Oncolytic adenovirus coding for shedding-resistant MICA enhances immune responses against tumors.

Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.

Enhanced removal of the endocrine disruptor compound Bisphenol A by adsorption onto green-carbon materials. Effect of real effluents on the adsorption process.

The high exposure to the endocrine disrupting compounds (EDC) in water represents a relevant issue for the health of living beings. The xenoestrogen Bisphenol A (BPA), a suspected EDC, is an industrial additive broadly used for manufacturing polycarbonate and epoxy resins. Due to its harmful effect in humans and the aquatic environment, an efficient method to remove BPA from wastewater is urgently required. The present work aims to study the adsorption of BPA from aqueous solutions onto carbonaceous materials, e.g., a synthesized carbon xerogel (RFX), a chemical-activated carbon from Kraft lignin (KLP) and a commercial activated carbon (F400) for comparative purposes. Batch kinetic and adsorption tests of BPA in ultrapure water were accomplished, finding higher adsorption capacities of BPA onto both F400 activated carbon (qsat = 407 mg g-1) and the biochar KLP (qsat = 220 mg g-1), versus to that obtained for the xerogel (qsat = 78 mg g-1). Furthermore, kinetic experiments revealed faster kinetic adsorption for RFX and KLP materials, achieving the equilibrium time within 24 h, attributed to their more-opened porous structure. Pseudo-first order, pseudo-second order, Elovich, intra-particle diffusion and film diffusion models were used to fit the experimental data. Thus, the BPA adsorption isotherms were analysed by Langmuir, Freundlich, Sips, Redlich-Peterson and Dual-site Langmuir (DLS) isotherm models.In addition, the influence of different aqueous matrices, such as a hospital wastewater, a wastewater treatment plant (WWTP) effluent and a river water, on BPA removal efficiency has been explored. These adsorption tests revealed a clear competitive effect between the target compound (BPA) and the natural organic matter content (NOM) present in the matrices for the active sites, resulting in a high decreasing of BPA adsorption removal.

Discharge properties of morphologically identified vestibular neurons recorded during horizontal eye movements in the goldfish.

Computational capability and connectivity are key elements for understanding how central vestibular neurons contribute to gaze-stabilizing eye movements during self-motion. In the well-characterized and segmentally distributed hindbrain oculomotor network of goldfish, we determined afferent and efferent connections along with discharge patterns of descending octaval nucleus (DO) neurons during different eye motions. Based on activity correlated with horizontal eye and head movements, DO neurons were categorized into two complementary groups that either increased discharge during both contraversive (type II) eye (e) and ipsiversive (type I) head (h) movements (eIIhI) or vice versa (eIhII). Matching time courses of slow-phase eye velocity and corresponding firing rates during prolonged visual and head rotation suggested direct causality in generating extraocular motor commands. The axons of the dominant eIIhI subgroup projected either ipsi- or contralaterally and terminated in the abducens nucleus, Area II, and Area I with additional recurrent collaterals of ipsilaterally projecting neurons within the parent nucleus. Distinct feedforward commissural pathways between bilateral DO neurons likely contribute to the generation of eye velocity signals in eIhII cells. The shared contribution of DO and Area II neurons to eye velocity storage likely represents an ancestral condition in goldfish that is clearly at variance with the task separation between mammalian medial vestibular and prepositus hypoglossi neurons. This difference in signal processing between fish and mammals might correlate with a larger repertoire of visuo-vestibular-driven eye movements in the latter species that potentially required a shift in sensitivity and connectivity within the hindbrain-cerebello-oculomotor network. NEW & NOTEWORTHY We describe the structure and function of neurons within the goldfish descending octaval nucleus. Our findings indicate that eye and head velocity signals are processed by vestibular and Area II velocity storage integrator circuitries whereas the velocity-to-position Area I neural integrator generates eye position solely. This ancestral condition differs from that of mammals, in which vestibular neurons generally lack eye position signals that are processed and stored within the nucleus prepositus hypoglossi.

PrPC Governs Susceptibility to Prion Strains in Bank Vole, While Other Host Factors Modulate Strain Features.

Bank vole is a rodent species that shows differential susceptibility to the experimental transmission of different prion strains. In this work, the transmission features of a panel of diverse prions with distinct origins were assayed both in bank vole expressing methionine at codon 109 (Bv109M) and in transgenic mice expressing physiological levels of bank vole PrPC (the BvPrP-Tg407 mouse line). This work is the first systematic comparison of the transmission features of a collection of prion isolates, representing a panel of diverse prion strains, in a transgenic-mouse model and in its natural counterpart. The results showed very similar transmission properties in both the natural species and the transgenic-mouse model, demonstrating the key role of the PrP amino acid sequence in prion transmission susceptibility. However, differences in the PrPSc types propagated by Bv109M and BvPrP-Tg407 suggest that host factors other than PrPC modulate prion strain features. IMPORTANCE: The differential susceptibility of bank voles to prion strains can be modeled in transgenic mice, suggesting that this selective susceptibility is controlled by the vole PrP sequence alone rather than by other species-specific factors. Differences in the phenotypes observed after prion transmissions in bank voles and in the transgenic mice suggest that host factors other than the PrPC sequence may affect the selection of the substrain replicating in the animal model.

Nanoobjects formed by ionic PAMAM dendrimers: hydrophilic/lipophilic modulation and encapsulation properties.

In this paper, we present the preparation and properties of some ionic PAMAM derivatives, which combine hydrophilic and lipophilic carboxylic acid chains as counter-ions for all protonable inner and outer amino groups. The amphiphilic nature of the final ionic codendrimers and, hence, their self-assembling features can be modulated by using different ratios between hydrophilic and lipophilic chains. In the bulk, these new materials self-organize into smectic A liquid crystal phases. In water, they self-assemble into different types of nano-objects depending on the molecular composition. The study of the morphology of these nano-structures, their cytotoxicity and their capability to encapsulate a lipophilic anticancer drug are reported herein. Some of these nanoobjects are non-cytotoxic and present good drug trapping ability, which make them interesting nanocarriers for applications in nanotechnology and biomedicine.

Liver transplantation in defects of cholesterol biosynthesis: the case of lathosterolosis.

We report the outcome of liver transplantation (LT) in the only surviving patient with lathosterolosis, a defect of cholesterol biosynthesis characterized by high lathosterol levels associated with progressive cholestasis, multiple congenital anomalies and mental retardation. From her diagnosis at age 2 she had shown autistic behavior, was unable to walk unaided and her sight was impaired by cataracts. By age 7 she developed end-stage liver disease. After a soul-searching discussion within the transplantation team, she was treated with LT as this represented her only lifesaving option. At 1-year follow-up, her lathosterol levels had returned to normal (0.61 mg/dL from 13.04 ± 2.65) and her nutrition improved. She began exploring her environment and walking by holding onto an adult's hand and then independently. Her brain magnetic resonance imaging (MRI) had shown a normal picture at age 1, whereas a volume reduction of white matter with ex vacuo ventricular dilatation and defective myelinization were observed before transplant. At 5-year follow-up, a complete biochemical recovery, an arrest of mental deterioration and a stable MRI picture were achieved, with a return to her every day life albeit with limitations. Timely liver transplant in defects of cholesterol biosynthesis might arrest the progression of neurological damage.

Managing IBD outside the gut: ocular manifestations.

Extraintestinal manifestations are common in inflammatory bowel disease (IBD), being reported in over 25% of patients. Ocular complications of IBD occur in around 10% of cases, but may precede systemic symptoms and are usually nonspecific. Complications of therapy, such as cataracts or glaucoma from steroid use or keratoconjunctivitis sicca related to 5-aminosalicylic acid medications, may also involve the eyes. The pathogenesis remains unclear, but factors such as the extent of intestinal disease, disease activity, and the presence of associated arthritis have been associated with ocular involvement. Conjunctivitis, episcleritis, scleritis and uveitis are by far the most common ophthalmic complications of IBD. However, posterior uveitis, intraretinal hemorrhages, vasculitis, choroiditis, optic neuropathy, and vaso-occlusive phenomena may also occur. The most frequent severe ocular manifestation is anterior uveitis (more common in women). It usually presents as a mild anterior nongranulomatous uveitis (60% of the cases). The inflammation in the eye and the inflammation in the gut are rarely correlated. Patients with uveitis, scleritis, and other anterior segment inflammation usually respond to steroids (topical, periocular or systemic). If the inflammation is resistant to steroids, or if appreciable steroid adverse effects are encountered, systemic immunosuppressive treatment should be considered; this is more likely in HLA-B27-positive patients with uveitis. Evaluation of the eye should be a routine component in the care of patients with IBD.

Relationship between choroidal thickness and vascular density in young healthy population.

BACKGROUND AND PURPOSE: The purpose is to analyze choroidal vascular density (VD) in healthy individuals and to compare it with choroidal thickness (CT). MATERIALS AND METHODS: Cross-sectional study enrolling healthy individuals between 18 and 35 years old of Caucasian race and with an axial length (AL) 21-26 mm. Choroid was imaged with swept-source optical coherence tomography angiography (OCTA) Triton DRI (Topcon) and a macular cube of 6 × 6 mm was obtained. CT values were automatically given by the software. VD values were obtained through codifying colors of the VD map into numbers. RESULTS: 102 (51 patients) were analyzed. Mean age was 27.32 ±â€¯3.94 years old, mean intraocular pressure was 18.07 ±â€¯2.38 mmHg, and mean AL was 23.71 ±â€¯0.66 mm. CT was higher in the vertical axis and lower when approaching nasal and temporal sides. The highest CT was in superior macula. The highest choroidal VD were in the fovea and in the juxtapapillary region. The lowest choroidal VD were found in superior and inferior macular areas. Moderate inverse correlations between CT and choroidal VD were found in the juxtapapillary and inferior regions. CONCLUSIONS: The choroid has a thickness pattern that differs from retina. Choroidal vessels represent a very high percentage of choroid in the peripapillary region and in the fovea. On the contrary, superior and inferior macula reveals low values of VD.

Brain derived neurotrophic factor maintains Brn3a expression in axotomized rat retinal ganglion cells.

The transcription factor Brn3a has been reported to be a good marker for adult rat retinal ganglion cells in control and injured retinas. However, it is still unclear if Brn3a expression declines progressively by the injury itself or otherwise its expression is maintained in retinal ganglion cells that, though being injured, are still alive, as might occur when assessing neuroprotective therapies. Therefore, we have automatically quantified the whole population of surviving Brn3a positive retinal ganglion cells in retinas subjected to intraorbital optic nerve transection and treated with either brain derived neurotrophic factor or vehicle. Brain derived neurotrophic factor is known to delay retinal ganglion cell death after axotomy. Thus, comparison of both groups would inform of the suitability of Brn3a as a retinal ganglion cell marker when testing neuroprotective molecules. As internal control, retinal ganglion cells were, as well, identified in all retinas by retrogradely tracing them with fluorogold. Our data show that at all the analyzed times post-lesion, the numbers of Brn3a positive retinal ganglion cells and of fluorogold positive retinal ganglion cells are significantly higher in the brain derived neurotrophic factor-treated retinas compared to the vehicle-treated ones. Moreover, detailed isodensity maps of the surviving Brn3a positive retinal ganglion cells show that a single injection of brain derived neurotrophic factor protects retinal ganglion cells throughout the entire retina. In conclusion, Brn3a is a reliable retinal ganglion cell marker that can be used to accurately measure the potential effect of a given neuroprotective therapy.

A novel influenza A virus mitochondrial protein that induces cell death.

While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.

Diagnostic Approach to Acute Liver Failure in Children: A Position Paper by the SIGENP Liver Disease Working Group.

Acute liver failure (ALF) is a clinical condition characterized by the abrupt onset of coagulopathy and biochemical evidence of hepatocellular injury, leading to rapid deterioration of liver cell function. In children, ALF has been characterized by raised transaminases, coagulopathy, and no known evidence of pre-existing chronic liver disease; unlike in adults, the presence of hepatic encephalopathy is not required to establish the diagnosis. Although rare, ALF has a high mortality rate without liver transplantation (LT). Etiology of ALF varies with age and geographical location, although it may remain indeterminate in a significant proportion of cases. However, identifying its etiology is crucial to undertake disease-specific management and evaluate indication to LT. In this position statement, the Liver Disease Working Group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) reviewed the most relevant studies on pediatric ALF to provide recommendations on etiology, clinical features and diagnostic work-up of neonates, infants and children presenting with ALF. Recommendations on medical management and transplant candidacy will be discussed in a following consensus conference.

New insights from modelling and estimation of mass transfer parameters in fixed-bed adsorption of Bisphenol A onto carbon materials.

The removal of Bisphenol A, 2,2-bis (4-hydroxyphenyl) propane (BPA) in fixed-bed columns was investigated by breakthrough adsorption tests at different operation conditions and further prediction by a mathematical model to describe the adsorption-diffusion process onto two synthesized carbon porous materials. In this study, a xerogel (RFX) prepared by an optimized conventional sol-gel method and a lignin-based activated carbon (KLP) obtained via chemical activation were used in batch and fixed-bed adsorption experiments. The materials were fully characterized and their adsorptive properties were compared to those obtained with a commercial activated carbon (F400). RFX and KLP materials reached the equilibrium adsorption in only 24 h, whereas F400 activated carbon required 48 h. In addition, F400 and KLP adsorbents showed higher equilibrium adsorption capacity values (qe = 0.40 and 0.22 kg/kg, for F400 and KLP, respectively) than that obtained for the xerogel (qe = 0.08 kg/kg). Both synthesized carbon-adsorbents were studied in fixed-bed adsorption tests, exploring the effect of the operation conditions, e.g., initial BPA concentration (0.005-0.04 kg/m3), weight of adsorbent (0.01-0.05 g) and volumetric flow rate (0.2 to 1.0 mL/min), on the adsorption performance of the column. All the tested adsorption columns reached the equilibrium in a very short time, due to the efficient dimensionless of the bed. Additionally, the regeneration of the exhausted adsorbent was studied, achieving the total reuse of the solids after three consecutive cycles using methanol as regeneration agent. Finally, a mathematical model based on mass conservation equations was proposed, allowing to efficiently fit the experimental BPA breakthrough curves and estimate the external and adsorbed-phase mass transfer coefficients with a high accuracy.

Long-standing mild hypertransaminasaemia caused by congenital disorder of glycosylation (CDG) type IIx.

A 32 year-old asymptomatic male came to our attention with a 21-year history, documented elsewhere, of puzzling increases in his serum transaminase level. At first, very low serum ceruloplasmin level suggested Wilson disease. Two liver biopsies showed mild portal inflammation, steatosis and mild fibrosis. Further investigation revealed low levels of the glycoproteins AT III and clotting factor XI, leading to a diagnosis of congenital disorder of glycosylation (CDG) type II. Further studies as to the cause of this 'apparently new' CDG, are ongoing. On the basis of our data and a literature review, we suggest that subjects with asymptomatic hypertransaminasaemia be screened for CDG.

Recent developments in radiotherapy for small-cell lung cancer: a review by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society).

Small-cell lung cancer (SCLC) accounts for 13% of all lung tumours. The standard treatment in patients with limited-stage disease is radiotherapy combined with chemotherapy. In extensive SCLC, the importance of consolidation thoracic radiotherapy in patients with a good treatment response has become increasingly recognized. In both limited and extensive disease, prophylactic cranial irradiation is recommended in patients who respond to treatment. New therapeutic approaches such as immunotherapy are being increasingly incorporated into the treatment of SCLC, although more slowly than in non-small cell lung cancer (NSCLC). Diverse radiation dose and fractionation schemes, administered in varying combinations with these new drugs, are being investigated. In the present study we review and update the role of radiotherapy in the treatment of SCLC. We also discuss the main clinical trials currently underway in order to identify future trends.

Diagnostic ability of Humphrey perimetry, Octopus perimetry, and optical coherence tomography for glaucomatous optic neuropathy.

PurposeTo evaluate and compare the diagnostic accuracy of the Humphrey Field Analyzer (HFA), Octopus perimetry, and Cirrus OCT for glaucomatous optic neuropathy.MethodsEighty-eight healthy individuals and 150 open-angle glaucoma patients were consecutive and prospectively selected. Eligibility criteria for the glaucoma group were intraocular pressure ≥21 mm Hg and glaucomatous optic nerve head morphology. All subjects underwent a reliable standard automated perimetry with the HFA and Octopus perimeter, and were imaged with the Cirrus OCT. Receiver-operating characteristic (ROC) curves were plotted for the threshold values and main indices of the HFA and Octopus, the peripapillary retinal nerve fiber layer thicknesses, and the optic nerve head parameters. Sensitivities at 85 and 95% fixed-specificities were also calculated. The best areas under the ROC curves (AUCs) were compared using the DeLong method.ResultsIn the glaucoma group, mean deviation (MD) was -5.42±4.6 dB for HFA and 3.90±3.6 dB for Octopus. The MD of the HFA (0.966; P<0.001), mean sensitivity of the Octopus (0.941; P<0.001), and average cup-to-disc (C/D) ratio measured by the Cirrus OCT (0.958; P<0.001) had the largest AUCs for each test studied. There were no significant differences among them. Sensitivities at 95% fixed-specificity were 82% for pattern standard deviation of the HFA, 81.3% for average C/D ratio of OCT, and 80% for the MD of the Octopus.ConclusionsHFA, Octopus, and Cirrus OCT demonstrated similar diagnostic accuracies for glaucomatous optic neuropathy. Visual field and OCT provide supplementary information and thus these tests are not interchangeable.

Targeted therapy combined with radiotherapy in non-small-cell lung cancer: a review of the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society).

In recent years, major advances in our understanding of the molecular biology of lung cancer, together with significant improvements in radiotherapy technologies, have revolutionized the treatment of non-small cell lung cancer (NSCLC). This has led to the development of new therapies that target molecular mutations specific to each tumor type, acting on the cell surface antigens or intracellular signaling pathways, or directly affecting cell survival. At the same time, ablative dose radiotherapy can be delivered safely in the context of metastatic disease. In this article, the GOECP/SEOR (Oncological Group for Study of Lung Cancer/Spanish Society of Radiation Oncology) reviews the role of new targeted therapies used in combination with radiotherapy in patients with locally advanced (stage III) NSCLC and in patients with advanced, metastatic (stage IV) NSCLC.

A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion.

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

Isolated liver transplantation in an infant with ultrashort gut.

Intestinal function in children with very short bowel syndrome and related intestinal failure may improve after isolated liver transplantation. An infant with an ultrashort gut, ileo-cecal valve, and whole colon received total parenteral nutrition from the first days of life. Enteral feeding failed because of the progressive dilatation of the jejunal portion and motility disorders. He developed early severe cholestatic liver disease (aspartate transferase 186, alanine transferase 103 U/L, serum bilirubin 8.4 mg/dL) and subsequent liver failure. At 8 months of age, he benefited from isolated liver transplantation (left segment graft from living donor). His early posttransplant evolution was characterized by recovery of oral alimentation, improvement of digestive and absorption functions, but he did not achieve TPN-independence. At 20 months, 50% to 60% of his energy needs were covered by parenteral nutrition and he has satisfactory growth indices (3rd percentile for weight and height), reduced stool volume, and frequency. Isolated liver transplantation allowed, in this particular case, time for further intestinal adaptation thereby avoiding the need for intestinal transplantation early in life.

Compatibility and stability of the novel anticancer agent ES-285 x HCl formulated with 2-hydroxypropyl-beta-cyclodextrin in infusion devices.

ES-285 x HCl is a novel marine-derived anticancer agent isolated from the clam Spisula polynyma. The compound is pharmaceutically formulated as a lyophilised product containing 25 or 50 mg ES-285 x HCl and 500 or 1000 mg 2-hydroxypropyl-beta-cyclodextrin per dosage unit and requires reconstitution with sterile water for injection before intravenous administration. The aim of this study was to determine the stability and compatibility of ES-285 x HCl in infusion devices. ES-285 x HCl was shown to be stable at concentrations of 10-1400 microg/ml after dilution in 5% dextrose in water and compatible with PE infusion containers and PE and silicone tubing. No sorption on- or into the administration set was observed at concentrations equal to or above 20 microg/ml. In conclusion, ES-285 x HCl infusion solutions can be administered without stability or sorption problems using a PE infusion container and PE or silicone tubing in concentrations equal or above 20 microg/ml in 3-hour or 24-hour infusion administration schedules.