Diagnosis and Treatment Strategy of Nasogenic Olfactory Dysfunction.

Since the global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a symptom of the onset of SARS-CoV-2, olfactory dysfunction (OD), has attracted tremendous attention. OD is not only a negative factor for quality of life but also an independent hazard and early biomarker for various diseases, such as Parkinson's and Huntington's diseases. Therefore, early identification and treatment of OD in patients are critical. Many etiological factors are responsible for OD based on current opinions. Sniffin'Sticks are recommended to identify the initial position (central or peripheral) for OD when treating patients clinically. It is worth emphasizing that the olfactory region in nasal cavity is recognized as the primary and critical olfactory receptor. Many nasal diseases, such as those with traumatic, obstructive and inflammatory causes, can lead to OD. The key question is no refined diagnosis or treatment strategy for nasogenic OD currently. This study summarizes the differences in medical history, symptoms, auxiliary examination, treatment and prognosis of different types of nasogenic OD by analyzing the current studies. We propose using olfactory training after 4-6 weeks of initial treatment for nasogenic OD patients with no significant improvement in olfaction. We hope that our research can provide valuable clinical guidance by systematically summarizing the clinical characteristics of nasogenic OD.

A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis.

A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCϵ) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCϵ and this SNP in esophageal carcinogenesis, we analyzed PLCϵ genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCϵ mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59-22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33-1.64 in low-incidence area; P = 0.008). In conclusion, the PLCϵ gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCϵ mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.

Activation of PLC by an endogenous cytokine (GBP) in Drosophila S3 cells and its application as a model for studying inositol phosphate signalling through ITPK1.

Using immortalized [3H]inositol-labelled S3 cells, we demonstrated in the present study that various elements of the inositol phosphate signalling cascade are recruited by a Drosophila homologue from a cytokine family of so-called GBPs (growth-blocking peptides). HPLC analysis revealed that dGBP (Drosophila GBP) elevated Ins(1,4,5)P3 levels 9-fold. By using fluorescent Ca2+ probes, we determined that dGBP initially mobilized Ca2+ from intracellular pools; the ensuing depletion of intracellular Ca2+ stores by dGBP subsequently activated a Ca2+ entry pathway. The addition of dsRNA (double-stranded RNA) to knock down expression of the Drosophila Ins(1,4,5)P3 receptor almost completely eliminated mobilization of intracellular Ca2+ stores by dGBP. Taken together, the results of the present study describe a classical activation of PLC (phospholipase C) by dGBP. The peptide also promoted increases in the levels of other inositol phosphates with signalling credentials: Ins(1,3,4,5)P4, Ins(1,4,5,6)P4 and Ins(1,3,4,5,6)P5. These results greatly expand the regulatory repertoire of the dGBP family, and also characterize S3 cells as a model for studying the regulation of inositol phosphate metabolism and signalling by endogenous cell-surface receptors. We therefore created a cell-line (S3ITPK1) in which heterologous expression of human ITPK (inositol tetrakisphosphate kinase) was controlled by an inducible metallothionein promoter. We found that dGBP-stimulated S3ITPK1 cells did not synthesize Ins(3,4,5,6)P4, contradicting a hypothesis that the PLC-coupled phosphotransferase activity of ITPK1 [Ins(1,3,4,5,6)P5+Ins(1,3,4)P3→Ins(3,4,5,6)P4+Ins(1,3,4,6)P4] is driven solely by the laws of mass action [Chamberlain, Qian, Stiles, Cho, Jones, Lesley, Grabau, Shears and Spraggon (2007) J. Biol. Chem. 282, 28117-28125]. This conclusion represents a fundamental breach in our understanding of ITPK1 signalling.

Defining signal transduction by inositol phosphates.

Ins(1,4,5)P(3) is a classical intracellular messenger: stimulus-dependent changes in its levels elicits biological effects through its release of intracellular Ca(2+) stores. The Ins(1,4,5)P(3) response is "switched off" by its metabolism to a range of additional inositol phosphates. These metabolites have themselves come to be collectively described as a signaling "family". The validity of that latter definition is critically examined in this review. That is, we assess the strength of the hypothesis that Ins(1,4,5)P(3) metabolites are themselves "classical" signals. Put another way, what is the evidence that the biological function of a particular inositol phosphate depends upon stimulus dependent changes in its levels? In this assessment, examples of an inositol phosphate acting as a cofactor (i.e. its function is not stimulus-dependent) do not satisfy our signaling criteria. We conclude that Ins(3,4,5,6)P(4) is, to date, the only Ins(1,4,5)P(3) metabolite that has been validated to act as a second messenger.

CircNMD3 relieves endothelial cell injury induced by oxidatively modified low-density lipoprotein through regulating miR-498/ BMP and activin membrane-bound inhibitor (BAMBI) axis.

Atherosclerosis (AS) is one of the most common vascular diseases. The endothelial injury theory indicates that atherosclerotic plaque is the result of endothelial cell injury. Recent studies have revealed that circRNAs are abnormally expressed in AS cell models, which are implicated in the regulation of various cell behaviors. In this study, we showed the downregulation of circNMD3 in AS, and studied its role in the model of endothelial cell injury by proliferation and apoptosis assay, caspase 3 activity assay, and ELISA. We also identified and validated its downstream targets by luciferase reporter assay, RNA pull-down experiment, Western blot, and RT-qPCR. CircNMD3 overexpression or miR-498 knockdown could inhibit the ox-LDL (oxidatively modified low-density lipoprotein)-induced injury in HUVEC (human umbilical vein endothelial cells), while the co-transfection of miR-498 mimic or siRNA targeting BAMBI (BMP and activin membrane bound inhibitor) attenuated the protective effect of circNMD3 overexpression. Overall, our data suggest that circNMD3 regulates the miR-498/BAMBI axis in endothelial cells to protect ox-LDL-induced damages. As a molecular sponge of miR-498, circNMD3 regulates the level of miR-498, which in turn modulates BAMBI expression and suppresses ox-LDL-induced injury in HUVECs.

Spatio-temporal analysis of EEG features during consciousness recovery in patients with disorders of consciousness.

OBJECTIVE: As consciousness recovery is not only dynamic but also involves interactions between various brain regions, elucidating the mechanism of recovery requires tracking cortical activity in spatio-temporal dimensions. METHODS: We tracked the cortical activities of 40 patients (mean age: 54.38 years; 28 males; 21 patients with minimally conscious states) with disorders of consciousness, and collected a total of 156 electroencephalographic signals. We investigated the longitudinal changes in EEG nonlinear dynamic features (i.e., approximate entropy, sample entropy, and Lempel-Ziv complexity) and relative wavelet energy along with consciousness recovery. RESULTS: Global EEG features showed a non-monotonic trend during consciousness recovery (P < 0.05). When the level of consciousness of patients was transferred to a minimally conscious state from an unresponsive wakefulness syndrome/ vegetative state, an inflection point appeared in the EEG features. The EEG feature change trends between the injured and uninjured areas were dissimilar (P < 0.05). Importantly, the degree of dissimilarity increased non-monotonically across the levels of consciousness (P < 0.05). CONCLUSIONS: EEG recovery was non-monotonic and dissimilar in spatio-temporal dimensions, with an inflection point. SIGNIFICANCE: These findings further clarify the process of consciousness recovery and provide assistance in exploring the mechanism of consciousness recovery.

Construction of a competing endogenous RNA network in head and neck squamous cell carcinoma by pan-cancer analysis.

Background: Head and neck squamous cell carcinoma (HNSC) is the sixth most common cancer worldwide, and new cases are anticipated to reach 1.08 million in 2030. Our study aimed to identify the competing endogenous RNAs (ceRNAs) involved in HNSC tumorigenesis. Methods: First, a pan-cancer correlation analysis was conducted on the expression and survival conditions of sideroflexin (SFXN3) based on data downloaded from the Xena database. Second, the upstream regulatory microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) of SFXN3 were predicted using the Encyclopedia of RNA Interactomes (ENCORI) database. Expression and survival analyses were subsequently used to construct lncRNA-miRNA-mRNA ceRNA network that correlated with HNSC. Third, the proportion of various types of immune cells in HNSC was calculated using the CIBERSORT algorithm. Finally, a correlation analysis was performed on SFXN3, including immune cell infiltration (ICI), clinical stage, and immune checkpoints. Results: The pan-cancer analysis suggested that SFXN3 was up-regulated in HNSC, and it correlated with poor prognosis. The ceRNA regulatory network MIR193BHG-miR-29c-3p-SFXN3 was identified as one of the potential biological regulatory pathways of HNSC. The upstream lncRNA MIR193BHG was associated with a poor prognosis in HNSC, and its target gene SFXN3 was correlated with tumor ICI, immune cell biomarkers, and immune checkpoints. Conclusions: By performing ceRNA analysis, our study demonstrated that MIR193HG-miR-29c-3p-SFXN3 is significantly involved in HNSC, and this action axis markedly affect the therapeutic effect and prognosis.

Clinicopathologic study of mantle cell lymphoma with epstein-barr virus infection: A case series and literature review.

Background: Mantle cell lymphoma (MCL) with Epstein-Barr virus (EBV) infection is rarely reported. The objective of this study was to analyze the prevalence and clinicopathological features of MCL with EBV infection in the largest series thus far. Methods: After screening 138 cases of MCL, we identified eight cases of MCL with EBV infection. Results: Most of them (7/8) had non-neoplastic bystander cells with positivity for EBV and no expression of latent membrane protein 1 (LMP1) and EBV nuclear antigen 2 (EBNA2). The cases of MCL with EBER positivity did not have abnormal immune function or other lymphomas. Moreover, their histopathological morphology was indicative of classical MCL. Cases of MCL with EBER positivity exhibited statistically significant differences in lactate dehydrogenase, anemia status, and MCL international prognostic index grouping (P=0.008, P=0.02, P=0.001, and P=0.011, respectively). The differences between the two groups in age, sex ratio, clinical manifestations, and immunohistochemical phenotypes were not statistically significant. Conclusions: The incidence of MCL with EBV infection was low (5.8%). Clinicopathologically, cases of MCL with EBER positivity were similar to their EBV-negative counterparts. Our findings revealed that most cells infected by EBV in MCL are background cells rather than tumor cells. This is inconsistent with data from previous studies, indicating that tumor cells in MCL may not be prone to EBV infection.

Low-Grade Adenosquamous Carcinoma of the Axilla of Breast Origin in a Male: A Case Report and Literature Review.

Low-grade adenosquamous carcinoma (LGASC) is a rare invasive tumor that occurs in breast parenchyma. It has previously only been reported in females. Herein, we describe the case of a 52-year-old male who presented with a palpable mass in his right axilla that he reported had been present for 20-years. This is the first report of a male patient with LGASC. Core needle biopsy pathology revealed a benign mass of mammary origin, but its type was initially misdiagnosed. It was only correctly identified via postoperative pathology after local excision, which indicated that the mass exhibited the typical pathological characteristics of LGASC. Immunohistochemical analysis revealed positive expression of estrogen receptor, which was inconsistent with the typical "triple-negative" immunophenotype of LGASC. After resection of the mass the patient was advised to participate in regular outpatient follow-up. In conclusion, LGASC should be considered in male patients with a mass lesion in their breast or axilla, even when core needle biopsy indicates a benign mass of breast origin. One-stage local resection is recommended for the treatment of male patients with LGASC, but it is crucial to ensure that the margins are negative and postoperative adjuvant radiotherapy is not recommended.

Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptor.

The P2Y14 receptor was initially identified as a G protein-coupled receptor activated by UDP-glucose and other nucleotide sugars. We have developed several cell lines that stably express the human P2Y14 receptor, allowing facile examination of its coupling to native Gi family G proteins and their associated downstream signaling pathways (J Pharmacol Exp Ther 330:162-168, 2009). In the current study, we examined P2Y14 receptor-dependent inhibition of cyclic AMP accumulation in human embryonic kidney (HEK) 293, C6 glioma, and Chinese hamster ovary (CHO) cells stably expressing this receptor. Not only was the human P2Y14 receptor activated by UDP-glucose, but it also was activated by UDP. The apparent efficacies of UDP and UDP-glucose were similar, and the EC50 values (74, 33, and 29 nM) for UDP-dependent activation of the P2Y14 receptor in HEK293, CHO, and C6 glioma cells, respectively, were similar to the EC50 values (323, 132, and 72 nM) observed for UDP-glucose. UDP and UDP-glucose also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in P2Y14 receptor-expressing HEK293 cells but not in wild-type HEK293 cells. A series of analogs of UDP were potent P2Y14 receptor agonists, but the naturally occurring nucleoside diphosphates, CDP, GDP, and ADP exhibited agonist potencies over 100-fold less than that observed with UDP. Two UDP analogs were identified that selectively activate the P2Y14 receptor over the UDP-activated P2Y6 receptor, and these molecules stimulated phosphorylation of ERK1/2 in differentiated human HL-60 promyeloleukemia cells, which natively express the P2Y14 receptor but had no effect in wild-type HL-60 cells, which do not express the receptor. We conclude that UDP is an important cognate agonist of the human P2Y14 receptor.

Enhanced potency of nucleotide-dendrimer conjugates as agonists of the P2Y14 receptor: multivalent effect in G protein-coupled receptor recognition.

The P2Y(14) receptor is a G protein-coupled receptor activated by uridine-5'-diphosphoglucose and other nucleotide sugars that modulates immune function. Covalent conjugation of P2Y(14) receptor agonists to PAMAM (polyamidoamine) dendrimers enhanced pharmacological activity. Uridine-5'-diphosphoglucuronic acid (UDPGA) and its ethylenediamine adduct were suitable functionalized congeners for coupling to several generations (G2.5-6) of dendrimers (both terminal carboxy and amino). Prosthetic groups, including biotin for avidin complexation, a chelating group for metal complexation (and eventual magnetic resonance imaging), and a fluorescent moiety, also were attached with the eventual goals of molecular detection and characterization of the P2Y(14) receptor. The activities of conjugates were assayed in HEK293 cells stably expressing the human P2Y(14) receptor. A G3 PAMAM conjugate containing 20 bound nucleotide moieties (UDPGA) was 100-fold more potent (EC(50) 2.4 nM) than the native agonist uridine-5'-diphosphoglucose. A molecular model of this conjugate docked in the human P2Y(14) receptor showed that the nucleotide-substituted branches could extend far beyond the dimensions of the receptor and be available for multivalent docking to receptor aggregates. Larger dendrimer carriers and greater loading favored higher potency. A similar conjugate of G6 with 147 out of 256 amino groups substituted with UDPGA displayed an EC(50) value of 0.8 nM. Thus, biological activity was either retained or dramatically enhanced in the multivalent dendrimer conjugates in comparison with monomeric P2Y(14) receptor agonists, depending on size, degree of substitution, terminal functionality, and attached prosthetic groups.

Molecular recognition in the P2Y(14) receptor: Probing the structurally permissive terminal sugar moiety of uridine-5'-diphosphoglucose.

The P2Y(14) receptor, a nucleotide signaling protein, is activated by uridine-5'-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y(14) agonist. For example, the carboxylate group of uridine-5'-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this strategy retained P2Y(14) activity, and molecular modeling predicted close proximity of this chain to the second extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y(14) potency. For example, the [5'']ribose derivative had an EC(50) of 0.24muM. Selective monofluorination of the glucose moiety indicated a role for the 2''- and 6''-hydroxyl groups of 1 in receptor recognition. The beta-glucoside was twofold less potent than the native alpha-isomer, but methylene replacement of the 1''-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5'-diphosphoglucose also activates the P2Y(2) receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y(14)-selective.

The Prognostic Values Of Circulating Tumor Cells In Lung Carcinoma: An Analysis On 98 Chinese Patients.

AIM: To examine the prognostic values of circulating tumor cells (CTCs) in patients with advanced lung cancer. PATIENTS AND METHODS: A total of 98 patients with their CTCs enumerated in 2017 was recruited. Data were retrieved from medical records for comparison. Patients' overall survival (OS) and progression-free survival (PFS) were studied using Kaplan-Meier curve with log rank test. RESULTS: Seventy-three percent of the patients were male, and nearly half of the patients (44.8%) were smokers. Most tumors were adenocarcinoma (73.4%), and about 60% of the cases were diagnosed at stage IV. Half of the patients showing less than nine CTCs. Patients' OS were significantly associated with total CTC count (P=0.047), epithelial CTC count (P=0.027), mixed CTC count (P=0.004), and use of adjuvant chemotherapy (P=0.001). For PFS, it was strongly associated with tumor backgrounds (T stage, P=0.002; M stage, P=0.001; TMN stage, P<0.001), cancer biomarkers (CEA, P=0.004; CA125, P=0.004; CA153, P=0.045), and treatment strategy (surgical intervention, P=0.025; first-line chemotherapy, P<0.001). CONCLUSION: The present study clearly indicated the significant associations between CTC and overall survival of patients with lung cancer.

Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.

Ras-mediated intestinal epithelial cell transformation requires cyclooxygenase-2-induced prostaglandin E2 signaling.

Ras-mediated transformation is associated with upregulation of cyclooxygenase-2 (COX-2), which in turn promotes prostaglandin E2 (PGE2) synthesis and secretion. Although recent studies have identified molecular mechanisms by which Ras mediates upregulation of COX-2, conflicting observations have been made. Furthermore, while COX-2 upregulation has been shown to be important for Ras transformation, the signaling pathways initiated by PGE2-stimulation of EP family of heterotrimeric G protein-coupled receptors (GPCR) and contribution of PGE2 signaling to Ras-mediated transformation are issues that remain unresolved. In this study, we first determined that Raf effector pathway activation of the extracellular-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade alone was sufficient and necessary for COX-2 and PGE2 upregulation. However, Raf-independent regulation of the c-jun N-terminal kinase (JNK) and p38 MAPK cascades is also involved in COX-2 and PGE2 upregulation, with the JNK and p38 pathways exhibiting opposing roles in COX-2 and PGE2 upregulation. Furthermore, in contrast to previous studies, we found that an epidermal growth factor (EGF) receptor autocrine growth mechanism, another Raf-independent signaling mechanism, was necessary for COX-2 and PGE2 upregulation. Second, we determined that inhibition of EP1/2 receptor function blocked growth transformation by Ras, demonstrating that PGE2 upregulation is a key transforming function of COX-2. Finally, we found that PGE2 stimulated the activation of Ras and ERK, but not Akt, and reduced matrix deprivation-induced apoptosis, in untransformed epithelial cells. In summary, our studies define additional, multiple signaling mechanisms that promote COX-2 and PGE2 expression and show that COX-2-stimulated PGE2-EP receptor signaling is required for growth and survival transformation by Ras.

Down-regulation of protease-activated receptor-1 is regulated by sorting nexin 1.

Degradation or "down-regulation" of protease-activated receptor-1 (PAR1), a G protein-coupled receptor for thrombin, is critical for termination of receptor signaling. Toward understanding the molecular mechanisms by which activated PAR1 is internalized, sorted to lysosomes, and degraded, we investigated whether PAR1 interacted with sorting nexin 1 (SNX1). SNX1 is a membrane-associated protein that functions in lysosomal sorting of the epidermal growth factor receptor. In vitro biochemical binding assays revealed a specific interaction between a glutathione S-transferase fusion of SNX1 and PAR1. In HeLa cells, activated PAR1 colocalized with endogenous SNX1 and coimmunoprecipitated SNX1. SNX1 contains a phox homology domain predicted to bind phosphatidylinositol-3-phosphate and a C-terminal coiled-coil region. To assess SNX1 function, we examined the effects of SNX1 deletion mutants on PAR1 trafficking. Neither the N terminus nor phox homology domain of SNX1 affected PAR1 trafficking. By contrast, overexpression of SNX1 C-terminal domain markedly inhibited agonist-induced degradation of PAR1, whereas internalization remained virtually intact. Immunofluorescence microscopy studies revealed substantial PAR1 accumulation in an early endosome antigen-1-positive compartment in agonist-treated cells expressing SNX1 C terminus. By contrast, lysosome-associated membrane protein-1 distribution was unperturbed. Together, these findings strongly suggest a role for SNX1 in sorting of PAR1 from early endosomes to lysosomes. Moreover, this study provides the first example of a protein involved in lysosomal sorting of a G protein-coupled receptor in mammalian cells.

[SGP polymorphism in cultivated naked barley from Qinghai-Tibet plateau in China and the relationship between SGPs and starch content].

Starch granule proteins (SGPs) are minor components bound with starch granule, which mutation may be related to starch properties. This study investigated the variation of SGPs in cultivated naked barley from Qinghai-Tibet Plateau in China for the first time, and the relationship between SGPs and starch content was preliminarily done. Ten major SGPs and 16 types of patterns were present in 66 cultivated naked varieties, indicating SGPs in cultivated naked barley from Qinghai-Tibet Plateau in China are polymorphic. SGPs in Tibet and Sichuan naked barley were greatly different and SGPs were specific to origin of site. Significance test analysis demonstrates SGPs described in this study except for SGP1 may be related with the variation of starch content in different naked barley.

Efficacy and safety of combined directly acting antivirals for treatment of Chinese chronic hepatitis C patients in a real-world setting.

AIM: To assess the efficacy and safety of combined directly acting antivirals (DAAs) for the treatment of Chinese chronic hepatitis C (CHC) patients in a real-world setting. METHODS: Hospitalized CHC patients who were treated with DAAs at Peking University First Hospital between January 2015 and December 2016 were enrolled. Samples and clinical data were collected at 0 wk, 2 wk, 4 wk, 8 wk, 12 wk, or 24 wk during DAAs treatment and at 4 wk, 12 wk, and 24 wk after the end of treatment. RESULTS: Fifty-four patients who underwent DAAs treatment were included in our study, of whom 83.3% (45/54) achieved rapid virological response at 2 wk after treatment initiation (RVR 2) and 94.4% (51/54) achieved sustained virological response at 24 wk after the end of treatment (SVR 24). Serum creatinine and uric acid levels at the end of treatment were significantly increased compared with baseline levels (83.6 ± 17.9 vs 88.8 ± 19.4, P01 < 0.001; 320.8 ± 76.3 vs 354.5 ± 87.6, P01 < 0.001), and no significant improvements were observed at 24w after the end of treatment (83.6 ± 17.9 vs 86.8 ± 19.1, P02 = 0.039; 320.8 ± 76.3 vs 345.9 ± 89.4, P02 = 0.001). The total frequency of adverse events (AEs) during treatment was 33.3% (18/54), with major AEs being fatigue (16.7%), headache (7.4%), anorexia (7.4%), and insomnia (5.6%). CONCLUSION: Though based in a small cohort of patients, the abnormal changes in renal function indices and relative high frequency of AEs during combined DAAs treatment should be taken as a note of caution.

Molecular cloning and characterization of PLC-eta2.

PLC (phospholipase C) isoenzymes catalyse the conversion of PtdIns(4,5)P2 into the Ca2+-mobilizing second messenger, Ins(1,4,5)P3, and the protein kinase C-activating second messenger, diacylglycerol. With the goal of identifying additional mammalian PLC isoenzymes, we screened the NCBI non-redundant database using a BLAST algorithm for novel sequences with homology with the conserved PLC catalytic core. Two unique sequences corresponding to two unknown PLC isoenzymes were identified, and one of these, designated PLC-eta2, was cloned and characterized. Most of the coding sequence of PLC-eta2 was constructed from two ESTs (expressed sequence tags), which included an overlapping sequence that was confirmed by multiple ESTs and mRNAs. 5'-RACE (rapid amplification of cDNA ends) also identified an upstream exon not deduced from available EST or mRNA sequences. Sequence analysis of PLC-eta2 revealed the canonical domains of a PLC isoenzyme with an additional long C-terminus that contains a class II PDZ-binding motif. Genomic analyses indicated that PLC-eta2 is encoded by 23 exons. RT-PCR (reverse transcriptase-PCR) analyses illustrated expression of PLC-eta2 in human retina and kidney, as well as in mouse brain, eye and lung. RT-PCR with exon-specific primers also revealed tissue-specific expression of four splice variants in mouse that represent alternative use of sequences in exons 21, 22 and 23. PLC-eta2-specific antisera recognized one of these splice variants as an approx. 155 kDa species when expressed in COS-7 cells; PLC-eta2 natively expressed in 1321N1 human astrocytoma cells also migrated as an approx. 155 kDa species. PLC activity was observed in vitro and in vivo for three different constructs of PLC-eta2, each containing possible alternatively spliced first exons. Co-expression of PLC-eta2 with Gbeta1gamma2 dimers of heterotrimeric G-proteins resulted in marked stimulation of inositol lipid hydrolysis. Thus PLC-eta2 may in part function downstream of G-protein-coupled receptors.

Diagnostic value of fibulin-3 for malignant pleural mesothelioma: A systematic review and meta-analysis.

BACKGROUND: Several studies have investigated the diagnostic value of fibulin-3 for malignant pleural mesothelioma (MPM), but the results were various. Therefore, we performed a systematic review and meta-analysis to evaluate the diagnostic value of fibulin-3 for MPM. RESULTS: Eight studies were included in this work. The overall sensitivity of blood fibulin-3 were 0.87 (95% CI, 0.58 - 0.97) and 0.89 (95% CI, 0.77 - 0.95), respectively. The overall sensitivity and specificity of PF fibulin-3 for MPM were 0.73 (95% CI, 0.54 - 0.86) and 0.80 (95% CI, 0.60 - 0.91), respectively. The area under curve of blood and pleural effusion (PF) Fibulin-3 were 0.94 (95% CI, 0.91 - 0.96) 0.83 (95% CI, 0.79 - 0.86), respectively. METHODS: PubMed and EMBASE databases were searched up to July 29, 2016 to verify studies investigating the diagnostic value of fibulin-3 for MPM. The quality of eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy tool (QUADAS-2). The overall sensitivity and specificity were pooled using a bivariate model. CONCLUSION: Fibuoin-3 is a useful diagnostic marker for MPM.