Khanfriedrichsen9234

We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.Healthy development of the gut microbiome provides long-term health benefits. Children raised in countries with high infectious disease burdens are frequently exposed to diarrhoeal pathogens and antibiotics, which perturb gut microbiome assembly. A recent cluster-randomized trial leveraging >4,000 child observations in Dhaka, Bangladesh, found that automated water chlorination of shared taps effectively reduced child diarrhoea and antibiotic use. In this substudy, we leveraged stool samples collected from 130 children 1 year after chlorine doser installation to examine differences between treatment and control children's gut microbiota. Water chlorination was associated with increased abundance of several bacterial genera previously linked to improved gut health; however, we observed no effects on the overall richness or diversity of taxa. Several clinically relevant antibiotic resistance genes were relatively more abundant in the gut microbiome of treatment children, possibly due to increases in Enterobacteriaceae. While further studies on the long-term health impacts of drinking chlorinated water would be valuable, we conclude that access to chlorinated water did not substantially impact child gut microbiome development in this setting, supporting the use of chlorination to increase global access to safe drinking water.

To assess the relationship of retinal pigment clump (RPC) size and its location with visual acuity and retinal neovascularisation in eyes with type 2 macular telangiectasia (MacTel).

In this cross-sectional study, eyes diagnosed with type 2 MacTel showing RPC were included. Area occupied by pigment was measured on the multicolour image using the area tool on the Spectralis, Heidelberg machine. Pigment location within retinal layers was noted with OCT. Analysis was performed to identify factors associated with poor vision and proliferative disease.

Sixty-two eyes of 42 patients diagnosed with type 2 MacTel and RPC were included. The mean age was 64.31 ± 10.19 years. There were 13 (31%) males and 29 (69%) females in the study. 74% of patients were diabetics and the mean logMAR visual acuity of the participants was 0.619 ± 0.359. Univariate and multivariate binary logistic regression analysis identified female gender (p = 0.026), increasing RPC size (p = 0.008) and its presence above the outer plexiform layer (p = 0.006) to be associated with poor vision and proliferative disease in type 2 MacTel.

Our data identified female gender, larger pigment size and its location above the OPL to be associated with poor vision and proliferative disease. This data may be useful for further improving the current system for staging disease severity in type 2 MacTel.

Our data identified female gender, larger pigment size and its location above the OPL to be associated with poor vision and proliferative disease. This data may be useful for further improving the current system for staging disease severity in type 2 MacTel.

To investigate predictors for macular atrophy (MA) involving the fovea after photodynamic therapy (PDT) followed by pro re nata (PRN) treatment for polypoidal choroidal vasculopathy (PCV).

This prospective observational study analysed treatment-naïve eyes with symptomatic PCV without MA at baseline which were followed up for 5 years. All eyes were initially treated with PDT, followed by a PRN regimen of anti-vascular endothelial growth factor (VEGF) therapy and/or PDT. We assigned eyes with and eyes without development of MA involving the fovea 5 years after the initial treatment into MA and non-MA groups, respectively. Baseline parameters and the number of treatments were compared between the two groups.

Seventy-two eyes of 69 consecutive patients were included, and 29 eyes of 29 patients were analysed. Twelve (41%) and 17 (59%) eyes were assigned into the MA and non-MA groups, respectively. There were significant differences in subfoveal choroidal thickness (226.2 ± 47.8 μm vs. 278.8 ± 68.1 μm, P = 0.03) and number of anti-VEGF injections (13.7 ± 9.6 vs. 5.4 ± 5.6, P = 0.007) between the MA and non-MA groups, but not in the number of PDT sessions (P = 0.71). Best-corrected visual acuity at 5 years in the MA group was lower than in the non-MA group (P = 0.048).

Our long-term observation suggests that a thin subfoveal choroid at baseline and many followed anti-VEGF injections in a PRN regimen increase the risk for development of MA involving the fovea 5 years after PDT.

Our long-term observation suggests that a thin subfoveal choroid at baseline and many followed anti-VEGF injections in a PRN regimen increase the risk for development of MA involving the fovea 5 years after PDT.Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and its dismal prognosis indicates the urgent need to elucidate the potential oncogenic mechanisms. SIRT7 is a classic NAD+-dependent deacetylase that stabilizes the transformed state of cancer cells. However, its functional roles in PDAC are still unclear. Here, we found that SIRT7 expression is upregulated and predicts poor prognosis in PDAC. Then we screened the new interacting proteins of SIRT7 by mass spectrometry and the results showed that SIRT7 can interact with O-GlcNAc transferase (OGT). O-GlcNAcylation stabilizes the SIRT7 protein by inhibiting its interaction with REGγ to prevent degradation, and hyper-O-GlcNAcylation in pancreatic cancer cells leads to hypoacetylation of H3K18 via SIRT7, which promotes transcriptional repression of several tumour suppressor genes. In addition, SIRT7 O-GlcNAcylation at the serine 136 residue (S136) is required to maintain its protein stability and deacetylation ability. In vivo and in vitro experiments showed that blocking SIRT7 O-GlcNAcylation at S136 attenuates tumour progression. Collectively, we demonstrate that O-GlcNAcylation is an important post-translational modification of SIRT7 in pancreatic cancer cells, and elucidating this mechanism of SIRT7 is expected to pave the way for the development of novel therapeutic methods in the future.Ferroptosis is a recently defined form of regulated cell death, which is biochemically and morphologically distinct from traditional forms of programmed cell death such as apoptosis or necrosis. It is driven by iron, reactive oxygen species, and phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage and breakdown of membrane integrity. Tetrahydropiperine Numerous cellular signaling pathways and molecules are involved in the regulation of ferroptosis, including enzymes that control the cellular redox status. Alterations in the ferroptosis-regulating network can contribute to the development of various diseases, including cancer. Evidence suggests that ferroptosis is commonly suppressed in cancer cells, allowing them to survive and progress. However, cancer cells which are resistant to common chemotherapeutic drugs seem to be highly susceptible to ferroptosis inducers, highlighting the great potential of pharmacologic modulation of ferroptosis for cancer treatment. Non-coding RNAs (ncRNAs) are considered master regulators of various cellular processes, particularly in cancer where they have been implicated in all hallmarks of cancer. Recent work also demonstrated their involvement in the molecular control of ferroptosis. Hence, ncRNA-based therapeutics represent an exciting alternative to modulate ferroptosis for cancer therapy. This review summarizes the ncRNAs implicated in the regulation of ferroptosis in cancer and highlights their underlying molecular mechanisms in the light of potential therapeutic applications.

There has been an increasing need to update the recommended values of Korean exposure factors for adults aged 19 and older, as using exposure factors developed over a decade ago could reduce risk assessment reliability.

Exposure factor data have been compiled and standardized using the latest national statistical reports and academic literature, as well as studies conducted from 2016 to 2018.

The updated data contained anthropometric parameters, inhalation rates, food and drinking water ingestion rates, and time-activity patterns and provided technical information on Koreans' exposure factors classified by sex, age group, per capita and general population, and doer-only for various exposure assessments.

Although the average life expectancy, body weight, body surface area, and inhalation rate increased slightly compared to the 2007 Korean Exposure Factor Handbook, differences various in food consumption were remarkable. Because of Asians' similar food preferences, the intake rate of grain products and ntly vary depending on the exposure factors related to human behaviors and characteristics. Therefore the exposure factors need to be continuously updated along with more extensive survey areas and improved measurement methods. We utilized the existing data with the aim to develop general exposure factors for risk assessment in Korean aged ≥19 years. Measurements and questionnaire surveys were also performed if there were no existing data. This study provided the currently updated exposure factor information for Koreans and could be compared to those of other countries.