Neoplasia intraepitelial vulvar diferenciada

Orientadora : Profª. Drª. Rita Maira ZanineMonografia (especialização) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Curso de Especialização em Tocoginecologia AvançadoInclui referências: p. 17-20Resumo: A neoplasia intraepitelial vulvar diferenciada (NIVd) é um dos principais precursores do carcinoma vulvar de células escamosas (CEC) não relacionados ao HPV. Embora esta seja uma entidade rara, o seu tratamento pode deixar sequelas importantes consequentes à extensão cirúrgica e mutilação. O diagnóstico da NIVd permanece sendo um desafio pois se trata de uma patologia cujas características podem mimetizar outras condições benignas, retardando o seu tratamento e contribuindo para sua evolução em carcinoma. Este trabalho é uma revisão de literatura que mostra os principais aspectos clínicos, histológicos e imunohistoquímicos utilizados para auxiliar no diagnóstico da NIVd. Sua clínica é sutil e histologicamente ela apresenta células escamosas aumentadas, núcleo vesicular grande e macronucléolos, aspectos também encontrados em lesões benignas. Como diagnósticos diferenciais se encontram várias condições, como a neoplasia intraepitelial vulvar usual (NIVu), líquen escleroso vulvar, líquen simples crônico e hiperplasia celular escamosa de vulva. Diversos marcadores imunohistoquímicos vêm sendo estudados e aplicados para auxiliar na diferenciação entre lesões potencialmente malignas e benignas. Devido ao alto índice de malignização em um tempo mais curto, se comparado à NIVu, é necessário que o seu reconhecimento seja feito o mais precocemente possível, evitando assim a necessidade de um tratamento mais agressivo com consequente perda de funcionalidade e dor permanentes.Abstract: Differentiated vulvar intraepithelial neoplasia (dVIN) is one of the main precursors of vulvar squamous cell carcinoma (SCC) not related to HPV. Although this is a rare entity, its treatment can leave important sequelae resulting from surgical extension and mutilation. The diagnosis of dVIN remains a challenge since it is a pathology whose characteristics can mimic other benign conditions, delaying its treatment its evolution into carcinoma. This study is a literature review that shows the main clinical, histological and immunohistochemical aspects used to aid in the diagnosis of dVIN. Its clinicis subtle and histologically it presents enlarged squamous cells, large vesicular nucleus and macronucleoli, aspects also found in benign lesions. Differential diagnoses include various conditions, such as usual vulvar intraepithelial neoplasia (uVIN), vulvar lichen sclerosus, chronic simple lichen and vulvar squamous cell hyperplasia. Several immunohistochemical markers have been studied and applied to help differentiate between potentially malignant and benign lesions. Due to the high rate of malignancy in a shorter time, when compared to uVIN, its recognition must be done as early as possible, thus avoiding the need for a more aggressive treatment with consequent permanent loss of functionality and pain

Experimental demonstration of quantum source coding

We report an experimental demonstration of Schumacher's quantum noiseless coding theorem. Our experiment employs a sequence of single photons each of which represents three qubits. We initially prepare each photon in one of a set of 8 non-orthogonal codeword states corresponding to the value of a block of three binary letters. We use quantum coding to compress this quantum data into a two-qubit quantum channel and then uncompress the two-qubit channel to restore the original data with a fidelity approaching the theoretical limit.Comment: 5 pages, 4 figure

Minimum-error discrimination between three mirror-symmetric states

We present the optimal measurement strategy for distinguishing between three quantum states exhibiting a mirror symmetry. The three states live in a two-dimensional Hilbert space, and are thus overcomplete. By mirror symmetry we understand that the transformation {|+> -> |+>, |-> -> -|->} leaves the set of states invariant. The obtained measurement strategy minimizes the error probability. An experimental realization for polarized photons, realizable with current technology, is suggested.Comment: 4 pages, 2 figure

Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis.

Naive pluripotency is manifest in the preimplantation mammalian embryo. Here we determine transcriptome dynamics of mouse development from the eight-cell stage to postimplantation using lineage-specific RNA sequencing. This method combines high sensitivity and reporter-based fate assignment to acquire the full spectrum of gene expression from discrete embryonic cell types. We define expression modules indicative of developmental state and temporal regulatory patterns marking the establishment and dissolution of naive pluripotency in vivo. Analysis of embryonic stem cells and diapaused embryos reveals near-complete conservation of the core transcriptional circuitry operative in the preimplantation epiblast. Comparison to inner cell masses of marmoset primate blastocysts identifies a similar complement of pluripotency factors but use of alternative signaling pathways. Embryo culture experiments further indicate that marmoset embryos utilize WNT signaling during early lineage segregation, unlike rodents. These findings support a conserved transcription factor foundation for naive pluripotency while revealing species-specific regulatory features of lineage segregation.We thank Peter Humphreys for assistance with imaging, and Samuel Jameson and staff for mouse husbandry. We are grateful to Charis Drummer, Ayako Sedohara, Akiko Shimada, Yuko Yamada, Ryo Oiwa, and Takeshi Kuge for technical support with marmoset embryo recovery. Illumina sequencing was provided by Bettina Haase and Dinko Pavlinic at the EMBL Genomics Core Facility. This work was supported by funding from the Wellcome Trust, the Genome Biology Unit of the European Molecular Biology Laboratory, BBSRC grants BB/G015678/1 and BB/M004023/1, an MRC Centenary Award, and the Louis Jeantet Foundation. A.S. is a Medical Research Council Professor.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.devcel.2015.10.01

Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed from Those of Human P450 2A6

ABSTRACT The common marmoset (Callithrix jacchus), a New World primate species, is potentially a useful animal model for preclinical studies in drug development. However, cytochrome P450 (P450) enzymes have not been fully identified and characterized in marmosets. In this study, we identified P450 2A6 cDNA with the sequence highly identical (91-94%) to human P450 2A6, 2A7, and 2A13 cDNA and cynomolgus monkey P450 2A23, 2A24, and 2A26 cDNA. Among the tissue types examined, marmoset P450 2A6 mRNA was most abundantly expressed in livers where P450 2A6 protein was also detected by immunoblotting. Phylogenetic analysis showed that marmoset P450 2A6 was more closely clustered with human and cynomolgus monkey P450 2As than P450 2As of dog, rat, and mouse (the species also used in drug metabolism). Marmoset P450 2A6 heterologously expressed in Escherichia coli membranes efficiently catalyzed 7-ethoxycoumarin O-deethylation, similar to human P450 2A6 and 2A13 and cynomolgus monkey P450 2A23, 2A24, and 2A26, but much less effectively coumarin 7-hydroxylation, showing some difference as well. Interestingly, marmoset P450 2A6 and cynomolgus monkey P450 2A23 catalyzed phenacetin O-deethylation, which is catalyzed by human P450 1A2 and 2A13, but not by P450 2A6. Marmoset P450 2A6 also exhibited catalytic activity toward testosterone by the multiple sites, but not rat P450 2A-specific testosterone 7a-hydroxylation activity. These results indicated that marmoset P450 2A6 had functional characteristics different from those of human and cynomolgus monkey P450 2As in terms of partially different substrate specificities and catalytic activities, indicating its importance of further studies for P450 2A-dependent drug metabolism in marmosets

Effects of Wnt-β-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs

Marmoset Cytochrome P450 3A4 Ortholog Expressed in Liver and Small-Intestine Tissues Efficiently Metabolizes Midazolam, Alprazolam, Nifedipine, and Testosterone

ABSTRACT Common marmosets (Callithrix jacchus), small New World primates, are increasingly attracting attention as potentially useful animal models for drug development. However, characterization of cytochrome P450 (P450) 3A enzymes involved in the metabolism of a wide variety of drugs has not investigated in marmosets. In this study, sequence homology, tissue distribution, and enzymatic properties of marmoset P450 3A4 ortholog, 3A5 ortholog, and 3A90 were investigated. Marmoset P450 3A forms exhibited high amino acid sequence identities (88-90%) to the human and cynomolgus monkey P450 3A orthologs and evolutionary closeness to human and cynomolgus monkey P450 3A orthologs compared with other P450 3A enzymes. Among the five marmoset tissues examined, P450 3A4 ortholog mRNA was abundant in livers and small intestines where P450 3A4 ortholog proteins were immunologically detected. Three marmoset P450 3A proteins heterologously expressed in Escherichia coli membranes catalyzed midazolam 19-and 4-hydroxylation, alprazolam 4-hydroxylation, nifedipine oxidation, and testosterone 6b-hydroxylation, similar to cynomolgus monkey and human P450 3A enzymes. Among the marmoset P450 3A enzymes, P450 3A4 ortholog effectively catalyzed midazolam 19-hydroxylation, comparable to microsomes from marmoset livers and small intestines. Correlation analyses with 23 individual marmoset liver microsomes suggested contributions of P450 3A enzymes to 19-hydroxylation of both midazolam (human P450 3A probe) and bufuralol (human P450 2D6 probe), similar to cynomolgus monkey P450 3A enzymes. These results indicated that marmoset P450 3A forms had functional characteristics roughly similar to cynomolgus monkeys and humans in terms of tissue expression patterns and catalytic activities, suggesting marmosets as suitable animal models for P450 3A-dependent drug metabolism

Abundant Occurrence of Basal Radial Glia in the Subventricular Zone of Embryonic Neocortex of a Lissencephalic Primate, the Common Marmoset Callithrix jacchus

Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), glutamate aspartate transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor typ

Web-Based Content on Diet and Nutrition Written in Japanese: Infodemiology Study Based on Google Trends and Google Search

The increased availability of content of uncertain integrity obtained through the internet is a major concern. To date, however, there has been no comprehensive scrutiny of the fitness-for-purpose of web-based content on diet and nutrition. This cross-sectional study aims to describe diet- and nutrition-related web-based content written in Japanese, identified via a systematic extraction strategy using Google Trends and Google Search. We first identified keywords relevant for extracting web-based content (eg, blogs) on diet and nutrition written in Japanese using Google Trends. This process included identification of 638 seed terms, identification of approximately 1500 pairs of related queries (top) and search terms, the top 10% of which were extracted to identify 160 relevant pairs of related queries (top) and search terms, and identification of 107 keywords for search. We then extracted relevant web-based content using Google Search. The content (N=1703) examined here was extracted following a search based on 107 keywords. The most common themes included food and beverages (390/1703, 22.9%), weight management (366/1703, 21.49%), health benefits (261/1703, 15.33%), and healthy eating (235/1703, 13.8%). The main disseminators were information technology companies and mass media (474/1703, 27.83%), food manufacturers (246/1703, 14.45%), other (236/1703, 13.86%), and medical institutions (214/1703, 12.57%). Less than half of the content (790/1703, 46.39%) clearly indicated the involvement of editors or writers. More than half of the content (983/1703, 57.72%) was accompanied by one or more types of advertisement. The proportion of content with any type of citation reference was 40.05% (682/1703). The themes and disseminators of content were significantly associated with the involvement of editors or writers, accompaniment with advertisement, and citation of reference. In particular, content focusing on weight management was more likely to clearly indicate the involvement of editors or writers (212/366, 57.9%) and to be accompanied by advertisement (273/366, 74.6%), but less likely to have references cited (128/366, 35%). Content from medical institutions was less likely to have citation references (62/214, 29%). This study highlights concerns regarding the authorship, conflicts of interest (advertising), and the scientific credibility of web-based diet- and nutrition-related information written in Japanese. Nutrition professionals and experts should take these findings seriously because exposure to nutritional information that lacks context or seems contradictory can lead to confusion and backlash among consumers. However, more research is needed to draw firm conclusions about the accuracy and quality of web-based diet- and nutrition-related content and whether similar results can be obtained in other major mass media or social media outlets and even other languages. [Abstract copyright: ©Kentaro Murakami, Nana Shinozaki, Nana Kimoto, Hiroko Onodera, Fumi Oono, Tracy A McCaffrey, M Barbara E Livingstone, Tsuyoshi Okuhara, Mai Matsumoto, Ryoko Katagiri, Erika Ota, Tsuyoshi Chiba, Yuki Nishida, Satoshi Sasaki. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.11.2023.

PfMFR3: A multidrug-resistant modulator in Plasmodium falciparum

In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stag