Modeling Melanoma Heterogeneity In Vitro: Redox, Resistance and Pigmentation Profiles.

Microenvironment and transcriptional plasticity generate subpopulations within the tumor, and the use of BRAF inhibitors (BRAFis) contributes to the rise and selection of resistant clones. We stochastically isolated subpopulations (C1, C2, and C3) from naïve melanoma and found that the clones demonstrated distinct morphology, phenotypic, and functional profiles: C1 was less proliferative, more migratory and invasive, less sensitive to BRAFis, less dependent on OXPHOS, more sensitive to oxidative stress, and less pigmented; C2 was more proliferative, less migratory and invasive, more sensitive to BRAFis, less sensitive to oxidative stress, and more pigmented; and C3 was less proliferative, more migratory and invasive, less sensitive to BRAFis, more dependent on OXPHOS, more sensitive to oxidative stress, and more pigmented. Hydrogen peroxide plays a central role in oxidative stress and cell signaling, and PRDXs are one of its main consumers.

Gastric Organoids: Progress and Remaining Challenges.

The stomach is a complex and physiologically necessary organ, yet large differences in physiology between mouse and human stomachs have impeded translation of physiological discoveries and drug screens performed using murine gastric tissues. Gastric cancer (GC) is a global health threat, with a high mortality rate and limited treatment options. The heterogeneous nature of GC makes it poorly suited for current "one size fits all" standard treatments.

A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation.

Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids.

Interferon-γ directly induces gastric epithelial cell death and is required for progression to metaplasia.

Chronic inflammation of the gastric mucosa, often caused by autoimmune gastritis and/or infection with Helicobacter pylori, can lead to atrophy of acid-secreting parietal cells with metaplasia of remaining cells. The histological pattern marks a critical step in the progression from chronic gastritis to gastric cancer, yet underlying mechanism(s) of inflammation-induced cell death of gastric epithelial cells are poorly understood. We investigated direct effects of a type 1 cytokine associated with autoimmunity and infection, interferon-γ (IFN-γ), on gastric epithelial cells.

Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis.

Background & Aims: Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined.

Corticosterone activity during early weaning reprograms molecular markers in rat gastric secretory cells.

Gastric epithelial cells differentiate throughout the third postnatal week in rats, and become completely functional by weaning time. When suckling is interrupted by early weaning (EW), cell proliferation and differentiation change in the gastric mucosa, and regulatory mechanisms might involve corticosterone activity. Here we used EW and RU486 (glucocorticoid receptor antagonist) to investigate the roles of corticosterone on differentiation of mucous neck (MNC) and zymogenic cells (ZC) in rats, and to evaluate whether effects persisted in young adults.

Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach.

Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin.

Identification of alanyl aminopeptidase (CD13) as a surface marker for isolation of mature gastric zymogenic chief cells.

Injury and inflammation in the gastric epithelium can cause disruption of the pathways that guide the differentiation of cell lineages, which in turn can cause persistent alterations in differentiation patterns, known as metaplasia. Metaplasia that occurs in the stomach is associated with increased risk for cancer. Methods for isolating distinct gastric epithelial cell populations would facilitate dissection of the molecular and cellular pathways that guide normal and metaplastic differentiation.

Transforming growth factor β1 increases p27 levels via synthesis and degradation mechanisms in the hyperproliferative gastric epithelium in rats.

Throughout postnatal development, the gastric epithelium expresses Transforming Growth Factor beta1 (TGFβ1), but it is also exposed to luminal peptides that are part of milk. During suckling period, fasting promotes the withdrawal of milk-born molecules while it stimulates gastric epithelial cell proliferation. Such response can be reversed by exogenous TGFβ1, as it directly affects cell cycle through the regulation of p27 levels.

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations.

Objective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.

Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study.

Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.

Regulation of corticosterone function during early weaning and effects on gastric cell proliferation.

Objectives: The development of the gastrointestinal tract depends on many elements, including glucocorticoids. In the current study, we evaluated the effects of early weaning on corticosterone function and the growth of rat gastric mucosa.

Methods: By using Wistar rats submitted to early weaning at 15 d, we analyzed plasma corticosterone, corticosteroid-binding globulin (CBG), and glucocorticoid receptor (GR) distribution in the gastric epithelium.

MAPK signaling pathway regulates p27 phosphorylation at threonin 187 as part of the mechanism triggered by early-weaning to induce cell proliferation in rat gastric mucosa.

During rat postnatal development, gastric cell proliferation and differentiation depend on many elements, which include dietary pattern, hormones, growth factors and their signaling pathways. Among them, EGFR activity is increased through MAPK and Src cascades in response to early weaning that represents the abrupt transition from milk to solid food. We herein investigated the direct involvement of ERK pathway in the control of cell cycle progression during early weaning, and studied the specific role of p27.

MAPKs and signal transduction in the control of gastrointestinal epithelial cell proliferation and differentiation.

Mitogen-activated protein kinase (MAPK) pathways are activated by several stimuli and transduce the signal inside cells, generating diverse responses including cell proliferation, differentiation, migration and apoptosis. Each MAPK cascade comprises a series of molecules, and regulation takes place at different levels. They communicate with each other and with additional pathways, creating a signaling network that is important for cell fate determination.

EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats.

Objectives: Early weaning (EW) increases proliferation of the gastric epithelium in parallel with higher expression of transforming growth factor alpha and its receptor epidermal growth factor receptor (EGFR). The primary objective of the present study was to examine involvement of EGFR signalling in regulating mucosal cell proliferation during the early weaning period.

Materials And Methods: Fifteen-day-old rats were split into two groups: suckling (control) and EW, in which pups were separated from the dam.

Early weaning accelerates the differentiation of mucous neck cells in rat gastric mucosa: possible role of TGFalpha/EGFR.

The development of the gastric mucosa is controlled by hormones, growth factors and feeding behavior. Early weaning (EW), which means the abrupt interruption of suckling, increases proliferation and differentiation in the rat gastric epithelium. Transforming growth factor alpha (TGFalpha) is secreted in the stomach, binds to the epidermal growth factor receptor (EGFR) and may control cell proliferation, differentiation and migration.

Intestinal damage in strongyloidiasis: the imbalance between cell death and proliferation.

Strongyloidiasis is an endemic tropical parasitosis caused by Strongyloides stercoralis that also affects immigrants in nontropical countries. The nematode colonizes the duodenum and upper jejunum, inducing mucosal alterations. Because integrity is essential for a functional barrier, we aimed to study apoptosis and proliferation in the small bowel epithelium infected with S.

Gd-DTPA in clinical MR of the brain: 2. Extraaxial lesions and normal structures.

Fifteen patients with suspected extraaxial tumors were evaluated with MR before and after intravenous injection of Gadolinium-DTPA (Gd-DTPA). Meningiomas (7), neurinomas (4), chordomas (2), a previously irradiated dural metastasis, and a giant aneurysm were studied. All the lesions except the dural metastasis enhanced.

Gd-DTPA in clinical MR of the brain: 1. Intraaxial lesions.

Over 35 intraaxial lesions in 15 patients suspected of having intracranial tumors were studied with MR before and after injection of Gadolinium-DTPA (Gd-DTPA). Diseases included primary and metastatic brain tumors, plaques of multiple sclerosis, occult arteriovenous malformations, lymphoma, toxoplasmosis, and pituitary adenoma. The precontrast T2-weighted sequence (SE 2000/30, 60) was found to be most sensitive in detecting intraaxial lesions, showing 17 lesions that were not seen on the post-Gd-DTPA T1-weighted sequence (SE 500/30).

Congenital heart disease: gated MR imaging in 72 patients.

Seventy-two patients (aged 2 months to 75 years; mean 23 years) with a variety of congenital anomalies of the heart and great vessels underwent ECG-gated magnetic resonance (MR) imaging using the multisectional spin-echo technique (0.35 Tesla). The ability to define segmental anatomy and intracardiac anomalies on transverse, sagittal, and coronal images was evaluated.

Magnetic resonance imaging in pulmonary arterial hypertension.

Magnetic resonance imaging (MRI) was used to examine the right ventricle and pulmonary arteries in 17 patients with pulmonary artery (PA) hypertension documented by cardiac catheterization. The study population consisted of 7 patients with primary pulmonary hypertension, 7 with Eisenmenger's syndrome and 3 with pulmonary hypertension secondary to lung disease. The MRI studies of patients were compared with those of 10 normal volunteers.

Magnetic resonance imaging in patients with congenital heart disease.

Magnetic resonance imaging (MRI) was conducted with use of the spin-echo technique (0.35 Tesla) in 22 patients with a variety of congenital and cardiovascular anomalies and in 16 normal volunteers. Electrocardiographic (ECG) synchronization of the data acquisition produced transverse, parasagittal, and coronal tomograms that were used to define size and relationship of the great vessels and internal cardiac structures.