than in the remaining studied communities, whereas the crop field showed the lowest levels of consumption along with the absence of captured rodents. Seed consumption of Gleditsia and Robinia among the four grassland communities (which did not differ in rodent abundance) was negatively associated with the availability of alternative food. Laboratory feeding trials showed a higher consumption of Gleditsia seeds in the non‐choice than in the cafeteria‐style feeding trials, while the consumption of Robinia seeds did not differ in the absence or presence of alternative seeds. These patterns indicate that the contribution of resident granivores to invasion resistance might depend on colonizer species identity, recipient community type and season of the year. We suggest that rodent preferences for different invader seeds will interact with the availability of alternative food in the local habitat in influencing the amount of predator‐mediated biotic resistance to invasion.