Combsalexandersen0246

SMAD3 plays a central role in cancer metastasis, and its hyperactivation is linked to poor cancer outcomes. Thus, it is critical to understand the upstream signaling pathways that govern SMAD3 activation. Here, we report that SMAD3 underwent methylation at K53 and K333 (K53/K333) by EZH2, a process crucial for cell membrane recruitment, phosphorylation, and activation of SMAD3 upon TGFB1 stimulation. Mechanistically, EZH2-triggered SMAD3 methylation facilitated SMAD3 interaction with its cellular membrane localization molecule (SARA), which in turn sustained SMAD3 phosphorylation by the TGFB receptor. Pathologically, increased expression of EZH2 expression resulted in the accumulation of SMAD3 methylation to facilitate SMAD3 activation. EZH2-mediated SMAD3 K53/K333 methylation was upregulated and correlated with SMAD3 hyperactivation in breast cancer, promoted tumor metastasis, and was predictive of poor survival outcomes. We used 2 TAT peptides to abrogate SMAD3 methylation and therapeutically inhibit cancer metastasis. Collectively, these findings reveal the complicated layers involved in the regulation of SMAD3 activation coordinated by EZH2-mediated SMAD3 K53/K333 methylation to drive cancer metastasis.Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist, is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable trilineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects, including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2-proficient normal hematopoietic stem and progenitor cells, in part because of its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2 mutant-associated or TET deficiency-associated myeloid malignancies.

Pyroptosis is a new form of programmed cell death (PCD), also known as cellular inflammatory necrosis. Its discovery has resulted in a novel approach to the progression and medication resistance of breast cancer (BC). However, there is still a significant gap in the investigation of pyroptosis-related genes in BC.

The mRNA expression profiles and clinical data of BC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Then, using the TCGA cohort, we created a predictive multigene signature including pyroptosis-related genes and verified it using the two GEO cohorts. A pyroptosis-related gene signature was created by combining several bioinformatics and statistical methodologies to predict patient prognosis and responses to immunotherapy and chemotherapy. Furthermore, a nomogram based on the gene signature and clinicopathological markers was created to better classify the risk and quantify the risk assessment of individual patients.

A pyroptosis-relarelated gene signature classified the patients into two groups high-risk and low-risk. When combined with clinical variables, the risk score was discovered to be an independent predictor of overall survival (OS) in BC patients. Some immunological pathways and genes were linked to pyroptosis, according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) evaluations. Patients in the high-risk group had a worse prognosis and were not very sensitive to immunotherapy. However, several chemotherapeutic agents were predicted to have greater potential for patients in the high-risk group. Finally, a nomogram was developed that included a classifier based on the 15 pyroptosis-related genes, tumor stage, age, and histologic grade. This nomogram demonstrated good classification capacity and might help with clinical decision-making in BC.

Thyroid dysfunction is associated with relevant disturbances in glucose metabolism. Moreover, thyroid function undergoes important changes with ageing. The objective of this study was to investigate the association of thyroid function with insulin resistance with particular consideration of possible age-related effect modifications.

A sample of 4193 participants from two independent epidemiological studies, the Study of Health in Pomerania-TREND-0 and the Berlin Aging Study II, was included in this cross-sectional analysis.

Insulin resistance was estimated by homeostasis model of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI). Associations of thyroid biomarkers (thyroid-stimulating hormone, free thyroxine, and free triiodothyronine (fT3)) with parameters of glucose metabolism were analysed by regression models adjusted for age, sex, smoking status, and study site.

A higher fT3 was significantly associated with higher fasting glucose and higher fasting and 2-h postload insulin levationships.[This corrects the article DOI .].Localized disease heterogeneity on imaging extracted via radiomics approaches have recently been associated with disease prognosis and treatment response. Traditionally, radiomics analyses leverage texture operators to derive voxel- or region-wise feature values towards quantifying subtle variations in image appearance within a region-of-interest (ROI). With the goal of mining additional voxel-wise texture patterns from radiomic "expression maps", we introduce a new RADIomic Spatial TexturAl descripTor (RADISTAT). This was driven by the hypothesis that quantifying spatial organization of texture patterns within an ROI could allow for better capturing interactions between different tissue classes present in a given region; thus enabling more accurate characterization of disease or response phenotypes. RADISTAT involves (a) robustly identifying sub-compartments of low, intermediate, and high radiomic expression (i.e. heterogeneity) in a feature map and (b) quantifying spatial organization of sub-compartments via graph interactions. RADISTAT was evaluated in two clinically challenging problems (1) discriminating nodal/distant metastasis from metastasis-free rectal cancer patients on post-chemoradiation T2w MRI, and (2) distinguishing tumor progression from pseudo-progression in glioblastoma multiforme using post-chemoradiation T1w MRI. Across over 800 experiments, RADISTAT yielded a consistent discriminatory signature for tumor progression (GBM) and disease metastasis (RCa); where its sub-compartments were associated with pathologic tissue types (fibrosis or tumor, determined via fusion of MRI and pathology). In a multi-institutional setting for both clinical problems, RADISTAT resulted in higher classifier performance (11% improvement in AUC, on average) compared to radiomic descriptors. Furthermore, combining RADISTAT with radiomic descriptors resulted in significantly improved performance compared to using radiomic descriptors alone.This pilot comparative study evaluates the usability of the alternative approaches to magnetic resonance (MR) cardiac triggering based on ballistocardiography (BCG) fiber-optic sensor (O-BCG) and pneumatic sensor (P-BCG). The comparison includes both the objective and subjective assessment of the proposed sensors in comparison with a gold standard of ECG-based triggering. The objective evaluation included several image quality assessment (IQA) parameters, whereas the subjective analysis was performed by 10 experts rating the diagnostic quality (scale 1 - 3, 1 corresponding to the best image quality and 3 the worst one). Moreover, for each examination, we provided the examination time and comfort rating (scale 1 - 3). The study was performed on 10 healthy subjects. All data were acquired on a 3 T SIEMENS MAGNETOM Prisma. In image quality analysis, all approaches reached comparable results, with ECG slightly outperforming the BCG-based methods, especially according to the objective metrics. The subjective evaluation proved the best quality of ECG (average score of 1.68) and higher performance of P-BCG (1.97) than O-BCG (2.03). In terms of the comfort rating and total examination time, the ECG method achieved the worst results, i.e. the highest score and the longest examination time 2.6 and 1049 s, respectively. selleck compound The BCG-based alternatives achieved comparable results (P-BCG 1.5 and 806 s; OBCG 1.9, 908 s). This study confirmed that the proposed BCG-based alternative approaches to MR cardiac triggering offer comparable quality of resulting images with the benefits of reduced examination time and increased patient comfort.Total anomalous pulmonary venous connection (TAPVC) is a rare but mortal congenital heart disease in children and can be repaired by surgical operations. However, some patients may suffer from pulmonary venous obstruction (PVO) after surgery with insufficient blood supply, necessitating special follow-up strategy and treatment. Therefore, it is a clinically important yet challenging problem to predict such patients before surgery. In this paper, we address this issue and propose a computational framework to determine the risk factors for postoperative PVO (PPVO) from computed tomography angiography (CTA) images and build the PPVO risk prediction model. From clinical experiences, such risk factors are likely from the left atrium (LA) and pulmonary vein (PV) of the patient. Thus, 3D models of LA and PV are first reconstructed from low-dose CTA images. Then, a feature pool is built by computing different morphological features from 3D models of LA and PV, and the coupling spatial features of LA and PV. Finally, four risk factors are identified from the feature pool using the machine learning techniques, followed by a risk prediction model.