AIM™ platform: A new immunotherapy approach for viral diseases.

In addition to complications of acute diseases, chronic viral infections are linked to both malignancies and autoimmune disorders. Lack of adequate treatment options for Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), and human papillomavirus (HPV) remains. The NexImmune Artificial Immune Modulation (AIM) nanoparticle platform can be used to direct T cell responses by mimicking the dendritic cell function. In one application, AIM nanoparticles are used ex vivo to enrich and expand (E+E) rare populations of multi-antigen-specific CD8+ T cells for use of these cells as an AIM adoptive cell therapy. This study has demonstrated using E+E CD8+ T cells, the functional relevance of targeting EBV, HTLV-1, and HPV. Expanded T cells consist primarily of effector memory, central memory, and self-renewing stem-like memory T cells directed at selected viral antigen peptides presented by the AIM nanoparticle. T cells expanded against either EBV- or HPV-antigens were highly polyfunctional and displayed substantial in vitro cytotoxic activity against cell lines expressing the respective antigens. Our initial work was in the context of exploring T cells expanded from healthy donors and restricted to human leukocyte antigen (HLA)-A*02:01 serotype. AIM Adoptive Cell Therapies (ACT) are also being developed for other HLA class I serotypes. AIM adoptive cell therapies of autologous or allogeneic T cells specific to antigens associated with acute myeloid leukemia and multiple myeloma are currently in the clinic. The utility and flexibility of the AIM nanoparticle platform will be expanded as we advance the second application, an AIM injectable off-the-shelf nanoparticle, which targets multiple antigen-specific T cell populations to either activate, tolerize, or destroy these targeted CD8+ T cells directly in vivo, leaving non-target cells alone. The AIM injectable platform offers the potential to develop new multi-antigen specific therapies for treating infectious diseases, cancer, and autoimmune diseases.

Estilos de vida saludables en niños de una institución de educación inicial / Healthy lifestyle in children of an institution initial education

Introducción: El objetivo de este estudio fue caracterizar los estilos de vida saludables de niños y niñas en etapa inicial atendidos en la Fundación Guardería Infantil La Alquitrana del Ministerio del Poder Popular de Petróleo, Distrito Capital, Venezuela y establecer relaciones entre los factores que influyen en los estilos de vida del grupo. Métodos: Es una investigación de campo, descriptiva, prospectiva, transversal y analítica, realizada durante el periodo febrero-marzo 2018. Se diseñó un instrumento para recolectar la información a través de preguntas abiertas y cerradas. Se tomaron las mediciones antropométricas. Resultados: Según valores del IMC, se tiene que 91,03% de los niños está en el rango de Normalidad; mientras que 8,97% tiene Riesgo de sobrepeso y Obesidad. La evaluación semicuantitativa del consumo de alimentos, revela que 67,26%, tiene una dieta Adecuada, 21,98%tienen una dieta inadecuada por exceso y sólo 10,76% una dieta inadecuada por déficit. La frecuencia de consumo revelo mayor consumo de carnes, huevos, frutas, evidenciándose una dieta variada, pero baja en consumo de pescado y lácteos.67,26% no realiza ninguna actividad física. Se obtuvieron altas correlaciones: entre Peso-Talla, Peso-Kcal/día y Talla-Kcal/día(r>0,82); diferencias significativas, por sexo, entre Peso (t =1,85> 1,65 = t1;0,05) y Talla (t = 1,69 < t1;0,05). Además, hay asociación entre Estrato social-Ingreso, Estrato social-Actividad Física, Estrato social-Lactancia materna y Estado Nutricional con Lactancia materna, Actividad Física y Momento de comida(p < 0,001). Conclusiones: El estilo de vida de estos niños esta caracterizado por: Estrato social, ingreso, lactancia materna,actividad física y estado Nutricional(AU)

Introduction: The objective of this research was to characterize the healthy lifestyles of boys and girls in the initial stage attended by the La Alquitrana Child Care Foundation of the Ministry of Popular Petroleum Power, Capital District, Venezuela and determine the relationships between the factors that influence the styles of group life. Methods: It is a field research, descriptive, prospective, transversal and analytical, carried out during the period February-March 2018. An instrument was designed to collect the information through open and closed questions. Anthropometric measurements weretaken. Results: According to the BMI values obtained, 91,03% of the children are in the Normality range; while 8,97% have arisk of overweight and obesity. The semi-quantitative evaluation of food consumption reveals that 67,26% have an adequate diet,21,98% have an inadequate diet in excess and only 10,76% havean inadequate diet due to deficits. The frequency of consumption revealed greater consumption of meat, eggs, fruits, evidencing avaried diet, but low in consumption of fish and dairy. 67,26% do not perform any physical activity. High correlations were obtained between Weight-Size, Weight-Kcal / day and Size-Kcal / day (r> 0,82); significant differences, by sex, between Weight (t = 1,85> 1,65 = t1; 0,05) and Size (t = 1,69

Radiodermatitis: Clinical Summary of the ONS Guidelines™ for Cancer Treatment-Related Radiodermatitis.

Approximately 50%-70% of patients with cancer will receive radiation therapy. Radiodermatitis is one of the most common side effects of radiation therapy, with as many as 95% of patients experiencing some degree of skin change. Radiodermatitis can cause pain, itching, and burning and potentially has a significant impact on a patient's quality of life. If radiodermatitis becomes severe, it can cause treatment interruption. The prevalence of radiodermatitis coupled with the effect this side effect can have on quality of life prompts the need for evidence-based recommendations for management.

ONS Guidelines™ for Cancer Treatment-Related Radiodermatitis.

PURPOSE: Radiodermatitis is a side effect of radiation therapy. Evidence-based interventions to minimize severity or delay progression are important for clinical care. This guideline intends to support individuals with cancer, clinicians, and others in decisions regarding radiodermatitis treatment. METHODOLOGIC APPROACH: A panel of healthcare professionals with patient representation was convened to develop a national clinical practice guideline for the management of radiodermatitis. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology and the National Academies of Sciences, Engineering, and Medicine criteria for trustworthy guidelines were followed. The Cochrane Collaboration risk-of-bias tool was used, and certainty of the evidence was assessed using the GRADE approach. A quantitative and narrative synthesis of the evidence was completed. FINDINGS: The panel agreed on eight recommendations and made a conditional recommendation for deodorant/antiperspirant. Aloe vera and oral curcumin had knowledge gaps and were recommended only in the context of a clinical trial. The panel suggested against emu oil, calendula, and nonsteroidal interventions. IMPLICATIONS FOR NURSING: This guideline summarizes evidence-based interventions for the management of radiodermatitis to guide clinical care. SUPPLEMENTARY MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //bit.ly/2GEwJtT.

AIM Platform: A Novel Nano Artificial Antigen-Presenting Cell-Based Clinical System Designed to Consistently Produce Multi-Antigen-Specific T-Cell Products with Potent and Durable Anti-Tumor Properties.

Over the last decade, tremendous progress has been made in the field of adoptive cell therapy. The two prevailing modalities include endogenous non-engineered approaches and genetically engineered T-cell approaches. Endogenous non-engineered approaches include dendritic cell-based systems and tumor-infiltrating lymphocytes (TIL) that are used to produce multi-antigen-specific T-cell products. Genetically engineered approaches, such as T-cell receptor engineered cells and chimeric antigen receptor T cells are used to produce single antigen-specific T-cell products. It is noted by the authors that there are alternative methods to sort for antigen-specific T cells such as peptide multimer sorting or cytokine secretion assay-based sorting, both of which are potentially challenging for broad development and commercialization. In this review, we are focusing on a novel nanoparticle technology that generates a non-engineered product from the endogenous T-cell repertoire. The most common approaches for ex vivo activation and expansion of endogenous, non-genetically engineered cell therapy products rely on dendritic cell-based systems or IL-2 expanded TIL. Hurdles remain in developing efficient, consistent, controlled processes; thus, these processes still have limited access to broad patient populations. Here, we describe a novel approach to produce cellular therapies at clinical scale, using proprietary nanoparticles combined with a proprietary manufacturing process to enrich and expand antigen-specific CD8+ T-cell products with consistent purity, identity, and composition required for effective and durable anti-tumor response.

Soluble MHC class I complexes for targeted immunotherapy.

Major histocompatibility complexes (MHC) have been used for more than two decades in clinical and pre-clinical approaches of tumor immunotherapy. They have been proven efficient for detecting anti-tumor-specific T cells when utilized as soluble multimers, immobilized on cells or artificial structures such as artificial antigen-presenting cells (aAPC) and have been shown to generate effective anti-tumor responses. In this review we summarize the use of soluble MHC class I complexes in tumor vaccination studies, highlighting the different strategies and their contradicting results. In summary, we believe that soluble MHC class I molecules represent an exciting tool with great potential to impact the understanding and development of immunotherapeutic approaches on many levels from monitoring to treatment.

DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.

UNLABELLED: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. SIGNIFICANCE: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.

Characterization of visual pigments, oil droplets, lens and cornea in the whooping crane Grus americana.

Vision has been investigated in many species of birds, but few studies have considered the visual systems of large birds and the particular implications of large eyes and long-life spans on visual system capabilities. To address these issues we investigated the visual system of the whooping crane Grus americana (Gruiformes, Gruidae), which is one of only two North American crane species. It is a large, long-lived bird in which UV sensitivity might be reduced by chromatic aberration and entrance of UV radiation into the eye could be detrimental to retinal tissues. To investigate the whooping crane visual system we used microspectrophotometry to determine the absorbance spectra of retinal oil droplets and to investigate whether the ocular media (i.e. the lens and cornea) absorb UV radiation. In vitro expression and reconstitution was used to determine the absorbance spectra of rod and cone visual pigments. The rod visual pigments had wavelengths of peak absorbance (λmax) at 500 nm, whereas the cone visual pigment λmax values were determined to be 404 nm (SWS1), 450 nm (SWS2), 499 nm (RH2) and 561 nm (LWS), similar to other characterized bird visual pigment absorbance values. The oil droplet cut-off wavelength (λcut) values similarly fell within ranges recorded in other avian species: 576 nm (R-type), 522 nm (Y-type), 506 nm (P-type) and 448 nm (C-type). We confirm that G. americana has a violet-sensitive visual system; however, as a consequence of the λmax of the SWS1 visual pigment (404 nm), it might also have some UV sensitivity.

Decitabine induces delayed reactive oxygen species (ROS) accumulation in leukemia cells and induces the expression of ROS generating enzymes.

PURPOSE: Azanucleoside DNA methyltransferase (DNMT) inhibitors are currently approved by the U.S. Food and Drug Administration for treatment of myelodysplastic syndrome. The relative contributions of DNMT inhibition and other off-target effects to their clinical efficacy remain unclear. Data correlating DNA methylation reversal and clinical response have been conflicting. Consequently, it is necessary to investigate so-called off-target effects and their impact on cell survival and differentiation. EXPERIMENTAL DESIGN: Flow cytometry was used for cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation analysis. Gene expression analysis was performed using real-time PCR. DNA methylation was detected by methylation-specific PCR. Mitochondrial membrane potential was analyzed using JC-1 dye staining. Western blotting was used for quantitative protein expression analysis. RESULTS: 5-Aza-2'-deoxycytidine (DAC) induced cell-cycle arrest and apoptosis in leukemia cells. p53 expression was dispensable for DAC-induced apoptosis. DAC induced delayed ROS accumulation in leukemia cells but not in solid tumor cells and p53 expression was dispensable for ROS increase. ROS increase was deoxycytidine kinase dependent, indicating that incorporation of DAC into nuclear DNA is required for ROS generation. ROS accumulation by DAC was caspase-independent and mediated the dissipation of the mitochondrial membrane potential. Concordantly, ROS scavengers diminished DAC-induced apoptosis. DAC induced the expression of different NADPH oxidase isoforms and upregulated Nox4 protein expression in an ATM-dependent manner, indicating the involvement of DNA damage signaling in Nox4 upregulation. CONCLUSION: These data highlight the importance of mechanisms other than DNA cytosine demethylation in modulating gene expression and suggest investigating the relevance of ROS accumulation to the clinical activity of DAC.

Demethylation demystification.

The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?

Cp-jeez! Aza-natomy!

In this issue of Blood, Yan et al study the anatomy of azanuceoside methylation reversal.