Ayalagay9329

DKK1 was capable of suppressing the profibrogenic differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis. In conclusion, this study not only provides a further in-depth understanding of the pathogenesis of pulmonary fibrosis, but also reveals a potential therapeutic strategy for disorders associated with pulmonary fibrosis.Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid β-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype.O-GlcNAcylation is important in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The glycosyltransferase EGF domain-specific O-linked GlcNAc transferase (EOGT) acts as a key participant in glycosylating NOTCH1. A-83-01 in vivo High-throughput sequencing of specimens from 30 advanced PDAC patients identified SHCBP1 and EOGT as factors of poor prognosis. We hypothesized that they could mediate PDAC progression by influencing NOTCH1 O-GlcNAcylation. Thus, 186 PDAC tissue specimens were immunostained for EOGT and SHCBP1. Pancreatic cancer cell lines and nude mouse models were used for in vitro and in vivo experiments. Respectively, The protein expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation, migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice, whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. We further clarified the molecular mechanisms by which EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, Subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells.PRoline-Rich Transmembrane protein-2 (PRRT2) is a recently described neuron-specific type-2 integral membrane protein with a large cytosolic N-terminal domain that distributes in presynaptic and axonal domains where it interacts with several presynaptic proteins and voltage-gated Na+ channels. Several PRRT2 mutations are the main cause of a wide and heterogeneous spectrum of paroxysmal disorders with a loss-of-function pathomechanism. The highest expression levels of PRRT2 in brain occurs in cerebellar granule cells (GCs) and cerebellar dysfunctions participate in the dyskinetic phenotype of PRRT2 knockout (KO) mice. We have investigated the effects of PRRT2 deficiency on the intrinsic excitability of GCs and the input-output relationships at the mossy fiber-GC synapses. We show that PRRT2 KO primary GCs display increased expression of Na+ channels, increased amplitude of Na+ currents and increased length of the axon initial segment, leading to an overall enhancement of intrinsic excitability. In acute PRRT2 KO cerebellar slices, GCs were more prone to action potential discharge in response to mossy fiber activation and exhibited an enhancement of transient and persistent Na+ currents, in the absence of changes at the mossy fiber-GC synapses. The results support a key role of PRRT2 expressed in GCs in the physiological regulation of the excitatory input to the cerebellum and are consistent with a major role of a cerebellar dysfunction in the pathogenesis of the PRRT2-linked paroxysmal pathologies.Nowadays, pharmaceutical industry demands competitive and eco-friendly processes for active pharmaceutical ingredients (APIs) manufacturing. In this context, enzyme and whole-cell mediated processes offer an efficient, sustainable and cost-effective alternative to the traditional multi-step and environmentally-harmful chemical processes. Particularly, 2'-deoxyribosyltransferases (NDTs) have emerged as a novel synthetic alternative, not only to chemical but also to other enzyme-mediated synthetic processes. This review describes recent findings in the development and scaling up of NDTs as industrial biocatalysts, including the most relevant and recent examples of single enzymatic steps, multienzyme cascades, chemo-enzymatic approaches, and engineered biocatalysts. Finally, to reflect the inventive and innovative steps of NDT-mediated bioprocesses, a detailed analysis of recently granted patents, with specific focus on industrial synthesis of nucleoside-based APIs, is hereunder presented.Rhodococci are bacteria which can survive under various extreme conditions, in the presence of toxic compounds, and in other hostile habitats. Their tolerance of unfavorable conditions is associated with the structure of their cell wall and their large array of enzymes, which degrade or detoxify harmful compounds. Their physiological and biotechnological properties, together with tools for their genetic manipulation, enable us to apply them in biotransformations, biodegradation and bioremediation. Many such biotechnological applications cause stresses that positively or negatively affect their efficiency. Whereas numerous reviews on rhodococci described their enzyme activities, the optimization of degradation or production processes, and corresponding technological solutions, only a few reviews discussed some specific effects of stresses on the physiology of rhodococci and biotechnological processes. This review aims to comprehensively describe individual stress responses in Rhodococcus strains, the interconnaps in current knowledge may motivate researchers working to fill these gaps.Biocatalysis has found enormous applications in sorts of fields as an alternative to chemical catalysis. In the pursue of green and sustainable chemistry, ionic liquids (ILs) have been considered as promising reaction media for biocatalysis, owing to their unique characteristics, such as nonvolatility, inflammability and tunable properties as regards polarity and water miscibility behavior, compared to organic solvents. In recent years, great developments have been achieved in respects to biocatalysis in ILs, especially for preparing various chemicals. This review tends to give illustrative examples with a focus on representative chemicals production by biocatalyst in ILs and elucidate the possible mechanism in such systems. It also discusses how to regulate the catalytic efficiency from several aspects and finally provides an outlook on the opportunities to broaden biocatalysis in ILs.

Radiotherapy (RT) for early breast cancer (BC) reduces the risk of recurrence and improves overall survival. However, thoracic RT may cause some incidental RT dose to the heart with subsequent risk of heart disease. During 2000-2010, CT-based RT planning was gradually introduced. The aim of this study was to investigate the risk of cardiac events in left-sided compared with right-sided BC patients treated during a non-CT-based (1999-2007) vs a CT-based period (2008-2016).

Information on BC and cardiac events among Danish women was obtained from population-based medical registers. Patients diagnosed with BC during 1999-2016, were included. A cardiac event was defined as coronary artery disease or severe valvular heart disease.

Among 29,662 patients, 22,056 received RT. For those irradiated during the non-CT-based period, the 10-year cumulative risk of cardiac event was 1.7% (95% CI 1.4-2.0) at median follow-up of 11.1years. The incidence rate ratio (IRR) for cardiac event in left-sided vs right-sided pat CT-based period, no increased risk of cardiac events in left-sided vs right-sided patients was observed within the first 10 years after RT, whilst information on cardiac events beyond 10 years after RT was limited.

Fast rotating closed-bore gantry linacs are ideally suited for breath-hold treatments due to reduced imaging and delivery times. We evaluated the reproducibility and stability of spirometer-guided breath-hold breast treatments, using intra-bore surface monitoring and portal imaging on Halcyon (Varian Medical Systems).

Seven left-sided breast cancer patients were treated in breath-hold using the SDX spirometer (Dyn'R) with an integrated boost volumetric arc protocol on Halcyon. A dual depth-camera surface scanning system monitored the left breast. The interfraction, intrafraction and intrabreath-hold motion was determined in the anterior-posterior (AP) and superior-inferior (SI) direction. Portal images (PI), acquired at a tangential gantry angle were manually registered to the planning-CT to determine inter- and intrafraction breath-hold errors for the SI and tangential-anterior-posterior ("AP") axis. Correlations between PI and surface imaging deviations were investigated. To evaluate workflow efficiencyble technique for monitoring breathing motion in closed-bore systems.

The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

For the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p<0.