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In this paper the design and implementation of an expert speech therapy system is presented. A brief presentation of involved speech therapy process is made. Also the base for designing and implementations of this system is presented too.

Ultrasonic waves generated and received by electromagnetic acoustic transducers (EMATs) are advantageous in non-destructive testing, mainly due to the ability to operate without physical contact with the medium under test. Nevertheless, they present a main drawback of less efficiency, which leads to a lower signal-to-noise ratio. To overcome this, the L-network impedance-matching network is often used in order to ensure maximum power transfer to the EMAT from the excitation electronics. There is a wide range of factors that affect an EMAT’s impedance, apart from the transducer itself; namely, the properties of the specimen material, temperature, and frequency. Therefore, to ensure optimal power transfer, the matching network’s configuration needs to be fine-tuned often. Therefore, the automation of the laborious process of manually adjusting the network is of great benefit to the use of EMAT transducers. In this work, a simplified one-parallel-element automatic matching network is proposed and its theoretical optimal value is derived. Next, an automatic matching network was designed and fabricated. Experiments were performed with two different EMATs at several frequencies obtaining good agreement with theoretical predictions. The automatic system was able to determine the best configuration for the one-element matching network and provided up to 5.6 dB gain, similar to a standard manual solution and considerably faster.

Outcomes are poor in patients with advanced or relapsed Ewing sarcoma (EWS) and current treatments have significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. MER proto-oncogene tyrosine kinase (MERTK) promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies in a variety of cancers. MERTK was ubiquitously expressed in five EWS cell lines and five patient samples. Moreover, data from CRISPR-based library screens indicated that EWS cell lines are particularly dependent on MERTK. Treatment with MRX-2843, a first-in-class, MERTK-selective tyrosine kinase inhibitor currently in clinical trials, decreased the phosphorylation of MERTK and downstream signaling in a dose-dependent manner in A673 and TC106 cells and provided potent anti-tumor activity against all five EWS cell lines, with IC50 values ranging from 178 to 297 nM. Inhibition of MERTK correlated with anti-tumor activity, suggesting MERTK inhibition as a therapeutic mechanism of MRX-2843. Combined treatment with MRX-2843 and BCL-2 inhibitors venetoclax or navitoclax provided enhanced therapeutic activity compared to single agents. These data highlight MERTK as a promising therapeutic target in EWS and provide rationale for the development of MRX-2843 for the treatment of EWS, especially in combination with BCL-2 inhibitors.

Two chiral imidazolium salts and one chiral triazolium salt were synthesized containing a chiral cyclohexane bridge based on the salen ligand framework of the Jacobsen-Katsuki epoxidation catalysts. They are promising NHC and aNHC ligand precursors for asymmetric epoxidation or C–H oxidation catalyzed by organometallic compounds. The ligand framework offers plenty of opportunities for modification.

Extracellular vesicles (EVs) are membrane structures enclosed by a lipid bilayer that are released into the extracellular space by all types of cells. EVs are involved in many physiological processes by transporting biologically active substances. Interest in EVs for diagnostic biomarker research and therapeutic drug delivery applications has increased in recent years. The realization of the full therapeutic potential of EVs is currently hampered by the lack of a suitable technology for the isolation and purification of EVs for downstream pharmaceutical applications. Anion Exchange Chromatography (AEX) is an established method in which specific charges on the AEX matrix can exploit charges on the surface of EVs and their interactions to provide a productive and scalable separation and purification method. The established AEX method using Eshmuno® Q, a strong tentacle anion exchange resin, was used to demonstrate the principal feasibility of AEX-based isolation and gain insight into isolated EV properties. Using several EV analysis techniques to provide a more detailed insight into EV populations during AEX isolation, we demonstrated that although the composition of CD9/63/81 remained constant for tetraspanin positive EVs, the size distribution and purity changed during elution. Higher salt concentrations eluted larger tetraspanin negative vesicles.

Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin‐28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B–lethal‐7 (let‐7; a microRNA that is a tumor suppressor)–lymphokine‐activated killer T‐cell‐originated protein kinase (PBK; also known as PDZ‐binding kinase) axis promotes G3 MB proliferation. LIN28B knockdown in G3‐MB‐patient‐derived cell lines leads to a significant reduction in cell viability and proliferation in vitro and in prolonged survival of mice with orthotopic tumors. The LIN28 inhibitor N‐methyl‐N‐[3‐(3‐methyl‐1,2,4‐triazolo[4,3‐b]pyridazin‐6‐yl)phenyl]acetamide (1632) significantly reduces G3 MB cell growth and demonstrates efficacy in reducing tumor growth in mouse xenograft models. Inhibiting PBK using HI‐TOPK‐032 also results in a significant reduction in G3 MB cell viability and proliferation. Together, these results highlight a critical role for the LIN28B–let‐7–PBK pathway in G3 MB and provide preliminary preclinical results for drugs targeting this pathway.

Abstract Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein–protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.

Neuroblastoma is the most common extracranial solid tumor in childhood and arises from neural crest cells of the developing sympathetic nervous system. Prostaglandin E2 (PGE2) has been identified as a key pro-inflammatory mediator of the tumor microenvironment (TME) that promotes neuroblastoma progression. We report that the interaction between the microRNA miR-574-5p and CUG-binding protein 1 (CUGBP1) induces the expression of microsomal prostaglandin E2 synthase 1 (mPGES-1) in neuroblastoma cells, which contributes to PGE2 biosynthesis. PGE2 in turn specifically induces the sorting of miR-574-5p into small extracellular vesicles (sEV) in neuroblastoma cell lines. sEV are one of the major players in intercellular communication in the TME. We found that sEV-derived miR-574-5p has a paracrine function in neuroblastoma. It acts as a direct Toll-like receptor 7/8 (TLR7/8) ligand and induces α-smooth muscle actin (α-SMA) expression in fibroblasts, contributing to fibroblast differentiation. This is particularly noteworthy as it has an opposite function to that in the TME of lung carcinoma, another PGE2 dependent tumor type. Here, sEV-derived miR-574-5p has an autokrine function that inhibits PGE2 biosynthesis in lung cancer cells. We report that the tetraspanin composition on the surface of sEV is associated with the function of sEV-derived miR-574-5p. This suggests that the vesicles do not only transport miRs, but also appear to influence their mode of action.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

In this study, we determine whether most teachers working in classrooms today can expect to work long enough in the same state to accrue higher benefits under their existing traditional pension, which provides monthly income based on age and service, than they would under a 401(k)-type savings plan of equal cost.

Sonic hedgehog (Shh)‐driven medulloblastoma (Shh MB) cells are dependent on constitutive Shh signaling, but targeted treatment of Shh MB has been ineffective due to drug resistance. The purpose of this study was to address the critical role of signal transducer and activator of transcription 3 (STAT3) in Shh signaling and drug resistance in Shh MB cells. Herein, we show that STAT3 is required for Smoothened (Smo)‐dependent Shh signaling and, in turn, is reciprocally regulated by Shh signaling, and demonstrate that STAT3 activity is critical for expression of HCK proto‐oncogene, Src family tyrosine kinase (Hck) in Shh MB. We also demonstrate that maintained STAT3 activity suppresses p21 expression and promotes colony formation of Shh MB cells, whereas dual treatment with inhibitors of both Smo and STAT3 results in marked synergistic killing and overcomes drug resistance in vitro of Smo antagonist‐resistant Shh MB cells. Finally, STAT3 inhibitor treatment significantly prevents in vivo tumor formation in genetically engineered Shh MB mice. Collectively, we show that STAT3 is necessary to maintain Shh signaling and thus is a potential therapeutic target to treat Shh MB and overcome anti‐Smo drug resistance.

Abstract Aim In order to evaluate the role of MMP-14 in ovarian cancer, a systematic review was conducted. Methods In March 2020, a search in Pubmed was performed with MMP-14 and ovarian cancer as search terms. After exclusion of the references not on MMP-14 or ovarian cancer or not in English, the studies found were classified into two categories: basic research and clinicopathological research. Results In total, 94 references were found of which 33 were excluded. Two additional articles were found in the reference lists of the included studies. Based on the full texts, another 4 were excluded. Eventually, 59 studies were included in the review, 32 on basic research and 19 on clinicopathological research. 8 studies fell in both categories. The basic research studies show that MMP-14 plays an important role in ovarian cancer in the processes of proliferation, invasion, angiogenesis and metastasis. In clinocopathological research, MMP-14 expression is found in most tumours with characteristics of poor prognosis but this immunohistochemical MMP-14 determination does not seem to be an independent predictor of prognosis. Conclusions From this systematic review of the literature concerning MMP-14 in ovarian cancer it becomes clear that MMP-14 plays various important roles in the pathophysiology of ovarian cancer. The exact translation of these roles in the pathophysiology to the importance of MMP-14 in clinicopathological research in ovarian cancer and possible therapeutic role of anti-MMP-14 agents needs further elucidation.