A preclinical model for the ATLL lymphoma subtype with insights into the role of microenvironment in HTLV-1-mediated lymphomagenesis

Abstract \uef7f View references (83) Adult T cell Leukemia/Lymphoma (ATLL) is a mature T cell malignancy associated with Human T cell Leukemia Virus type 1 (HTLV-1) infection. Among its four main clinical subtypes, the prognosis of acute and lymphoma variants remains poor. The long latency (3-6 decades) and low incidence (3-5%) of ATLL imply the involvement of viral and host factors in full-blown malignancy. Despite multiple preclinical and clinical studies, the contribution of the stromal microenvironment in ATLL development is not yet completely unraveled. The aims of this study were to investigate the role of the host microenvironment, and specifically fibroblasts, in ATLL pathogenesis and to propose a murine model for the lymphoma subtype. Here we present evidence that the oncogenic capacity of HTLV-1-immortalized C91/PL cells is enhanced when they are xenotransplanted together with human foreskin fibroblasts (HFF) in immunocompromised BALB/c Rag2-/-\u3b3c -/-mice. Moreover, cell lines derived from a developed lymphoma and their subsequent in vivo passages acquired the stable property to induce aggressive T cell lymphomas. In particular, one of these cell lines, C91/III cells, consistently induced aggressive lymphomas also in NOD/SCID/IL2R\u3b3c KO (NSG) mice. To dissect the mechanisms linked to this enhanced tumorigenic ability, we quantified 45 soluble factors released by these cell lines and found that 21 of them, mainly pro-inflammatory cytokines and chemokines, were significantly increased in C91/III cells compared to the parental C91/PL cells. Moreover, many of the increased factors were also released by human fibroblasts and belonged to the known secretory pattern of ATLL cells. C91/PL cells co-cultured with HFF showed features reminiscent of those observed in C91/III cells, including a similar secretory pattern and a more aggressive behavior in vivo. On the whole, our data provide evidence that fibroblasts, one of the major stromal components, might enhance tumorigenesis of HTLV-1-infected and immortalized T cells, thus throwing light on the role of microenvironment contribution in ATLL pathogenesis. We also propose that the lymphoma induced in NSG mice by injection with C91/III cells represents a new murine preclinical ATLL model that could be adopted to test novel therapeutic interventions for the aggressive lymphoma subtype

nickel removal by zero valent iron lapillus mixtures in column systems

Abstract The remediation of contaminated groundwater, through permeable reactive barrier (PRB) technology, has raised strong interest in the field of environmental geotechnics. The use of granular mixtures composed of zero valent iron (ZVI) together with an inert and/or porous material is a new strategy for preventing the decrease in hydraulic conductivity of PRBs composed of pure ZVI alone. In this paper, granular mixtures composed of ZVI and lapillus in different weight ratios were tested for nickel removal through column tests. The newly proposed material, lapillus, is a low-cost material (a by-product of pumice mining), readily available and efficient for nickel removal, as is shown by the benchmark column tests carried out in this paper. The weight ratio between ZVI and lapillus, the flow velocity and the initial contaminant concentration were the factors investigated in this paper since they can strongly influence the long-term removal efficiency and hydraulic behaviour of a PRB. The column tests results were analysed in terms of hydraulic conductivity, nickel removal efficiency and the distribution of the removed nickel along the column over time. The test results clearly showed the great potential of the proposed ZVI/lapillus granular mixtures in terms of both removal efficiency and long-term hydraulic conductivity

On the accuracy of interpolation based on single-layer artificial neural networks

In the present paper, we consider one-hidden layer ANNs with a feedforward architecture, also referred to as shallow or two-layer networks, so that the structure is determined by the number and types of neurons. The determination of the parameters that define the function, called training, is done via the resolution of the approximation problem, so by imposing the interpolation through a set of specific nodes. We present the case where the parameters are trained using a procedure that is referred to as Extreme Learning Machine (ELM) that leads to a linear interpolation problem. In such hypotheses, the existence of an ANN interpolating function is guaranteed. The focus is then on the accuracy of the interpolation outside of the given sampling interpolation nodes when they are the equispaced, the Chebychev, and the randomly selected ones. The study is motivated by the well-known bell-shaped Runge example, which makes it clear that the construction of a global interpolating polynomial is accurate only if trained on suitably chosen nodes, ad example the Chebychev ones. In order to evaluate the behavior when growing the number of interpolation nodes, we raise the number of neurons in our network and compare it with the interpolating polynomial. We test using Runge's function and other well-known examples with different regularities. As expected, the accuracy of the approximation with a global polynomial increases only if the Chebychev nodes are considered. Instead, the error for the ANN interpolating function always decays and in most cases we observe that the convergence follows what is observed in the polynomial case on Chebychev nodes, despite the set of nodes used for training

Glycosaminoglycans in the tongue of birds

We examined the literature to verify whether adaptations and modifications in the structure and glandular secretions of birds' tongues are related to habitat and can be ascribed to evolutionary processes. The data are discussed in relation to species taxonomy, following the Sibley and Ahlquist classification [C. G. Sibley and J. E. Alquist, Philogeny and Classification of Birds. A Study in Molecular Evolution (Yale University Press, New Haven, 1990)]. The following conclusions are drawn: gustatory papillae and taste buds are present in varying numbers in most species. The composition of gland secretions is also found to be variable. Proteic secretion is documented in Larus modestus, Sula variegata, Fulica atra only. Acid proteoglycans both with sulfomucins and carboxymucins, and also glycoproteins, are consistently found. Sialic and hyaluronic acids are found in many species. Our overview indicates that the presence or absence of gustatory papillae is related to adaptation processes that these structures undergo in response to environmental factors, and that the absence of front tongue glands can be ascribed to habitat and feeding habits. Referring to the Sibley and Ahlquist classification, proteins are present in the glandular secretion of less evolved species, whereas more evolved species exhibit a gradual decrease in proteins with the exception of hyaluronic acid, which is absent, and a progressive increase in glycoproteins and acid proteoglycans

HUMAN HERPESVIRUS 8 AND LYMPHOPROLIFERATIVE DISEASES

The spectrum of lymphoproliferative disorders linked to human herpesvirus 8 (HHV-8) infection has been constantly increasing since the discovery of its first etiologic association with primary effusion lymphoma (PEL). PEL is a rapidly progressing non-Hodgkin’s B-cell lymphoma that develops in body cavities in an effusional form. With the increase in the overall survival of PEL patients, as well as the introduction of HHV-8 surveillance in immunocompromised patients, the extracavitary, solid counterpart of PEL was later identified. Moreover, virtually all plasmablastic variants of multicentric Castleman’s disease (MCD) developing in HIV-1-infected individuals harbor HHV-8, providing a strong etiologic link between MCD and this oncogenic herpesvirus. Two other pathological conditions develop in HIV-1-infected persons concomitantly with MCD: MCD with plasmablastic clusters and MCD-associated plasmablastic lymphoma, the first likely representing an intermediate stage preceding the full neoplastic stage. MCD in leukemic phase has also been described, albeit much less commonly. The germinotropic lymphoproliferative disorder (GLPD) may resemble extracavitary PEL, but develops in immune competent HHV8-infected individuals, and, unlike the disorders described above, it responds well to conventional therapies. Almost all HHV-8-mediated lymphoproliferative disorders are the result of an interaction between HHV-8 infection and a dysregulated immunological system, leading to the formation of inflammatory niches in which B cells, at different developmental stages, are infected, proliferate and may eventually shift from a polyclonal state to a monoclonal/neoplastic disorder. Herein, we describe the association between HHV-8 and lymphoproliferative disorders and highlight the predominant distinctive features of each disease

Morphological, histochemical and immunohistochemical study of the gill epithelium in the abyssal teleost fish Coelorhynchus coelorhynchus

Histochemical and immunohistochemical study was carried out on nitrinergic innervation and neuroendocrine system in the gill epithelium of the abyssal fish Coelorhynchus coelorhynchus. The results showed that nNOS-positive nerve fibers, originating from the branchial arch were present in the subepithelial tissue of branchial primary filament. nNOS-positive neuroendocrine cells were also present in the primary filaments and secondary lamellae. Numerous mucous cells in the gill epithelium were AB/PAS-positive, while sialic acid was absent as confirmed by neuraminidase reaction and WGA lectin histochemistry. The mucus compounds in abyssal teleost fish are different from those found in pelagic species, being related to their living conditions. In abyssal species, greater numbers of chloride and neuroendocrine cells are involved in the movement of water and electrolytes. Neuroendocrine cells possess oxygen receptors which mediate the cardiovascular and ventilatory response to oxygen deficiency, as reported in teleost species. Besides, NO contributes through nervous stimulation to the regulation of vascular tone and blood circulation in the gill

The Human MDM2 Oncoprotein Increases the Transcriptional Activity and the Protein Level of the p53 Homolog p63

Genetic alteration of the p53 tumor suppressor gene, which monitors DNA damage and operates cell cycle checkpoints, is a major factor in the development of human malignancies. The p53 protein belongs to a family that also includes two structurally related proteins, p63 and p73. Although all three proteins share similar transcriptional functions and antiproliferative effects, each of them appears to play a distinct role in development and tumor suppression. One of the principal regulators of p53 activity is the MDM2 protein. The interaction of MDM2 with p53 inhibits p53 transcriptional activity and targets p53 for ubiquitin-dependent degradation. The ability of MDM2 to inhibit p53 functions is antagonized by the ARF oncosuppressor protein. We show here that like p53, the p63alpha and p63gamma isoforms are able to associate with human MDM2 (HDM2). Overexpression of HDM2 increased the steady-state level of intracellular p63 and enhanced its transcriptional activity. Both effects appeared to be counteracted by ARF coexpression. These data indicate that p63 can be activated by HDM2 under conditions in which p53 is inhibited. Therefore, HDM2 expression could support p63-specific transcriptional functions on a common set of genes, keeping interference by p53 at a minimum

Bioplastic from Renewable Biomass: A Facile Solution for a Greener Environment

AbstractEnvironmental pollutions are increasing day by day due to more plastic application. The plastic material is going in our food chain as well as the environment employing microplastic and other plastic-based contaminants. From this point, bio-based plastic research is taking attention for a sustainable and greener environment with a lower footprint on the environment. This evaluation should be made considering the whole life cycle assessment of the proposed technologies to make a whole range of biomaterials. Bio-based and biodegradable bioplastics can have similar features as conventional plastics while providing extra returns because of their low carbon footprint as long as additional features in waste management, like composting. Interest in competitive biodegradable materials is growing to limit environmental pollution and waste management problems. Bioplastics are defined as plastics deriving from biological sources and formed from renewable feedstocks or by a variation of microbes, owing to the ability to reduce the environmental effect. The research and development in this field of bio-renewable resources can seriously lead to the adoption of a low-carbon economy in medical, packaging, structural and automotive engineering, just to mention a few. This review aims to give a clear insight into the research, application opportunities, sourcing and sustainability, and environmental footprint of bioplastics production and various applications. Bioplastics are manufactured from polysaccharides, mainly starch-based, proteins, and other alternative carbon sources, such as algae or even wastewater treatment byproducts. The most known bioplastic today is thermoplastic starch, mainly as a result of enzymatic bioreactions. In this work, the main applications of bioplastics are accounted. One of them being food applications, where bioplastics seem to meet the food industry concerns about many the packaging-related issues and appear to play an important part for the whole food industry sustainability, helping to maintain high-quality standards throughout the whole production and transport steps, translating into cleaner and smarter delivery chains and waste management. High perspectives resides in agricultural and medical applications, while the number of fields of applications grows constantly, for example, structural engineering and electrical applications. As an example, bio-composites, even from vegetable oil sources, have been developed as fibers with biodegradable features and are constantly under research

Higginsianins A and B, two fungal diterpenoid α-pyrones with cytotoxic activity against human cancer cells

Two new diterpenoid α-pyrones, named higginsianins A and B, were isolated from the mycelium of the microbial fungus Colletotrichum higginsianum grown in liquid culture. In previous studies, we have shown that both compounds reduce viability of different types of cancer cells in culture. Here, we extend our previous observations and explore, at a deeper level, the cellular effects of higginsianins treatment. Higginisianins A and B reduce viability of A431, HeLa and H1299 cancer cells. Both compounds increase the level of the cell cycle inhibitor p21WAF and reduce the rate of cell proliferation. Cell cycle analyses reveal that higginsianins arrest cancer cells in S-phase. Furthermore, cells incubated with higginsianins reveal discrete γ-H2AX positive nuclear foci indicating the occurrence of DNA lesions. At longer incubation times, higginsianins induce massive cell detachment and non-apoptotic cell death. Human primary keratinocytes and spontaneously immortalized Hacat cells, a preneoplastic cell line model, are less sensitive to higginsianins effects. These findings suggest that higginsianins exhibit considerable cytotoxicity against a wide spectrum of malignant cells and may be considered as promising anticancer agents