Reverse the Resistance to PARP Inhibitors

One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand DNA, thus decreasing the chances of generating double-strand breaks in the genome. Therefore, the concept to block PARP enzymes by PARP inhibitor (PARPi) was appreciated in cancer treatment. PARPi has been designed and tested for many years and became a potential supplement for the conventional chemotherapy. However, increasing evidence indicates the appearance of the resistance to this treatment. Specifically, cancer cells may acquire new mutations or events that overcome the positive effect of these drugs. This paper describes several molecular mechanisms of PARPi resistance which were reported most recently, and summarizes some strategies to reverse this type of drug resistance

Associations between genetic variations in the FURIN gene and hypertension

<p>Abstract</p> <p>Background</p> <p>Hypertension is a complex disease influenced by multiple genetic and environmental factors. The Kazakh ethnic group is characterized by a relatively high prevalence of hypertension. Previous research indicates that the FURIN gene may play a pivotal role in the renin-angiotensin system and maintaining the sodium-electrolyte balance. Because these systems influence blood pressure regulation, we considered FURIN as a candidate gene for hypertension. The purpose of this study was to systematically investigate the association between genetic variations in the FURIN gene and essential hypertension in a Xinjiang Kazakh population.</p> <p>Methods</p> <p>We sequenced all exons and the promoter regions of the FURIN gene in 94 hypertensive individuals to identify genetic variations associated with the disorder. Genotyping was performed using the TaqMan polymerase chain reaction method for four representative common single nucleotide polymorphisms (SNPs, -7315C > T, 1970C > G, 5604C > G, 6262C > T) in 934 Kazakh Chinese people. One SNP (1970C > G) was replicated in 1,219 Uygur Chinese people.</p> <p>Results</p> <p>Nine novel and seven known single nucleotide polymorphisms were identified in the FURIN gene. The results suggest that 1970C > G was associated with a hypertension phenotype in Kazakh Chinese (additive model, <it>P </it>= 0.091; dominant model, <it>P = </it>0.031, allele model, <it>P </it>= 0.030), and after adjustment with logistic regression analysis, ORs were 1.451 (95%CI 1.106-1.905, <it>P </it>= 0.008) and 1.496 (95% 1.103-2.028, <it>P </it>= 0.01) in additive and dominant models, respectively. In addition, the association between 1970C > G and hypertension was replicated in Uygur subjects (additive model, <it>P </it>= 0.042; dominant model, <it>P </it>= 0.102; allele model, <it>P </it>= 0.027) after adjustment in additive and dominant models, ORs were 1.327 (95% 1.07-1.646), <it>P </it>= 0.01 and 1.307 (95%CI 1.015-1.681, <it>P </it>= 0.038), respectively. G allele carriers exhibited significant lower urinary Na⁺excretion rate than non-carriers in the Kazakh Chinese population (152.45 ± 76.04 uM/min vs 173.33 ± 90.02 uM/min, <it>P </it>= 0.007).</p> <p>Conclusion</p> <p>Our results suggest that the FURIN gene may be a candidate gene involved in human hypertension, and that the G allele of 1970C > G may be a modest risk factor for hypertension in Xinjiang Kazakh and Uygur populations.</p

Proposed clinical phases for the improvement of personalized treatment of checkpoint inhibitor–related pneumonitis

BackgroundCheckpoint inhibitor–related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined.MethodsWe conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase’s characteristics.ResultsThere were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P&lt;0.05). The main change in radiologic features was the absorption of the lesions, and 3 (3/11) patients in the chronic phase had persistent traction bronchiectasis. For histologic features, most patients had acute fibrinous pneumonitis in the acute phase (5/8), and most had organizing pneumonia in the subacute phase (5/6). Other histologic changes advanced over time, with the lesions entering a state of fibrosis. Moreover, the levels of interleukin-6, interleukin-10 and high-sensitivity C-reactive protein (hsCRP) increased in the acute phase and decreased as CIP progressed (IL-6: 17.9 vs. 9.8 vs. 5.7, P=0.018; IL-10: 4.6 vs 3.0 vs. 2.0, P=0.041; hsCRP: 88.2 vs. 19.4 vs. 14.4, P=0.005).ConclusionsThe general development process of CIP can be divided into acute, subacute, and chronic phases, upon which a better management strategy might be based devised

Auditory Evoked Fields Analysis Using EMD and ICA

The empirical mode decomposition (EMD) is a time-frequency analysis method for analyzing the nonlinear and non-stationary biomedical data which combined with the independent component analysis (ICA) approach allows for more powerful source noise reduction. This paper presents a novel technique for decomposing and localizing the magnetoencephalographic (MEG) data with auditory evoked fields (AEFs) experiment based on EMD and ICA associated with the source localization technique. Applying our technique to the unaveraged single-trial AEFs data, we demonstrate the simulation results.APSIPA ASC 2009: Asia-Pacific Signal and Information Processing Association, 2009 Annual Summit and Conference. 4-7 October 2009. Sapporo, Japan. Oral session: Advances in Signal Processing for Brain Data Analysis and Feature Extraction (5 October 2009)

Variational approach to anti-periodic boundary value problems involving the discrete p-Laplacian

Abstract Using critical point theory, we obtain the existence and multiplicity of nonzero solutions to anti-periodic boundary value problems with p-Laplacian in the case where the nonlinearities are p-sublinear at zero. Some examples are given to illustrate the results

Efficient Deep Learning Models for DGA Domain Detection

In recent years, cyberattacks using command and control (C&C) servers have significantly increased. To hide their C&C servers, attackers often use a domain generation algorithm (DGA), which automatically generates domain names for the C&C servers. Accordingly, extensive research on DGA domain detection has been conducted. However, existing methods cannot accurately detect continuously generated DGA domains and can easily be evaded by an attacker. Recently, long short-term memory- (LSTM-) based deep learning models have been introduced to detect DGA domains in real time using only domain names without feature extraction or additional information. In this paper, we propose an efficient DGA domain detection method based on bidirectional LSTM (BiLSTM), which learns bidirectional information as opposed to unidirectional information learned by LSTM. We further maximize the detection performance with a convolutional neural network (CNN) + BiLSTM ensemble model using Attention mechanism, which allows the model to learn both local and global information in a domain sequence. Experimental results show that existing CNN and LSTM models achieved F1-scores of 0.9384 and 0.9597, respectively, while the proposed BiLSTM and ensemble models achieved higher F1-scores of 0.9618 and 0.9666, respectively. In addition, the ensemble model achieved the best performance for most DGA domain classes, enabling more accurate DGA domain detection than existing models

Liquid phase hydrogenation of chloronitrobenzene to chloroaniline with PtM/CNTs (M=La, Ce, Pr, Nd and Sm) catalysts

1358-1363Hydrogenation properties of chloronitrobenzene with Pt/CNT and PtM/CNT catalysts (M = La, Ce, Pr, Nd and Sm) have been studied in ethanol at 303 K and normal pressure. The results show that the hydrogenation of chloronitrobenzene can be carried out with PtM/CNT catalysts. The conversion of chloronitrobenzene is above 99% and chloroaniline is the main product in hydrogenation with PtM/CNT catalysts. Electron deficient species of the second element promote the specific rate constant turnover frequency expressed as per surface Pt atom by activating the nitrogen-oxygen bond. PtCe/CNT catalyst exhibits the best catalytic activity (TOF = 0.47 s-1) and the highest yield of p-CAN (97.5 mol%). PtSm/CNT catalyst shows the best yields for m-CAN (98.0 mol%) and o-CAN (96.9 mol%). PtCe/CNT (1.0 wt%) catalyst exhibits good stability for hydrogenation of p chloronitrobenzen

Differentially expressed miRNA profiles of serum-derived exosomes in patients with sudden sensorineural hearing loss

ObjectivesThis study aimed to compare the expressed microRNA (miRNA) profiles of serum-derived exosomes of patients with sudden sensorineural hearing loss (SSNHL) and normal hearing controls to identify exosomal miRNAs that may be associated with SSNHL or serve as biomarkers for SSNHL.MethodsPeripheral venous blood of patients with SSNHL and healthy controls was collected to isolate exosomes. Nanoparticle tracking analysis, transmission electron microscopy, and Western blotting were used to identify the isolated exosomes, after which total RNA was extracted and used for miRNA transcriptome sequencing. Differentially expressed miRNAs (DE-miRNAs) were identified based on the thresholds of P &lt; 0.05 and |log2fold change| &gt; 1 and subjected to functional analyses. Finally, four exosomal DE-miRNAs, including PC-5p-38556_39, PC-5p-29163_54, PC-5p-31742_49, and hsa-miR-93-3p_R+1, were chosen for validation using quantitative real-time polymerase chain reaction (RT-qPCR).ResultsExosomes were isolated from serum and identified based on particle size, morphological examination, and expression of exosome-marker proteins. A total of 18 exosomal DE-miRNAs, including three upregulated and 15 downregulated miRNAs, were found in SSNHL cases. Gene ontology (GO) functional annotation analysis revealed that target genes in the top 20 terms were mainly related to “protein binding,” “metal ion binding,” “ATP binding,” and “intracellular signal transduction.” Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that these target genes were functionally enriched in the “Ras,” “Hippo,” “cGMP-PKG,” and “AMPK signaling pathways.” The expression levels of PC-5p-38556_39 and PC-5p-29163_54 were significantly downregulated and that of miR-93-3p_R+1 was highly upregulated in SSNHL. Consequently, the consistency rate between sequencing and RT-qPCR was 75% and sequencing results were highly reliable.ConclusionThis study identified 18 exosomal DE-miRNAs, including PC-5p-38556_39, PC-5p-29163_54, and miR-93-3p, which may be closely related to SSNHL pathogenesis or serve as biomarkers for SSNHL