Application of microRNA in Human Osteoporosis and Fragility Fracture: A Systemic Review of Literatures.

MicroRNAs (miRNAs) could serve as ideal entry points to the deregulated pathways in osteoporosis due to their relatively simple upstream and downstream relationships with other molecules in the signaling cascades. Our study aimed to give a comprehensive review of the already identified miRNAs in osteoporosis from human blood samples and provide useful information for their clinical application. A systematic literature search for relevant studies was conducted in the Pubmed database from inception to December 2020. We set two essential inclusion criteria: human blood sampling and design of controlled studies. We sorted the results of analysis on human blood samples according to the study settings and compiled the most promising miRNAs with analyzed diagnostic values. Furthermore, in vitro and in vivo evidence for the mechanisms of the identified miRNAs was also illustrated. Based on both diagnostic value and evidence of mechanism from in vitro and in vivo experiments, miR-23b-3p, miR-140-3p, miR-300, miR-155-5p, miR-208a-3p, and miR-637 were preferred candidates in diagnostic panels and as therapeutic agents. Further studies are needed to build sound foundations for the clinical usage of miRNAs in osteoporosis.

Integrate Weather Radar and Monitoring Devices for Urban Flooding Surveillance.

With the increase of extreme weather events, the frequency and severity of urban flood events in the world are increasing drastically. Therefore, this study develops ARMT (automatic combined ground weather radar and CCTV (Closed Circuit Television System) images for real-time flood monitoring), which integrates real-time ground radar echo images and automatically estimates a rainfall hotspot according to the cloud intensity. Furthermore, ARMT combines CCTV image capturing, analysis, and Fourier processing, identification, water level estimation, and data transmission to provide real-time warning information. Furthermore, the hydrograph data can serve as references for relevant disaster prevention, and response personnel may take advantage of them and make judgements based on them. The ARMT was tested through historical data input, which showed its reliability to be between 83% to 92%. In addition, when applied to real-time monitoring and analysis (e.g., typhoon), it had a reliability of 79% to 93%. With the technology providing information about both images and quantified water levels in flood monitoring, decision makers can quickly better understand the on-site situation so as to make an evacuation decision before the flood disaster occurs as well as discuss appropriate mitigation measures after the disaster to reduce the adverse effects that flooding poses on urban areas.

Protein-bounded uremic toxin p-cresylsulfate induces vascular permeability alternations.

The goal of the present studies is to investigate that the impact of p-cresylsulfate (PCS) on the endothelial barrier integrity via in situ exposure and systemic exposure. Vascular permeability changes induced by local injection of PCS were evaluated by the techniques of both Evans blue (EB) and India ink tracer. Rats were intravenously injected with EB or India ink followed by intradermal injections of various doses of PCS (0, 0.4, 2, 10 and 50 µmol/site) on rat back skins. At different time points, skin EB was extracted and quantified. The administration of India ink was used to demonstrate leaky microvessels. Skin PCS levels were also determined by liquid chromatography-mass spectrometry. We also investigated whether the increased endothelial leakage occurred in the aortic endothelium in rats treated with 5/6 nephrectomy and intraperitoneal injection of PCS 50 mg/kg/day for 4 weeks. The aortic endothelial integrity was evaluated by increased immunoglobulin G (IgG) leakage. High doses of PCS, but not lower doses, significantly induced vascular leakage as compared to saline injection and EB leakage exhibited in time-dependent manner. A time-correlated increase in leaky microvessels was detected in the tissues examined. The injected PCS declined with time and displayed an inverse relationship with vascular leakage. Chronic kidney disease (CKD) rats administered with PCS, compared to control rats, had significantly higher serum levels of PCS and apparent IgG deposition in the aortic intima. Increased endothelial leakage induced by PCS in skin microvessels and the aorta of CKD rats suggests that the PCS-induced endothelial barrier dysfunction.

Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic.

The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

Increased Levels of Total p-Cresylsulfate Are Associated with Pruritus in Patients with Chronic Kidney Disease.

BACKGROUND: Pruritus is a common and distressing symptom that affects patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresylsulfate (PCS) are uremic toxins with similar protein binding, dialytic clearance, and proinflammatory features. Pruritus in CKD may correlate better with uremic toxins than the glomerular filtration rate (GFR), suggesting that uremic toxins either in the central nervous system or peripherally may play an important role in the pathophysiology. OBJECTIVE: We sought to investigate the potential contribution of serum total IS and PCS to the pathogenesis of pruritus. METHODS: The serum levels of total IS and PCS concentrations were measured in all patients by using the Ultra Performance LC System. The characteristics of pruritus were assessed using a visual analog scale score and an interview questionnaire. RESULTS: Among the 320 CKD patients, 35% had pruritus. The patients with pruritus were older and had a higher frequency of diabetes mellitus, higher uric acid, calcium, phosphorus, creatinine, high-sensitivity C-reactive protein, and total IS and PCS levels, and lower albumin concentrations and estimated GFR (eGFR) than those without pruritus. Increasing concentrations of total PCS were independently and significantly associated with pruritus. Multiple logistic regression analysis revealed total PCS as an independent association factor for pruritus, even after full adjustment of known biomarkers. Furthermore, serum total PCS levels were positively associated with calcium, phosphorus, blood urea nitrogen, creatinine, and white blood cell count, and negatively associated with eGFR, hemoglobin, and hematocrit. CONCLUSION: Our results indicate that total PCS may play a role in the pathogenesis of pruritus.

Aortic smooth muscle cell alterations in mice systemically exposed to arsenic.

Previous epidemiological studies showed that chronic arsenic exposure is related to increased cardiovascular disease incidence. The detailed biochemical mechanisms by which arsenic exerts its effects remain unknown. Vascular disease progression is characterized by smooth muscle cell (SMC) phenotypic switching, vessel wall reorganization, and platelet-derived growth factor (PDGF) production. The objective of this study was to examine early biochemical and structural changes in the aortas of ICR mice systemically exposed to arsenic. Animals were fed sodium arsenite (20 mg/kg) via gavage 5 days/week or Milli-Q water only (control) for 8 weeks. Aortic proteins were subjected to two-dimensional (2-D) differential gel electrophoresis and proteomic studies. Two 2-D gel protein spots were identified as the same protein, smooth muscle (SM)22α, using proteomics. SM22α and Rho kinase 2 gene and protein expression were significantly decreased in the aortic tissue of arsenic-exposed mice compared with that of control mice. No atherosclerotic lesion formation or tissue injury was detected in the aortic wall of either the arsenic-fed or the control group. However, the percent (%) SMC area of the aortic wall was significantly decreased in arsenic-fed mice compared with that in control mice. Additionally, the expression levels of PDGF-BB and early growth response-1 (Egr-1) were significantly higher in the arsenic group than that in the control group. These findings reveal biochemical alterations of SM22α, PDGF, and Egr-1 in conjunction with decreased SMC area in the aortic wall of arsenic-fed mice. Arsenic may initiate aortic SMC alterations that subsequently lead to vascular dysfunction.

Adaptive responses to glucose restriction enhance cell survival, antioxidant capability, and autophagy of the protozoan parasite Trichomonas vaginalis.

BACKGROUND: To establish an infection in the vagina, Trichomonas vaginalis must adapt to various environmental cues for survival and further replication. Nutrient competition by lactobacilli, the major normal vaginal flora, is one of the mechanisms to limit the growth of other microorganisms. Additionally, lactobacilli produce H2O2 that can reduce the genital infections caused by other pathogens. Thus, the ability to overcome the metabolic stresses, such as glucose restriction (GR), as well as the oxidative stresses, is critical for T. vaginalis to establish an infection. METHODS: To gain insights into the molecular mechanisms of adaptation to GR, we utilized next-generation RNA sequencing (RNA-seq) to quantify the gene expression changes upon GR. Autophagy, a cytoprotective response to starvation, was monitored by using autophagy-specific staining, autophagy inhibition assay, and co-localization of autophagosomes with lysosomes. RESULTS: We demonstrated that GR promotes the survival of T. vaginalis. Besides, GR-cultivated cells exhibit higher H2O2 resistance. Our RNA-seq data revealed that genes involved in general energy metabolism were downregulated, whereas genes encoding glutamate metabolism-related aminotransferases were strikingly upregulated under GR. Furthermore, autophagy was first identified and characterized in T. vaginalis under GR. CONCLUSIONS: These data suggest that GR induces a metabolic reprogramming, enhancing antioxidant ability and autophagy for cellular homeostasis to maintain survival. GENERAL SIGNIFICANCE: Our work not only led to significant advances in understanding the transcriptional changes in response to GR but also provided possible strategies elicited by GR for T. vaginalis to adapt to the vaginal microenvironment.

Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis.

Both the detrimental effects of early life adversity and the beneficial effects of exercise on the hypothalamic-pituitary-adrenal (HPA) axis have been reported. Early life exposure to di-(2-ethylhexyl)-phthalate (DEHP) may impair the development of endocrine system. In this study, we investigated the effects of lactational DEHP exposure on stress responses in late adolescent female rats and examined the protective role of treadmill running. Sprague-Dawley dams were fed with DEHP (10mg/kg per day) or vehicle during lactation. After weaning, the female offspring rats were trained to exercise on a treadmill for 5 weeks and then stressed by exploring on an elevated plus maze. The activities of HPA axis were evaluated by measuring the plasma levels of ACTH and corticosterone, the expressions of adrenal enzymes cholesterol side-chain cleavage enzyme (CYP11A1) and cytochrome P-450 11ß-hydroxylase (CYP11B1), and the expression of hypothalamic glucocorticoid receptors (GR). The results demonstrate that DEHP-exposed rats exhibited enhanced anxiety-like behaviors. Increased hypothalamic GR and plasma ACTH levels, but decreased adrenal CYP11A1 and corticosterone levels, were observed in DEHP-exposed animals under stressed condition. Importantly, in DEHP-exposed animals, exercise during childhood-adolescence reduced anxiety-like behaviors by normalizing stress-induced alterations in ACTH level and adrenal CYP11A1 expression. The findings of this study suggest that treadmill running may provide beneficial effects on ameliorating the dysregulation of HPA axis in lactational DEHP-exposed adolescent female rats.

Comparison of the transverse cranial base dimension in different craniofacial skeletal relationships: A cone-beam computed tomography study.

Background/purpose: In comparing the cranial base's size, most cephalometric studies focused on the length and angle in the anteroposterior direction. However, investigating the anterior, middle, and posterior cranial base's transverse dimensions is challenging. This study aimed to investigate the transverse dimensions of the cranial base in different craniofacial skeletal patterns and sexes using cone-beam computed tomography (CBCT). Materials and methods: A total of 210 adults (105 males and 105 females), including three different skeletal relationships, were included in the study. The cranial base dimensions were measured on a three-dimensional image structure rendered by CBCT. Statistical methods included the Kappa statistic for analysis of consistency and reproducibility and the independent t-test for differences in cranial base dimensions between sexes. A general linear model (GLM) was used to compare the transverse size of the cranial base among skeletal Class I, II, and III groups. The Pearson correlation coefficient explored the correlation among the cranial base dimensions. Results: The cranial base dimensions did not differ significantly between skeletal Class I, II, and III. The more prominent cranial base size was found in males than females, except for the crista galli length (CGL) and cribriform ethmoid plate width (CEPW). The cranial base dimensions did not differ significantly between different skeletal relationships. Most dimensions have significant correlations in the middle and the posterior cranial base. Conclusion: The cranial base's transverse dimensions in Taiwanese adults show no significant differences between craniofacial skeletal relationships. In the middle and posterior cranial base, transverse measurements reveal significant sexual dimorphism.

Identification of putative miRNAs from the deep-branching unicellular flagellates.

MicroRNAs (miRNAs) are a class of extensively studied RNAi-associated small RNAs that play a critical role in eukaryotic gene regulation. However, knowledge on the miRNA and its regulation in unicellular eukaryotes is very limited. In order to obtain a better understanding on the origin of miRNA regulation system, we used deep-sequencing technology to investigate the miRNA expression pattern in four deep-branching unicellular flagellates: Giardia lamblia, Trichomonas vaginalis, Tritrichomonas foetus, and Pentatrichomonas hominis. In addition to the known miRNAs that have been described in G. lamblia and T. vaginalis, we identified 14 ancient animal miRNA families and 13 plant-specific families. Bioinformatics analysis also identified four novel miRNA candidates with reliable precursor structures derived from mature tRNAs. Our results indicated that miRNAs are likely to be a general feature for gene regulation throughout unicellular and multicellular eukaryotes and some of them may derive from unconventional ncRNAs such as snoRNA and tRNA.

Correlation between facial asymmetry of skeletal class III jaw relationship and morphology of the temporomandibular joint: A cone beam computed tomography study.

Background/purpose: Facial asymmetry is a common dentofacial deformity especially in skeletal Class III jaw relation. The purpose of this study was to evaluate the condylefossa relationship of Taiwanese people in skeletal Class III jaw relation with or without facial asymmetry by CBCT image. Materials and methods: CBCT images were collected from Kaohsiung Medical University Hospital and then divided into symmetric Class III group (Menton [Mn] deviation â‰¦ 4 mm) and asymmetric Class III group (Menton [Mn] deviation > 4 mm). Maxilla deviation, upper and lower dental midline deviation, joint space, condylar axial angle and condylar volume was measured. Independent t test was used for comparison between groups, and paired t test was applied for comparison between both condyles within each group. The Pearson correlation coefficient was used to analyze the correlation between skeletal midline deviations and joint morphology. Results: No significant difference was found in joint space between groups or between sides within each group, but we can find a significant difference in axial condylar angle easurement which was greater on the non-deviation side of condyle. Significant lesser condylar volume was also found on the deviation side in asymmetric group. There had a significant positive correlation between Mn point deviation, geometric center difference and condylar volume ratio. Conclusion: These results demonstrated that in the side with greater mandibular growth potential, the axis rotation in axial plane would be greater. In the side with lesser mandibular growth potential, the total condyle volume would be lesser, even though with large variation.

Condylar and ramus volume in asymmetric and symmetric skeletal class III malocclusion: A cone-beam computed tomography study.

Background/purpose: Among the craniofacial structures, the mandible is the only bony structure with movable joints. Each part (including condyle process, coronoid process, and ramus) of mandible would interaction with the muscles and proceed different osteogenesis progress. The objective of this study was to evaluate the mandibles with symmetric and asymmetric skeletal Class III jaw relations by quantifying differences in the condyle process, coronoid process and ramus on CBCT (Cone-beam computer tomography) images. Our hypothesis was that CBCT would reveal no voluminal differences between deviated and non-deviated mandibular segments in asymmetric skeletal Class III. Materials and methods: CBCT imagines were collected from dental department, KMUH and then divided into symmetric Class III group (Menton deviation < 4mm) and asymmetric Class III group (Menton deviation≧4mm). The mandibular structure would be segmented to ramus, condylar and coronoid process. Each volume was measured. Independent t test was used for comparison between groups, and paired t test was applied for comparison between both segmented parts within each group. Results: Significant differences between deviation and non-deviation sides in the asymmetric group were found in condylar and ramus segments for volumetric quantitative measurements. There has no significant difference in ramus parts between groups. Significant greater condylar volume was found in non-deviation side of asymmetric group. Conclusion: The results demonstrated that in the side with greater mandible growth potential, the condylar and the ramus volume would be greater as well. CBCT is a useful and accurate modality for quantification and evaluation of mandibular asymmetry.

Wide-range and area-selective threshold voltage tunability in ultrathin indium oxide transistors.

The scaling of transistors with thinner channel thicknesses has led to a surge in research on two-dimensional (2D) and quasi-2D semiconductors. However, modulating the threshold voltage (VT) in ultrathin transistors is challenging, as traditional doping methods are not readily applicable. In this work, we introduce a optical-thermal method, combining ultraviolet (UV) illumination and oxygen annealing, to achieve broad-range VT tunability in ultrathin In2O3. This method can achieve both positive and negative VT tuning and is reversible. The modulation of sheet carrier density, which corresponds to VT shift, is comparable to that obtained using other doping and capacitive charging techniques in other ultrathin transistors, including 2D semiconductors. With the controllability of VT, we successfully demonstrate the realization of depletion-load inverter and multi-state logic devices, as well as wafer-scale VT modulation via an automated laser system, showcasing its potential for low-power circuit design and non-von Neumann computing applications.

Changes in Facial Profile after Modified Anterior Maxillary Subapical Osteotomy.

(1) Background: This study explored the effects of modified anterior maxillary subapical osteotomy (AMSO) on facial profile changes in patients with bimaxillary protrusion. (2) Methods: Cephalograms of patients were collected preoperatively and over 2 months postoperatively. The following landmarks were recorded: pronasale (Prn), subnasale (Sn), labrale superius (Ls), anterior nasal spine (ANS), and incisor superius (Is). The following distances and angles were measured: ANS-Prn, ANS-Sn, ANS-Ls, Is-Sn, Is-Ls, SNA angle, and nasolabial (NLA) angle. (3) Results: Is and ANS were significantly retracted by 7.3 and 2.3 mm, respectively. Soft tissue landmarks (Prn, Sn, and Ls) were significantly retracted (1.2, 1.6, 4.4 mm, respectively). Postoperative changes in soft/hard tissue ratios were 0.54, 0.72, 0.31, and 0.60 for Prn/ANS, Sn/ANS, ANS/Is, and Ls/Is, respectively. The NLA angle was increased significantly by 7.1°. (4) Conclusions: The horizontal soft/hard tissue ratios of Sn/Is, ANS/Is, and Ls/Is were 0.22, 0.31, and 0.60, respectively. The NLA angle was increased significantly by 7.1°. The modified AMSO provides an increased blood supply, allows for direct vision, and results in fewer complications than other AMSO methods.

Vascular hyperpermeability in response to inflammatory mustard oil is mediated by Rho kinase in mice systemically exposed to arsenic.

The mechanisms underlying vascular dysfunction and cardiovascular disease induced by chronic arsenic exposure are not completely understood. We have previously shown that mice chronically fed sodium arsenite are hypersensitive to the permeability-increasing effects of inflammatory mustard oil. The aim of this study was to investigate whether RhoA/Rho kinase (ROCK)-mediated vascular leakage (hyperpermeability) is induced by mustard oil in mice systemically exposed to arsenic. Animals were orally fed water (control group) or sodium arsenite for 8weeks. We compared the blood pressure and microvessel density of the ears between these two groups. Both control and arsenic groups exhibited a similar mean arterial pressure and microvessel density. Microvessel permeability changes that occurred following mustard oil treatment in the presence of Y-27632, a ROCK inhibitor, were quantified using the Evans blue (EB) technique and vascular labeling with carbon particles. Both the excessive leakiness of EB and the high density of carbon-labeled microvessels upon stimulation with mustard oil in the arsenic-fed mice were reduced by Y-27632 treatment. However, RhoA and ROCK2 expression levels were similar between control and arsenic-fed mice. We further investigated ROCK2 levels and ROCK activity in the ears following mustard oil challenge. ROCK2 levels in mouse ears treated with mustard oil were higher in the arsenic group as compared with the control group. Following mustard oil application, ROCK activity was significantly higher in the arsenic-fed mice compared with the control mice. These findings indicate that increased ROCK2 levels and enhanced ROCK activity are responsible for mustard oil-induced vascular hyperpermeability in arsenic-fed mice.

Changes in Tongue Area, Pharyngeal Area, and Pharyngeal Airway Velocity after Correction of Mandibular Prognathism.

This study aimed to investigate the correlation between the amount of mandibular setback, and the related changes of the tongue area, pharyngeal area, and pharyngeal airflow velocity. Twenty-five patients treated for mandibular prognathism, and serial cephalograms were obtained (T1: preoperation, T2: more than one year postoperation). The postoperative area of the tongue, pharyngeal airway space, and pharyngeal airflow velocity were investigated. Statistical analysis was performed with the Student t-test and Pearson correlation. The amount of mandible setback was significant after surgery (12.8 mm; p < 0.001). The pharyngeal area was significantly reduced 115.5 mm2 (p = 0.046). There was a slight reduction of the tongue area (43.2 mm2; p = 0.305) and an increase of pharyngeal airflow velocity (0.3 m/s; p = 0.133). The Pearson correlation coefficient test showed no statistical significance among the amount of horizontal setback and vertical movement of the mandible, such as the reductions in the tongue area, the pharyngeal airway space, and the increase in pharyngeal airflow velocity. Larger amounts of mandibular setback caused a significant reduction of pharyngeal airway area, but without significant changes of the tongue area and pharyngeal airflow velocity.

Differences in the Buccal Bone Marrow Distance of ≤0.8 mm in the Mandible of Patients Undergoing Sagittal Split Ramus Osteotomy among the Different Skeletal Patterns: A Retrospective Study.

This study investigated the relationship between the thickness of the ramus and skeletal patterns using cone-beam computed tomography (CBCT) for sagittal split ramus osteotomy. Ninety participants were categorized into three skeletal patterns (Class I, Class II, and Class III). The first vertical slice (slice 0) was observed in the intact mandibular canal, and then moved forward to 40 mm (slice 21) with a 2 mm interval. The thickness of buccal bone marrow (B value) was measured. A B value of ≤0.8 mm was considered to be the major risk factor causing the occurrence of postoperative lower lip paresthesia. There were 461 sides with a B value of ≤0.8 mm. There was a significant difference in the skeletal patterns [Class III (198 sides: 15.7%) > Class I (159 sides: 12.6%) > Class II (104 sides: 8.3%)]. Class II participants had significantly larger B values (2.14 to 3.76 mm) and a lower occurrence rate (≤0.8 mm) than those of Class III participants (1.5 to 3 mm) in front of the mandibular foramen (from 6 mm to 20 mm). Class III participants had significantly shorter buccal bone marrow distance and a higher occurrence rate of B values (≤0.8 mm) than Class II.

Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy.

BACKGROUND: Cetuximab, the first approved EGFR targeting therapeutic antibody, is currently used to treat colorectal cancer and head and neck cancer. While effective, cetuximab is associated with a higher rate of skin rash, infusion reactions, and gastrointestinal toxicity, which was suggested to be linked to the presence of heterogeneous glycan contents on the Fab of the SP2/0-produced cetuximab. OBJECTIVE AND METHODS: To improve efficacy and minimize toxicity of EGFR inhibition treatment, we re-engineered cetuximab by humanizing its Fab regions and minimizing its glycan contents to generate HLX07. RESULTS: HLX07 binds to EGFR with similar affinity as cetuximab and shows better bioactivity compared to cetuximab in vitro. In vivo studies demonstrated that HLX07 significantly inhibited the growth of A431, FaDu, NCI-H292, and WiDr tumor cells and synergized them with chemotherapeutics and immune simulator agents such as anti-PD-1. In cynomolgus monkeys, 13-week repeat-dose GLP toxicokinetic studies showed minimal-to-mild toxicities in the dose range of up to 60 mg/kg/wk. In the preliminary phase 1 dose-escalation study, HLX07 had showed lower incidence of skin rashes with grade >2 severities. CONCLUSION: HLX07 is currently under phase 1/2 clinical development. We believe HLX07 would potentially be an alternative for patients who have been suffering from cetuximab-mediated toxicity.

Identification of microRNA in the protist Trichomonas vaginalis.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. However, miRNA has never been identified experimentally in protist. Direct cloning of 438 expressed miRNA tags by microRNA serial analysis of gene expression from the parasitic protist Trichomonas vaginalis identified nine candidate miRNAs. Bioinformatics analysis of the corresponding genomic region revealed that these miRNA candidates contain a classical stem-loop-stem structure of pre-microRNAs. Analysis of the 20 nt long mature tva-miR-001 showed that it is an intergenic miRNA located at the scaffold DS113596. Tva-miR-001 was differentially expressed in the trophozoite, pseudocyst and amoeboid stages. Based on the experimental results of the present study, we provided solid evidence that protist possesses a miRNA regulating network comparable with multicellular organisms for the first time.

P-Cresylsulfate, the Protein-Bound Uremic Toxin, Increased Endothelial Permeability Partly Mediated by Src-Induced Phosphorylation of VE-Cadherin.

The goal of our study was to investigate the impact of p-cresylsulfate (PCS) on the barrier integrity in human umbilical vein endothelial cell (HUVEC) monolayers and the renal artery of chronic kidney disease (CKD) patients. We measured changes in the transendothelial electrical resistance (TEER) of HUVEC monolayers treated with PCS (0.1-0.2 mM) similar to serum levels of CKD patients. A PCS dose (0.2 mM) significantly decreased TEER over a 48-h period. Both PCS doses (0.1 and 0.2 mM) significantly decreased TEER over a 72-h period. Inter-endothelial gaps were observed in HUVECs following 48 h of PCS treatment by immunofluorescence microscopy. We also determined whether PCS induced the phosphorylation of VE-cadherin at tyrosine 658 (Y658) mediated by the phosphorylation of Src. Phosphorylated VE-cadherin (Y658) and phosphorylated Src levels were significantly higher when the cells were treated with 0.1 and 0.2 mM PCS, respectively, compared to the controls. The endothelial barrier dysfunction in the arterial intima in CKD patients was evaluated by endothelial leakage of immunoglobulin G (IgG). Increased endothelial leakage of IgG was related to the declining kidney function in CKD patients. Increased endothelial permeability induced by uremic toxins, including PCS, suggests that uremic toxins induce endothelial barrier dysfunction in CKD patients and Src-mediated phosphorylation of VE-cadherin is involved in increased endothelial permeability induced by PCS exposure.