Aminoglycosides, a class of clinically important drugs, are widely used worldwide against gram-negative bacterial infections. However, there is growing evidence that aminoglycosides can cause hearing ...loss or balance problems. In this article, we mainly introduce the main mechanism of ototoxicity induced by aminoglycosides. Genetic analysis showed that the susceptibility of aminoglycosides was attributable to mutations in mtDNA, especially A1555G and C1494T mutations in 12S rRNA. In addition, the overexpression of NMDA receptors and the formation of free radicals also play an important role. Understanding the mechanism of ototoxicity induced by aminoglycosides is helpful to develop new therapeutic methods to protect hearing. In this article, the prevention methods of ototoxicity induced by aminoglycosides were introduced from the upstream and downstream aspects.
Epigenetic therapy is a novel tumor therapeutic method and refers to the targeting of the aberrant epigenetic modifications presumably at cancer-related genes by chemicals which are epigenetic ...targeting drugs (ETDs). Not like in treating hematopoietic cancer, the clinical trials investigating the potential use of ETDs in the solid tumor is not encouraging. Instead, the curative effects of ETD delivered together with DNA targeting chemo drugs (DTDs) are quite promising according to our meta-analysis. To investigate the synergistic mechanism of ETD and DTD drug combination, the therapeutic effect was studied using both cell lines and mouse engrafted tumors. Mechanically we show that HDAC inhibitors and DNMT inhibitors are capable of increasing the chromatin accessibility to cisplatin (CP) and doxorubicin (Dox) through chromatin decompaction globally. Consequently, the combination of ETD and DTD enhances the DTD induced DNA damage and cell death. Engrafted tumors in SCID mice also show increased sensitivity to irradiation (IR) or CP when the tumors were pretreated by ETDs. Given the limited therapeutic effect of ETD alone, these results strongly suggest that the combination of DTD, including irradiation, and ETD treatment is a very promising choice in clinical solid tumor therapy.
Neutrophil CD64 has been proposed as an early marker of sepsis. This study aims to evaluate the diagnostic utility of neutrophil CD64 for identification of early-onset sepsis in preterm neonates.
The ...prospective study was conducted in a neonatal intensive care unit between November 2010 and June 2011. Preterm neonates in whom infection was suspected when they were <12 hours of age were enrolled. Complete blood count with differential, blood culture, neutrophil CD11b and CD64 measurement were performed. Receiver operating characteristic curve analysis was performed to evaluate the performance of neutrophil CD64 as biomarker of sepsis.
A total of 158 preterm neonates was enrolled, 88 of whom were suspected infection. The suspected sepsis group was of lesser gestational age (P<0.001) and lower birth weight (P<0.001), compared with controls. The hematologic profiles of the suspected sepsis group were characterized by higher white blood cell count, neutrophil counts and C-reactive protein. The suspected sepsis neonates had significantly higher neutrophil CD64 expression compared with controls. Neutrophil CD64 had an area value under the curve of 0.869 with an optimal cutoff values of 1010 phycoerythrin molecules bound/cell and it had a high sensitivity (81.82%) and negative predictive value (77.4%). The level of neutrophil CD64 was independent of antibiotic therapy within 24 hours after the onset of sepsis in preterm neonates.
Neutrophil CD64 is a highly sensitive marker for suspected early-onset sepsis in preterm neonates. Our study suggests that neutrophil CD64 may be incorporated as a valuable marker to diagnose infection.
A water-soluble sulfated polysaccharide, F2-1, was obtained from the marine green alga,
, using ion-exchange and size-exclusion chromatography. Structure analysis showed that the F2-1 was a sulfated ...arabinan comprising Ara, Rha, Man, Gal, and Xyl with an 18% sulfate content and a molecular weight of 100 kDa. Methylation analysis combined with desulfation, GC-MS, IR, and NMR spectroscopy showed that the backbone of F2-1 was →4)-β-L-Ara
(1→ residue. Its 2-
and/or 3-
positions showed sulfate modification; additionally, the 2-
or 3-
position showed branch points. The side chains were composed of →5)-β-D-Gal
, (1→2,6)-β-D-Gal
(1→, (1→2)-β-L-Rha
4S, →4)-α-D-Glc
(1→, and terminal α-D-Gal
(1→ and β-D-Xyl
(1→. Polysaccharides containing β-D-galactofuranose are rarely found in seaweed. F2-1 exhibited significant anticoagulant activity in vitro. Our findings suggested that the green-tide alga,
, can be considered as a useful resource for bioactive polysaccharides.
Type I restriction-modification systems help establish the prokaryotic DNA methylation landscape and provide protection against invasive DNA. In addition to classical m6A modifications, non-canonical ...type I enzymes catalyze both m6A and m4C using alternative DNA-modification subunits M1 and M2. Here, we report the crystal structures of the non-canonical PacII_M1M2S methyltransferase bound to target DNA and reaction product S-adenosylhomocysteine in a closed clamp-like conformation. Target DNA binds tightly within the central tunnel of the M1M2S complex and forms extensive contacts with all three protein subunits. Unexpectedly, while the target cytosine properly inserts into M2's pocket, the target adenine (either unmethylated or methylated) is anchored outside M1's pocket. A unique asymmetric catalysis is established where PacII_M1M2S has precisely coordinated the relative conformations of different subunits and evolved specific amino acids within M2/M1. This work provides insights into mechanisms of m6A/m4C catalysis and guidance for designing tools based on type I restriction-modification enzymes.
A power amplifier’s linearity determines the emission signal’s quality and the efficiency of the system. Nonlinear distortion can result in system bit error, out-of-band radiation, and interference ...with other channels, which severely influence communication system’s quality and reliability. Starting from the third-order intermodulation point of the milimeter wave (mm-Wave) power amplifiers, the circuit’s nonlinearity is compensated for. The analysis, design, and implementation of linear class AB mm-Wave power amplifiers based on GlobalFoundries 45 nm CMOS silicon-on-insulator (SOI) technology are presented. Three single-ended and differential stacked power amplifiers have been implemented based on cascode cells and triple cascode cells operating in U-band frequencies. According to nonlinear analysis and on-wafer measurements, designs based on triple cascode cells outperform those based on cascode cells. Using single-ended measurements, the differential power amplifier achieves a measured peak power-added efficiency (PAE) of 47.2% and a saturated output power (
P
sat
) of 25.2 dBm at 44 GHz. The amplifier achieves a
P
sat
higher than 23 dBm and a maximum PAE higher than 25% in the measured bandwidth from 44 GHz to 50 GHz.
Short text classification methods have achieved significant progress and wide application on text data such as Twitter and Weibo. However, the extremely short chinese texts like tax invoice data are ...different with traditional short texts in lackness of contextual semantic information, feature sparseness and extremely short length. The existing short text classification methods are difficult to achieve a satisfactory performance in these texts. To address these problems, this paper proposes a text classification method based on bidirectional semantic extension for extremely short texts like Chinese tax invoice data. More specifically, firstly, the Chinese knowledge graph is introduced for extending bidirectional semantic of texts and label data to expand the extremely short texts and ease the problem of feature sparseness; secondly, the hash vectorization is used to avoid the semantic problem caused by the lackness of contextual information. Experimental results conducted the real tax invoice dataset demonstrate the effectiveness of our proposed method.
Genetic mutations in TP53 contribute to human malignancies through various means. To date, there have been a variety of therapeutic strategies targeting p53, including gene therapy to restore normal ...p53 function, mutant p53 rescue, inhibiting the MDM2-p53 interaction, p53-based vaccines, and a number of other approaches. This review focuses on the functions of TP53 and discusses the aberrant roles of mutant p53 in various types of cancer. Recombinant human p53 adenovirus, trademarked as Gendicine, which is the first anti-tumor gene therapy drug, has made tremendous progress in cancer gene therapy. We herein discuss the biological mechanisms by which Gendicine exerts its effects and describe the clinical responses reported in clinical trials. Notably, the clinical studies suggest that the combination of Gendicine with chemotherapy and/or radiotherapy may produce more pronounced efficacy in slowing tumor growth and progression than gene therapy/chemotherapy alone. Finally, we summarize the methods of administration of recombinant human p53 adenovirus for different cancer types to provide a reference for future clinical trials.
To explore the quality of high-resolution CT images information in the evaluation of pulmonary nodule interface and internal structure of nodules in lung tissue, as well as the value of early ...diagnosis of lung cancer associated with infection, high-resolution CT images were used as the research object. Through the analysis of the computerized detection and diagnosis (Computer-Aided Diagnosis (CAD)) of lung cancer, the high-resolution CT was further explored in the process of clinical imaging doctors in the diagnosis of lung cancer, and more conditions were created for the application of medical image processing in the early diagnosis of lung cancer. The research results show that CAD can automatically and accurately complete the automatic segmentation of the lung region in the CT image by applying the automatic segmentation algorithm for a series of processing and analysis of the CT image, that is, generating high-resolution CT images. It can enhance the pulmonary nodules in CT images and improve the accuracy of lung nodule detection, which is of great value in the diagnosis of early lung cancer. CAD diagnosis of lung lesions based on high-resolution CT images is studied, which can provide reference for imaging physicians to diagnose early lung cancer. However, in the automatic identification of benign and malignant lesions in the lungs, it is necessary to further improve the analysis function of similar nodules, which will be an important step for humans in the diagnosis and treatment of diseases.
Conventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy.
We developed an advanced noninvasive prenatal diagnosis method based on ...massively parallel sequencing. The Noninvasive Fetal Trisomy (NIFTY) test, combines an optimized Student's t-test with a locally weighted polynomial regression and binary hypotheses. We applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping.
16 of 16 trisomy 21, 12 of 12 trisomy 18, two of two trisomy 13, three of four 45, X, one of one XYY and two of two XXY abnormalities were correctly identified. But one false positive case of trisomy 18 and one false negative case of 45, X were observed. The test performed with 100% sensitivity and 99.9% specificity for autosomal aneuploidies and 85.7% sensitivity and 99.9% specificity for sex chromosomal aneuploidies. Compared with three previously reported z-score approaches with/without GC-bias removal and with internal control, the NIFTY test was more accurate and robust for the detection of both autosomal and sex chromosomal aneuploidies in fetuses.
Our study demonstrates a powerful and reliable methodology for noninvasive prenatal diagnosis.
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