Leishmaniose cutânea experimental: I - sobre a susceptibilidade do primata Cebus apella (Cebidae) a infecção pela Leishmania (Viannia) lainsoni Silveira, Shaw, Braga e Ishikawa, 1987

Foi investigada a susceptibilidade do primata Cebus apella (Cebidae) à infecção experimental pela Leishmaiua (Viannia) lainsoni, com o objetivo de estudara patogenia desse parasita, ainda pouco conhecido para o homem. Dessa forma, cinco espécimens jovens daquele primata, 2 machos e 3 fêmeas, foram inoculados, intraderme, em oito sítios diferentes da região dorsal da cauda com 3 x 10(6) de promastigotas do parasita (MHOMZBR/81/M6426, Benevides, Pará), obtidas de cultura da fase estacionária. Em seguida às inoculações, a infecção experimental nos animais foi comprovada, não só pela presença de amastigotas do parasita na pele dos animais inoculados, mas, também, pela concomitância desse achado associado ao desenvolvimento de lesão cutânea nos pontos da pele onde o parasita foi inoculado. Diante desses resultados, ficou demonstrada a susceptibilidade do primata Cebus apella à infecção experimental pela Leishmama lainsoni cujo período de infecção durou quase quatro meses, suficiente para testar drogas antileishmanióticas e estudar a patogênese da doença causada por este parasita.The susceptibility of the monkey Cebus apella (Cebidae) to experimental infection by Leishmania (Viannia) lainsoni has been investigated. For this purpose, five young monkeys, 2 males and 3 females, were intradermally, inoculated, in eight different places along the dorsal surface of the tail with 3 x 10(6) promastigotes of the parasite (MHOM/BR/81/M6426, Benevides, Pará), from stationary phase culture in Difco B45 medium. After inoculations, infection in the monkeys was indicated by the presence of amastigotes in the skin lesions produced in these animals at the points of inoculation, confirming the susceptibility of the monkey Cebus apella to experimental infection by Leishmania lainsoni, with an infection period of four months. This represents a suitable period for testing antileishmanial drugs or studying the pathogenesis of the disease caused by this parasite

Leishmaniose cutânea experimental: II - aspectos evolutivos da infecção no primata Cebus apella (Cebidae) pela Leishmania (V.) Braziliensis e L. (L.) Amazonensis

Objetivando avaliar o potencial do primata C. apella como modelo experimental da leishmaniose cutânea, produzida pela L. (V.) braziliensis e L. (L.) Amazonensis , inocularam-se, via intradérmica, 3 X 10(6) de promastigotas dessas leishmanias, em 8 sítios da cauda de 10 espécimens desse primata, 5 deles com a L. (V.) braziliensis e outros 5 com a L. (L.) Amazonensis . Posteriormente, às inoculações, o exame semanal dos animais e biópsias mensais, revelaram os seguintes resultados relativos a cada parasita: a) L. (V.) braziliensis : o período de incubação foi de 15-20 dias; aos 30 dias evidenciaram-se lesões pápulo-eritematosas, que evoluíram para nódulos ao fim de 60 dias; no 3.° mês, notou-se ulceração espontânea destas lesões e, no 4° mês, deu-se o início da reparação das lesões ulceradas, culminando com a cura em um dos animais após 5 meses, em dois após 6 meses, noutro após 7 meses e, no último, após 10 meses. Quanto ao parasitismo nas lesões, foi demonstrado nos 5 animais, até 90 dias; depois disto, somente em 2 até 120 dias e, por fim, até 180 dias apenas naquele que curou depois de 10 meses, b) L. (L.) Amazonensis : o período de incubação foi de 20 dias; aos 30 dias notou- se lesões pápulo-eritematosas, que também evoluíram para nódulos ao fim de 60 dias, porém, a partir do 3.° mês, estas lesões regrediram rapidamente ao fim de 90 dias, quando não mais detectou-se o parasita na pele dos animais. Em relação aos testes de Montenegro, somente 2 dos 5 animais infectados com a L. (V.) braziliensis reagiram ao teste, 60 e 90 dias após as inoculações. Os resultados observados permitiram confirmar a infectividade do C. apella a estas leishmanias e, também, reforçar a indicação desse primata como modelo experimental da leishmaniose cutânea causada por estes parasitas.As a means of assessing the usufulness of the monkey Cebus apella as an experimental model for the study of cutaneous leishmaniasis, 5 of these animals were inoculated intradermally at 8 sites along the tail with 3 X 106 promastigotes of L. (V.) braziliensis , while a further 5 monkeys received similar inoculations with 3 X 10(6) promastigotes of L. (L.) Amazonensis . Following the inoculations, weekly examinations and monthly biopsies showed evolution of resulting skin lesions to be as follows: a) L. (V.) braziliensis : lesions were first visible 15-20 days postinoculation (p.i), and at 30 days they were clearly of an etythematous-papular nature, which assumed a nodular form at 60 days; after 3 months a spontaneous ulceration of these lesions was noted and, at 4 months, the initiation of healing. In one animal total healing was apparent 5 months p.i; in two others at 6 months, in another monkey after 7 months, and in the last animal at 10 months p.i. Amastigotes were demonstrated in smears from the lesions of all monkeys up to 90 days p.i; up to 120 days in two animals, and at 180 days p.i. in the monkey which showed resolution of the lesions after 10 months, b) L. (L.) Amazonensis lesions were first apparent after 20 days p. i; at 30 days they were of an en'thematous-papular nature, developing into nodules at 60 days. From the third month of infection onwards, however, the lesions diminished rapidly and, at 90 days p.i. amastigotes were no longer detectable in the skin. With regards to the Montenegro (leishmanin) skin tests, only two of the monkeys (infected with L. (V.) braziliensis ) gave positive reactions, at 60 and 9 ) days p. i. These results confirm the susceptibility of C. apella to infections with both L. (V.) braziliensis and L. (L.) Amazonensis , and support previous indications that this monkey may serve as an useful experimental model for the study of cutaneous leishmaniasis caused by these parasites

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Post-Weaning Protein Malnutrition Increases Blood Pressure and Induces Endothelial Dysfunctions in Rats

Malnutrition during critical periods in early life may increase the subsequent risk of hypertension and metabolic diseases in adulthood, but the underlying mechanisms are still unclear. We aimed to evaluate the effects of post-weaning protein malnutrition on blood pressure and vascular reactivity in aortic rings (conductance artery) and isolated-perfused tail arteries (resistance artery) from control (fed with Labina®) and post-weaning protein malnutrition rats (offspring that received a diet with low protein content for three months). Systolic and diastolic blood pressure and heart rate increased in the post-weaning protein malnutrition rats. In the aortic rings, reactivity to phenylephrine (10−10–3.10−4 M) was similar in both groups. Endothelium removal or L-NAME (10−4 M) incubation increased the response to phenylephrine, but the L-NAME effect was greater in the aortic rings from the post-weaning protein malnutrition rats. The protein expression of the endothelial nitric oxide isoform increased in the aortic rings from the post-weaning protein malnutrition rats. Incubation with apocynin (0.3 mM) reduced the response to phenylephrine in both groups, but this effect was higher in the post-weaning protein malnutrition rats, suggesting an increase of superoxide anion release. In the tail artery of the post-weaning protein malnutrition rats, the vascular reactivity to phenylephrine (0.001–300 µg) and the relaxation to acetylcholine (10−10–10−3 M) were increased. Post-weaning protein malnutrition increases blood pressure and induces vascular dysfunction. Although the vascular reactivity in the aortic rings did not change, an increase in superoxide anion and nitric oxide was observed in the post-weaning protein malnutrition rats. However, in the resistance arteries, the increased vascular reactivity may be a potential mechanism underlying the increased blood pressure observed in this model