Clinicopathological aspects and proviral load of adulthood infective dermatitis associated with HTLV-1: Comparison between juvenile and adulthood forms

Background Infective dermatitis associated with human T-cell lymphotropic virus type-1 (HTLV-1), (IDH), is a chronic eczema occurring in HTLV-1 infected children. Rare cases of adulthood IDH have been reported and no study until now aimed to compare juvenile and adulthood IDH. Methodology/Principal findings Twelve cases of adulthood IDH followed for a mean time of 7.5 years were analyzed according to clinicopathological and molecular aspects, comparing them to juvenile IDH cases. Diagnosis was based on the modified major criteria used for juvenile IDH. Proviral load (PVL) assessment was performed by real-time PCR technique. Adulthood IDH presented similar clinicopathological and molecular aspects compared to juvenile IDH. The morphology of lesions and areas of involvement were similar, except for the involvement of the ankles and inframammary folds in the adulthood form. HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) occurred in six adulthood IDH patients, with almost equal frequency. However, at least in two patients, HAM/TSP appeared prior to IDH, differently from what was observed in juvenile IDH. Conclusions/Significance Adulthood IDH is similar to juvenile IDH according to clinicopathological aspects and PVL levels. Therefore, the same modified major diagnostic criteria for juvenile IDH can be applied to both forms.This work was supported by the Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (http://www.cnpq.br/), grant number 409985/2016-3, received by AL and by the Fundac¸ão de Amparo a Pesquisa do Estado da Bahia (http://www.fapesb.ba.gov.br), grant number 4345/2012. This project has also received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Marie Curie grant agreement num 799850 (LF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

HTLV-1 proviral load in infective dermatitis associated with HTLV-1 does not increase after the development of HTLV-1-associated myelopathy/tropical spastic paraparesis and does not decrease after IDH remission

Introduction Infective dermatitis associated with HTLV-1 (IDH) is a recurrent eczema which affects children vertically infected with HTLV-1. In Bahia, Brazil, we recently reported that 47% of IDH patients also develop juvenile HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive disabling disorder which is typically reported in adult HTLV-1 carriers. IDH may also predispose to adult T-cell leukemia/lymphoma, a neoplasm associated with HTLV-1. The factors relating to the development of HTLV-1-associated juvenile diseases have not yet been defined. HTLV-1 proviral load (PVL) is one of the main parameters related to the development of HTLV-1 associated diseases in adults. In the current study, we investigated the role of PVL in IDH and juvenile HAM/TSP. Methodology/Principal findings This is a cohort study that included fifty-nine HTLV-1 infected children and adolescents, comprising 16 asymptomatic carriers, 18 IDH patients, 20 patients with IDH and HAM/TSP (IDH/HAM/TSP) and five with HAM/TSP. These patients were followed-up for up to 14 years (median of 8 years). We found that PVL in IDH and IDH/HAM/TSP patients were similarly higher than PVL in juvenile asymptomatic carriers (p<0.0001). In those IDH patients who developed HAM/TSP during follow-up, PVL levels did not vary significantly. HAM/TSP development did not occur in those IDH patients who presented high levels of PVL. IDH remission was associated with an increase of PVL. Inter-individual differences in PVL were observed within all groups. However, intra-individual PVL did not fluctuate significantly during follow-up. Conclusions/Significance High PVL in IDH patients was not necessary indicative of progression to HAM/TSP. PVL did not decrease after IDH remission. The maintenance of high PVL after remission could favor early development of ATL. Therefore, IDH patients would have to be followed-up even after remission of IDH and for a long period of time.This work was supported by the Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB, www.fapesb.ba.gov.br) [Grant number RED0028/2012 to L.F.], Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, www.cnpq.br)[Grant number 409985/ 2016-3 to A.L.B.]. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Marie Curie grant (https://ec.europa.eu) [agreement number 799850 to L.F.] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Porcine Digestible Peptides (PDP) in Weanling Diets Regulates the Expression of Genes Involved in Gut Barrier Function, Immune Response and Nutrient Transport in Nursery Pigs

CRAG 10.3390/ani10122368This study was conducted to investigate the effects of dietary supplementation of porcine digestible peptides (PDP), spray-dried plasma (SDP), or a combination of both, on growth performance and the expression of genes related to intestinal function of weaned pigs. A total of 180 piglets (trial 1) and 198 piglets (trial 2) were used to evaluate the partial substitution of soybean ingredients with 2% SDP or 2% PDP (trial 1), and with 3% SDP or the combination of 1% SDP and 2% PDP (SDP-PDP; trial 2) during the pre-starter period (0-14 days). The gene expression of 56 genes was quantified in a qPCR platform in jejunum and ileum samples obtained from piglets 14 d after weaning (trial 2). Piglets fed SDP, PDP and SDP-PDP had a higher body weight (BW), average daily gain (ADG) and feed efficiency (G:F) than the soybean control on day 14 (p < 0.05). In addition, the combination of SDP and PDP upregulated ten genes in jejunum samples (p < 0.05) related to intestinal function. More research is needed to confirm that gene expression upregulation by PDP in combination with SDP has an impact on intestinal function and to elucidate its underlying mechanisms

Identification of eQTLs associated with lipid metabolism in Longissimus dorsi muscle of pigs with different genetic backgrounds

Altres ajuts: Ph.D grant from the Generalitat de Catalunya (ECO/1788/2014) i CERCA Programme/Generalitat de CatalunyaIntramuscular fat content and its fatty acid composition affect porcine meat quality and its nutritional value. The present work aimed to identify genomic variants regulating the expression in the porcine muscle (Longissimus dorsi) of 45 candidate genes for lipid metabolism and fatty acid composition in three experimental backcrosses based on the Iberian breed. Expression genome-wide association studies (eGWAS) were performed between the muscle gene expression values, measured by real-time quantitative PCR, and the genotypes of 38,426 SNPs distributed along all chromosomes. The eGWAS identified 186 eSNPs located in ten Sus scrofa regions and associated with the expression of ACSM5, ACSS2, ATF3, DGAT2, FOS and IGF2 (FDR < 0.05) genes. Two expression quantitative trait loci (eQTLs) for IGF2 and ACSM5 were classified as cis-acting eQTLs, suggesting a mutation in the same gene affecting its expression. Conversely, ten eQTLs showed trans-regulatory effects on gene expression. When the eGWAS was performed for each backcross independently, only three common trans-eQTL regions were observed, indicating different regulatory mechanisms or allelic frequencies among the breeds. In addition, hotspot regions regulating the expression of several genes were detected. Our results provide new data to better understand the functional regulatory mechanisms of lipid metabolism genes in muscle

Analysis of porcine IGF2 gene expression in adipose tissue and its effect on fatty acid composition

Altres ajuts: Ph.D grant from the Generalitat de Catalunya (ECO/1788/2014) i CERCA Programme/Generalitat de CatalunyaIGF2:g.3072G>A polymorphism has been described as the causal mutation of a maternally imprinted QTL for muscle growth and fat deposition in pigs. The objective of the current work was to study the association between the IGF2:g.3072G>A polymorphism and the IGF2 gene expression and its effect on fatty acid composition in adipose tissue in different pig genetic backgrounds. A cis-eQTL region associated with the IGF2 mRNA expression in adipose tissue was identified in an eGWAS with 355 animals. The IGF2 gene was located in this genomic interval and IGF2g.3072G>A was the most significant SNP, explaining a 25% of the gene expression variance. Significant associations between IGF2:g.3072G>A polymorphism and oleic (C18:1(n-9); p-value = 4.18x10), hexadecanoic (C16:1(n-9); p-value = 4.04x10), linoleic (C18:2(n-6); p-value = 6.44x10), α-linoleic (C18:3(n-3); p-value = 3.30x10), arachidonic (C20:4(n-6); p-value = 9.82x10) FAs and the MUFA/PUFA ratio (p-value = 2.51x10) measured in backfat were identified. Animals carrying the A allele showed an increase in IGF2 gene expression and higher PUFA and lower MUFA content. However, in additional studies was observed that there could be other proximal genetic variants affecting FA composition in adipose tissue. Finally, no differences in the IGF2 gene expression in adipose tissue were found between heterozygous animals classified according to the IGF2:g.3072G>A allele inherited from the father (AG or AG). However, pyrosequencing analysis revealed that there is imprinting of the IGF2 gene in muscle and adipose tissues, with stronger differences among the paternally and maternally inherited alleles in muscle. Our results suggested that IGF2:g.3072G>A polymorphism plays an important role in the regulation of IGF2 gene expression and can be involved in the fatty acid composition in adipose tissue. In both cases, further studies are still needed to deepen the mechanism of regulation of IGF2 gene expression in adipose tissue and the IGF2 role in FA composition

Novel Endometrial Cancer Models Using Sensitive Metastasis Tracing for CXCR4-Targeted Therapy in Advanced Disease

Advanced endometrial cancer (EC) lacks therapy, thus, there is a need for novel treatment targets. CXCR4 overexpression is associated with a poor prognosis in several cancers, whereas its inhibition prevents metastases. We assessed CXCR4 expression in EC in women by using IHC. Orthotopic models were generated with transendometrial implantation of CXCR4-transduced EC cells. After in vitro evaluation of the CXCR4-targeted T22-GFP-H6 nanocarrier, subcutaneous EC models were used to study its uptake in tumor and normal organs. Of the women, 91% overexpressed CXCR4, making them candidates for CXCR4-targeted therapies. Thus, we developed CXCR4(+) EC mouse models to improve metastagenesis compared to current models and to use them to develop novel CXCR4-targeted therapies for unresponsive EC. It showed enhanced dissemination, especially in the lungs and liver, and displayed 100% metastasis penetrance at all clinically relevant sites with anti-hVimentin IHC, improving detection sensitivity. Regarding the CXCR4-targeted nanocarrier, 60% accumulated in the SC tumor; therefore, selectively targeting CXCR4(+) cancer cells, without toxicity in non-tumor organs. Our CXCR4(+) EC models will allow testing of novel CXCR4-targeted drugs and development of nanomedicines derived from T22-GFP-H6 to deliver drugs to CXCR4(+) cells in advanced EC. This novel approach provides a therapeutic option for women with metastatic, high risk or recurrent EC that have a dismal prognosis and lack effective therapies

Indel detection from Whole Genome Sequencing data and association with lipid metabolism in pigs

The selection in commercial swine breeds for meat-production efficiency has been increasing among the past decades, reducing the intramuscular fat content, which has changed the sensorial and technological properties of pork. Through processes of natural adaptation and selective breeding, the accumulation of mutations has driven the genetic divergence between pig breeds. The most common and well-studied mutations are single-nucleotide polymorphisms (SNPs). However, insertions and deletions (indels) usually represents a fifth part of the detected mutations and should also be considered for animal breeding. In the present study, three different programs (Dindel, SAMtools mpileup, and GATK) were used to detect indels from Whole Genome Sequencing data of Iberian boars and Landrace sows. A total of 1,928,746 indels were found in common with the three programs. The VEP tool predicted that 1,289 indels may have a high impact on protein sequence and function. Ten indels inside genes related with lipid metabolism were genotyped in pigs from three different backcrosses with Iberian origin, obtaining different allelic frequencies on each backcross. Genome-Wide Association Studies performed in the Longissimus dorsi muscle found an association between an indel located in the C1q and TNF related 12 (C1QTNF12) gene and the amount of eicosadienoic acid (C20:2(n-6))

Porcine Digestible Peptides (PDP) in Weanling Diets Regulates the Expression of Genes Involved in Gut Barrier Function, Immune Response and Nutrient Transport in Nursery Pigs

This study was conducted to investigate the effects of dietary supplementation of porcine digestible peptides (PDP), spray-dried plasma (SDP), or a combination of both, on growth performance and the expression of genes related to intestinal function of weaned pigs. A total of 180 piglets (trial 1) and 198 piglets (trial 2) were used to evaluate the partial substitution of soybean ingredients with 2% SDP or 2% PDP (trial 1), and with 3% SDP or the combination of 1% SDP and 2% PDP (SDP-PDP; trial 2) during the pre-starter period (0-14 days). The gene expression of 56 genes was quantified in a qPCR platform in jejunum and ileum samples obtained from piglets 14 d after weaning (trial 2). Piglets fed SDP, PDP and SDP-PDP had a higher body weight (BW), average daily gain (ADG) and feed efficiency (G:F) than the soybean control on day 14 (p < 0.05). In addition, the combination of SDP and PDP upregulated ten genes in jejunum samples (p < 0.05) related to intestinal function. More research is needed to confirm that gene expression upregulation by PDP in combination with SDP has an impact on intestinal function and to elucidate its underlying mechanisms

Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibidor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibidor therapy.This work was supported by a grant from the Dutch Cancer Society through the Oncode Institute. Al.V. was supported by the Fondo de Investigaciones Sanitarias, FIS (PI16-01898, and by the Spanish Association Against Cancer, AECC (CGB14142035THOM) and Ideas Semilla project (IDEAS098VILL-IDEAS16) and Generalitat de Catalunya (2014SGR364). L.F. received a European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie, grant agreement number 799850. E.N. was funded by Instituto Carlos III through the project PI18/00920. We thank CERCA Program/Generalitat de Catalunya for their institutional support and grant 2017SGR448