Papillary thyroid carcinomas (PTCs) that invade into local structures are associated with a poor prognosis, but the mechanisms for PTC invasion are incompletely defined, limiting the development of ...new therapies. To characterize biological processes involved in PTC invasion, we analyzed the gene expression profiles of microscopically dissected intratumoral samples from central and invasive regions of seven widely invasive PTCs and normal thyroid tissue by oligonucleotide microarray and performed confirmatory expression and functional studies. In comparison with the central regions of primary PTCs, the invasive fronts overexpressed TGF β, NFκB and integrin pathway members, and regulators of small G proteins and CDC42. Moreover, reduced levels of mRNAs encoding proteins involved in cell-cell adhesion and communication were identified, consistent with epithelial-to-mesenchymal transition (EMT). To confirm that aggressive PTCs were characterized by EMT, 34 additional PTCs were examined for expression of vimentin, a hallmark of EMT. Overexpression of vimentin was associated with PTC invasion and nodal metastasis. Functional, in vitro studies demonstrated that vimentin was required both for the development and maintenance of a mesenchymal morphology and invasiveness in thyroid cancer cells. We conclude that EMT is common in PTC invasion and that vimentin regulates thyroid cancer EMT in vitro.
Chromosome 3q26-29 is a critical region of genomic amplification in lung squamous cell carcinomas (SCC). Identification of candidate drivers in this region could help uncover new mechanisms in the ...pathogenesis and potentially new targets in SCC of the lung.
We conducted a meta-analysis of seven independent datasets containing a total of 593 human primary SCC samples to identify consensus candidate drivers in 3q26-29 amplicon. Through integrating protein-protein interaction network information, we further filtered for candidates that may function together in a network. Computationally predicted candidates were validated using RNA interference (RNAi) knockdown and cell viability assays. Clinical relevance of the experimentally supported drivers was evaluated in an independent cohort of 52 lung SCC patients using survival analysis.
The meta-analysis identified 20 consensus candidates, among which four (SENP2, DCUN1D1, DVL3, and UBXN7) are involved in a small protein-protein interaction network. Knocking down any of the four proteins led to cell growth inhibition of the 3q26-29-amplified SCC. Moreover, knocking down of SENP2 resulted in the most significant cell growth inhibition and downregulation of DCUN1D1 and DVL3. Importantly, a gene expression signature composed of SENP2, DCUN1D1, and DVL3 stratified patients into subgroups with different response to adjuvant chemotherapy.
Together, our findings show that SENP2, DCUN1D1, and DVL3 are candidate driver genes in the 3q26-29 amplicon of SCC, providing novel insights into the molecular mechanisms of disease progression and may have significant implication in the management of SCC of the lung.
There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known ...therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis.
Abstract In this study, we conducted the clinicopathological characterization of a non-pathogenic FAdV-D serotype 11 strain MX95, isolated from healthy chickens, and its entire genome was sequenced. ...Experiments in SPF chickens revealed that the strain is a non-pathogenic virus that did not cause death at challenge doses of 1×106 TCID50. Additionally, the infection in SPF chickens caused no apparent damage in most of the organs analyzed by necropsy and histopathology, but it did cause inclusion body hepatitis; nevertheless it did not generate severe infectious clinical symptoms. The virus was detected in several chicken organs, including the lymphoid organs, by real-time polymerase chain reaction (PCR) until 42 days. The genome of FAdV-11 MX95 has a size of 44,326 bp, and it encodes 36 open reading frames (ORFs). Comparative analysis of the genome indicated only 0.8% dissimilarity with a highly virulent serotype 11 that was previously reported.
This study characterised two bio-binders (named Bio A and Bio B) derived from pine wood resins and designed for full replacement of asphalt binder. Bio A and Bio B were compared to a petroleum-based ...asphalt binder (AC 30/45). Elemental analysis, Fourier-Transform Infrared Spectroscopy, Gas Chromatography-Mass Spectrometry, Thermogravimetric analysis, and Linear Viscoelastic characterisation were applied to evaluate the materials studied. The susceptibility to aging was evaluated by comparing unaged and short-term aged samples of the three binders. Bio A showed a penetration grade of 29 (0.1 mm) and softening point of 55.2°C, while Bio B showed 21 (0.1 mm) and 57°C, respectively. AC 30/45 showed a penetration grade of 30 (0.1 mm) and softening point of 55°C. Bio B was found as more prone to aging than Bio A and AC30/45. This result might be related to the higher presence of saturated fatty acid methyl esters in Bio B.
Highly virulent fowl aviadenoviruses (genus: Aviadenovirus) represent a significant risk in poultry farming that may contribute to increased mortality rates and may adversely affect the growth ...performance of poultry flocks. In this study, we performed the clinicopathological characterization of a FAdV strain SHP95 isolated from a commercial farm and its whole genome sequencing. The study revealed that the isolated strain is a highly virulent serotype 4 FAdV that can cause 100% mortality in day-old specific pathogen free (SPF) chickens with a dose of 2.5 × 10 ⁵ TCID ₅₀. At a lower viral dose (1.5 × 10 ⁴ TCID ₅₀), the infection in day-old SPF chickens caused 40% mortality and lesions characteristic for Hepatitis-hydropericardium syndrome (HHS). The viral strain was detectable by real time PCR in chicken organs, including the lymphoid organs until day 28 after infection. The whole genome assembly of strain SHP95 revealed a size of 45,641 bp, which encodes for 42 viral open reading frame (ORF). The comparative analysis in the genome shows 98.1% similarity between strain SHP95 and other FAdV-4 genomes reported. The major differences in the genome sequence between pathogenic and non-pathogenic fowl Adenovirus were identified in the right arm of the genome.
Tuberculosis (TB) is considered the oldest pandemic in human history. The emergence of multidrug-resistant (MDR) strains is currently considered a serious global health problem. As components of the ...innate immune response, antimicrobial peptides (AMPs) such as cathelicidins have been proposed to have efficacious antimicrobial activity against
(
). In this work, we assessed a cathelicidin from water buffalo,
, (WBCATH), determining in vitro its antitubercular activity (MIC), cytotoxicity and the peptide effect on bacillary loads and cytokines production in infected alveolar macrophages. Our results showed that WBCATH has microbicidal activity against drug-sensitive and MDR
, induces structural mycobacterial damage demonstrated by electron microscopy, improves
killing and induces the production of protective cytokines by murine macrophages. Furthermore, in vivo WBCATH showed decreased bacterial loads in a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive or MDR mycobacteria. In addition, a synergistic therapeutic effect was observed when first-line antibiotics were administered with WBCATH. These results were supported by computational modeling of the potential effects of WBCATH on the cellular membrane of
Thus, this water buffalo-derived cathelicidin could be a promising adjuvant therapy for current anti-TB drugs by enhancing a protective immune response and potentially reducing antibiotic treatment duration.
Bisphenol A (BPA) is a compound used in the manufacture of a wide variety of everyday materials that, when released into the environment, causes multiple detrimental effects on humans and other ...organisms. The reason for this review is to provide an overview of the presence, distribution, and concentration of BPA in water, soil, sediment, and air, as well as the process of release and migration, biomagnification, and exposure mechanisms that cause various toxic effects in humans. Therefore, it is important to seek efficient and economic strategies that allow its removal from the environment and prevent it from reaching humans through food chains. Likewise, the main removal techniques are analyzed, focusing on biological treatments, particularly the most recent advances in the degradation of BPA in different environmental matrices through the use of ligninolytic fungi, non-ligninolytic fungi and yeasts, as well as the possible routes of metabolic processes that allow their biotransformation or biodegradation due to their efficient extracellular enzyme systems. This review supports the importance of the application of new biotechnological tools for the degradation of BPA.
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•Production, release and distribution of BPA in different environmental matrices.•Process of bioconcentration, bioaccumulation and biomagnification of BPA through trophic chains.•Biodegradation of BPA by ligninolytic, non-ligninolytic fungi and yeasts.•Description of fungal metabolic pathways and major enzymes involved in BPA degradation.
Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present ...proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on
in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with
. Low-dose dexamethasone treatment increased the clearance capacity of
by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB.
The aims of the study were to determine (1) whether the presence of High blood pressure (HBP) states in the youth associate a steeper rate of age-related change in arterial geometrical and wall ...properties with respect to subjects with no previous cardiovascular risk factor (CRF) exposure, (2) in which parameters and in what magnitude, and (3) the existence of a gender-related difference in the impact of this condition on arterial properties. 300 individuals (mean/range: 15/4–29 years; 133 females) were included. Two groups were assembled: (1) Reference: nonprevious exposure to traditional CRF and (2) HBP: subjects with arterial hypertension and/or elevated blood pressure (BP) levels during the study. Additionally, HBP subjects were separated in BP-related subgroups. Measured parameters were (1) central (aortic) arterial BP and aortic pulse wave analysis parameters, (2) carotid and femoral artery local (pressure-strain elastic modulus) and regional (pulse wave velocity; PWV) stiffness, and (3) arterial diameters and carotid intima-media thickness (CIMT). Age-related changes in these parameters (absolute values and z-scores) were explored by obtaining simple linear regression models for each group. HBP presented a steeper rate of change (accelerated vascular aging; VA) for most of the parameters assessed, mainly in central (aortic) hemodynamics. VA increased as the HBP level got higher. Both males’ and females’ aging rates were affected by this condition, but females presented a more marked relative age-related increase with HBP exposure. HBP states in the youth gradually associate accelerated VA, with a progressive hemodynamic-structural-functional onset of damage, with females presenting a more marked relative HBP-associated arterial repercussion.
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