Erichsensnedker8815

The oncogenic EWSFli1 fusion protein is a key transcriptional mediator of Ewing sarcoma initiation, progression, and therapeutic resistance. Mithramycin A (MithA) is a potent and specific inhibitor of transcription mediated by the EWSFli1. We tested the hypothesis that pretreatment with MithA could selectively radiosensitize EWSFli1

tumor cells by altering the transcriptional response to radiation injury.

A panel of 4 EWSFli1

and 3 EWSFli1

Ewing sarcoma cell lines and 1 nontumor cell line were subjected to MithA dose-response viability assays to determine the relative potency of MithA in cells possessing or lacking the EWSFli1 fusion. Radiosensitization by MithA was evaluated by clonogenic survival assays invitro and in a murine xenograft model. DNA damage was evaluated by comet assay and γ-H2Ax flow cytometry. Immunoblotting, flow cytometry, and reverse-transcription, polymerase chain reaction were used to evaluate DNA damage-induced signaling and repair processes and apoptosis.

We found that MithA alone could potently and selectively inhibit the growth of EWSFli1

tumor cells, but not cells lacking this fusion. Pretreatment with MithA for 24 hours before irradiation significantly reduced clonogenic survival invitro and delayed tumor regrowth invivo, prolonging survival of EWSFli1

tumor-bearing mice. Although MithA did not increase the level of DNA double-strand breaks, mechanistic studies revealed that MithA pretreatment selectively inhibited DNA double-strand break repair through downregulation of EWSFli1-mediated transcription, leading to tumor cell death by apoptosis.

Our data indicate that MithA is an effective radiosensitizer of EWSFli1

tumors and may achieve better local control at lower doses of radiation.

Our data indicate that MithA is an effective radiosensitizer of EWSFli1+ tumors and may achieve better local control at lower doses of radiation.

Transforming growth factor-β (TGF-β) mediated super-activation of urethra fibroblasts contributes to the progression of traumatic urethral stricture (TUS), and the Rho-associated kinase inhibitors, Fasudil, might be a novel therapeutic agent for TUS, but the underlying mechanisms had not been studied.

The primary urethral fibroblasts (PUFs) were isolated from rabbit urethral scar tissues and cultured in vitro, and the PUFs were subsequently treated with TGF-β (10μg/L) to simulate the realistic conditions of TUS pathogenesis. Next, the PUFs were exposed to Fasudil (50μM) and autophagy inhibitor 3-methyladenine (3-MA) treatment. Genes expression was examined by Western Blot and immunofluorescence staining, and cellular functions were determined by MTT assay and Transwell assay.

TGF-β promoted cell proliferation, migration, autophagy, and secretion of extracellular matrix (ECM), including collagen I and collagen III, which were reversed by co-treating cells with both Fasudil and 3-MA. In addition, TGF-β treatment decreased the expression levels of phosphorylated Akt (p-Akt) and mTOR (p-mTOR) to inactivate the Akt/mTOR pathway in the PUFs, which could be re-activated by Fasudil. Then, the fibroblasts were treated with the Pan-Akt inhibitor (GDC-0068), and we surprisingly found that GDC-0068 abrogated the inhibiting effects of Fasudil on cell autophagy and proliferation in the PUFs treated with TGF-β.

Fasudil regulated Akt/mTOR pathway mediated autophagy to hamper TGF-β-mediated super-activation in PUFs, which supported that Fasudil might be an ideal candidate therapeutic agent for TUS treatment for clinical utilization.

Fasudil regulated Akt/mTOR pathway mediated autophagy to hamper TGF-β-mediated super-activation in PUFs, which supported that Fasudil might be an ideal candidate therapeutic agent for TUS treatment for clinical utilization.

EV-A71 is a common causative agent of hand foot and mouth disease. In mainland China, EV-A71 subgenotype C4 has been the sole circulating genotype since 2008, and was used in the production of multiple licensed vaccines. Here, we report the first detection EV-A71 C1 strains in China.

Full genomic sequence were obtained. The origin of the EV-A71 C1 strains were tracked down by Bayesian inferences. Recombination was analyzed using Simplot program. And the antigenicity were tested using the microneutralization test.

The C1-GD2019 shared high identity with the C1-like lineage recently identified in Europe and was introduced into Guangdong in 2018-2019. Close genetic relatedness between the C1-GD2019 and Europe C1-like strains were observed except for the 3D-3'UTR region. The late showed high similarity with CVA genomes. Antigenic variance was found. The C1-GD2019 could not be effectively neutralized by EV-A71 C4a neutralizing antibody positive samples.

This is the first report of EV-A71 subgenotype C1 isolated in China. It is a recombinant strain originating from C1-like strains recently identified in Europe and CVA strains. The different antigenicity between the C1 strains and C4a vaccine strains highlighted the importance on closely monitoring the EV-A71 C1 strains in China.

This is the first report of EV-A71 subgenotype C1 isolated in China. It is a recombinant strain originating from C1-like strains recently identified in Europe and CVA strains. The different antigenicity between the C1 strains and C4a vaccine strains highlighted the importance on closely monitoring the EV-A71 C1 strains in China.Photothermal immunotherapy has emerged as one of the most potent approaches for cancer treatment, but this strategy has suffered from the lack of biodegradability of the photoresponsive materials. In this study, we aimed to develop biodegradable materials for photothermal immunotherapy. To this end, we designed a DNA CpG hydrogel (DH, generated by rolling-circle amplification), loaded it with bis-(3'-5')-cyclic dimeric guanosine monophosphate (G/DH), and coated the formulation with melanin (Mel/G/DH). Mel/G/DH exhibited a temperature increase upon near infrared (NIR) illumination. In vitro, Mel/G/DH plus NIR (808 nm) irradiation, induced the exposure of calreticulin on CT26 cancer cells, and significantly activated the maturation of dendritic cells (DC). In vivo, local administration of Mel/G/DH (+NIR) exerted photothermal killing of primary tumors and induced maturation of DC in lymph nodes. Treatment of primary tumors with Mel/G/DH(+NIR) prevented the growth of rechallenged tumors at a distant site. Survival was 100% in mice treated with Mel/G/DH(+NIR), 5-fold higher than the group treated with Mel/G(+NIR). Mel/G/DH(+NIR) treatment remodeled the immune microenvironment of distant tumors, increasing cytotoxic T cells and decreasing Treg cells. Enitociclib Taken together, the results of this study suggest the potential of Mel/G/DH as a platform for modulating tumor immune microenvironment aimed at preventing the recurrence of distant tumors.

Desmin is the major intermediate filament (IF) protein in human heart and skeletal muscle. So-called 'desminopathies' are disorders due to pathogenic variants in the DES gene and are associated with skeletal myopathies and/or various types of cardiomyopathies. So far, only a limited number of DES pathogenic variants have been identified and functionally characterized.

Using a Sanger- and next generation sequencing (NGS) approach in patients with various types of cardiomyopathies, we identified two novel, non-synonymous missense DES variants p.(Ile402Thr) and p.(Glu410Lys). Mutation carriers developed dilated (DCM) or arrhythmogenic cardiomyopathy (ACM), and cardiac conduction disease, leading to spare out the exercise-induced polymorphic ventricular tachycardia; we moved this variant to data in brief. To investigate the functional impact of these four DES variants, transfection experiments using SW-13 and H9c2 cells with native and mutant desmin were performed and filament assembly was analyzed by confocal microscopy. The DES_p.(Ile402Thr) and DES_p.(Glu410Lys) cells showed filament assembly defects forming cytoplasmic desmin aggregates. link2 Furthermore, immunohistochemical and ultrastructural analysis of myocardial tissue from mutation carriers with the DES_p.(Glu410Lys) pathogenic variant supported the in vitro results.

Our in vitro results supported the classification of DES_p.(Ile402Thr) and DES_p.(Glu410Lys) as novel pathogenic variants and demonstrated that the cardiac phenotypes associated with DES variants are diverse and cell culture experiments improve in silico analysis and genetic counseling because the pathogenicity of a variant can be clarified.

Our in vitro results supported the classification of DES_p.(Ile402Thr) and DES_p.(Glu410Lys) as novel pathogenic variants and demonstrated that the cardiac phenotypes associated with DES variants are diverse and cell culture experiments improve in silico analysis and genetic counseling because the pathogenicity of a variant can be clarified.Growing evidence implicates histone H3 lysine 9 methylation in tumorigenesis. The SUV family of H3K9 methyltransferases, which include G9a, GLP, SETDB1, SETDB2, SUV39H1 and SUV39H2 deposit H3K9me1/2/3 marks at euchromatic and heterochromatic regions, catalyzed by their conserved SET domain. In cancer, this family of enzymes can be deregulated by genomic alterations and transcriptional mis-expression leading to alteration of transcriptional programs. In solid and hematological malignancies, studies have uncovered pro-oncogenic roles for several H3K9 methyltransferases and accordingly, small molecule inhibitors are being tested as potential therapies. However, emerging evidence demonstrate onco-suppressive roles for these enzymes in cancer development as well. Here, we review the role H3K9 methyltransferases play in tumorigenesis focusing on gene targets and biological pathways affected due to misregulation of these enzymes. We also discuss molecular mechanisms regulating H3K9 methyltransferases and their influence on cancer. Finally, we describe the impact of H3K9 methylation on therapy induced resistance in carcinoma. Converging evidence point to multi-faceted roles for H3K9 methyltransferases in development and cancer that encourages a deeper understanding of these enzymes to inform novel therapy.

Gastroparesis (GP) is a multifactorial disease associated with a large burden on the health care systems. Pyloric-directed therapies including gastric peroral endoscopic myotomy (G-POEM) can be effective in improving patient quality of life and symptom severity. We report on the safety and efficacy of G-POEM and its impact on the quality of life of patients managed at a large referral center.

Consecutive patients with confirmed GP referred for G-POEM due to failure of medical therapy were included. All patients were assessed at baseline and then at 1, 3, 6, and 12 and 24 months after G-POEM using validated symptom and quality of life instruments, including the Gastroparesis Cardinal Symptom Index (GCSI), Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM), and 36-Item Short Form Survey (SF-36). link3 Patients were evaluated before and 6 months after the procedure with EGD, 4-hour scintigraphy, and pyloric EndoFLIP. Technical success was defined as the ability to perform full-thickced 6 months after G-POEM (10.2%) compared with baseline (36.5%, P< .001). We report a significant reduction in the number of emergency department visits and days spent in the hospital up to 24 months after G-POEM.

G-POEM appears to be a safe and feasible treatment alternative for refractory GP with significant short-term and mid-term improvements in overall symptoms, quality of life scores, and health care utilization.

G-POEM appears to be a safe and feasible treatment alternative for refractory GP with significant short-term and mid-term improvements in overall symptoms, quality of life scores, and health care utilization.