bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Identification of Putative MicroRNAs in Cassava (Manihot esculenta Crantz) and Their Functional Landscape in Cellular Regulation
Authors: Yawichai Amika , Kalapanulak Saowalak , Thammarongtham Chinae , Saithong Treenut
Published: June 2019

MicroRNAs are small noncoding RNAs, involved in the regulation of many cellular processes in plants. Hundreds of miRNAs have been identified in cassava by various techniques, yet these identifications were constrained by a lack of miRNA templates and the narrow range of conditions in transcriptome study. In this research, we conducted genome-wide analysis identification, whereby miRNAs from cassava genome were thoroughly screened using bioinformatics approach independent of predefined templates and studied conditions. Our work provided a catalog of putative mature miRNAs and explored the landscape of miRNAome in cassava. These putative miRNAs were validated using statistical analysis as well as available cassava expression data. We showed that the crowded locations of cassava miRNAs are consistent with other plants and animals and hypothesized to have the same evolutionary origin. At least 10 conserved miRNAs were identified in cassava based on the comparative study of miRNA conservation. Finally, investigation of miRNAs and target gene relationships enabled us to envisage the complexities of cellular regulatory systems modulated at posttranscriptional level.
A PI‐Type Sliding Mode Controller Design for PMSG‐Based Wind Turbine
Authors: Liu Jun , Zhou Feihang , Zhao Chencong , Wang Zhuoran
Published: June 2019

Because the PMSG (permanent magnet synchronous generator)‐based WECS (wind energy conversion system) has some uncertainties, the conventional control strategy with poor robustness is sometimes difficult to meet the performance requirements of control. In order to ensure efficient and stability of the system, this paper proposed a novel PI (proportional‐integral)‐type SMC (sliding mode control) strategy for PMSG‐based WECS uncertainties and presented the detailed analysis and design process. Compared with the conventional control method, the PI‐type SMC proposed in this paper not only can make the closed‐loop system globally stable, but also has a better robustness and slightly reduced the current ripple and distortion. Finally, the simulation results verify the correctness and effectiveness of this algorithm.
Climate Change Impacts on Winter Wheat Yield in Northern China
Authors: Geng Xiu , Wang Fang , Ren Wei , Hao Zhixin
Published: June 2019

Exploring the impacts of climate change on agriculture is one of important topics with respect to climate change. We quantitatively examined the impacts of climate change on winter wheat yield in Northern China using the Cobb–Douglas production function. Utilizing time-series data of agricultural production and meteorological observations from 1981 to 2016, the impacts of climatic factors on wheat production were assessed. It was found that the contribution of climatic factors to winter wheat yield per unit area (WYPA) was 0.762–1.921% in absolute terms. Growing season average temperature (GSAT) had a negative impact on WYPA for the period of 1981–2016. A 1% increase in GSAT could lead to a loss of 0.109% of WYPA when the other factors were constant. While growing season precipitation (GSP) had a positive impact on WYPA, as a 1% increase in GSP could result in 0.186% increase in WYPA, other factors kept constant. Then, the impacts on WYPA for the period 2021–2050 under two different emissions scenarios RCP4.5 and RCP8.5 were forecasted. For the whole study area, GSAT is projected to increase 1.37°C under RCP4.5 and 1.54°C under RCP8.5 for the period 2021–2050, which will lower the average WYPA by 1.75% and 1.97%, respectively. GSP is tended to increase by 17.31% under RCP4.5 and 22.22% under RCP8.5 and will give a rise of 3.22% and 4.13% in WYPA. The comprehensive effect of GSAT and GSP will increase WYPA by 1.47% under RCP4.5 and 2.16% under RCP8.5.
Common Core Bacterial Biomarkers of Bladder Cancer Based on Multiple Datasets
Authors: Mai Guoqin , Chen Limei , Li Ran , Liu Quan , Zhang Haoran , Ma Yingfei
Published: June 2019

Recent studies have shown that microorganisms may be associated with the onset and development of bladder cancer. The purpose of this study is to identify the common core bacteria associated with bladder cancer. We characterized the urinary microbial profile of the individuals with bladder cancer by 16S rRNA gene sequencing, and the results of 24 bladder cancer samples collected in our laboratory reveal 31 common core bacteria at genera level. In addition, the abundance of four common core bacteria is significantly higher in bladder cancer samples than in samples from nondiseased people analyzed by LEfSe, based on two previous datasets. In particular, the abundance of Acinetobacter is much higher in bladder cancer samples. It has been reported that Acinetobacter is involved not only in biofilm formation but also in the adhesion and invasion of epithelial cells, the spread of bacteria caused by the degradation of phospholipids in the mucosal barrier, and the escape of the host immune response. Thus, Acinetobacter may be related to bladder cancer and is a potential microbial marker of bladder cancer. However, due to the limited number of participants, further studies are needed to better understand the role of microorganisms in bladder cancer to provide novel biomarkers for diagnosis, prognosis, and therapy.
Neuroglobin Expression Models as a Tool to Study Its Function
Authors: Luyckx Evi , Van Acker Zoë P. , Ponsaerts Peter , Dewilde Sylvia
Published: June 2019

Neuroglobin (Ngb) is an evolutionary conserved member of the globin family with a primary expression in neurons of which the exact functions remain elusive. A plethora ofin vivoandin vitromodel systems has been generated to this day to determine the functional biological roles of Ngb. Here, we provide a comprehensive overview and discussion of the different Ngb models, covering animal and cellular models of both overexpression and knockout strategies. Intriguingly, an in-depth literature search of available Ngb expression models revealed crucial discrepancies in the outcomes observed in different models. Not only does the level of Ngb expression—either physiologically, overexpressed, or downregulated—alter its functional properties, the experimental setup, beingin vitroorin vivo, does impact the functional outcome as well and, hence, whether or not a physiological and/or therapeutic role is ascribed to Ngb. These differences could highlight either technical or biological adaptations and should be considered until elucidation of the Ngb biology.
Existence and Continuous Dependence on Initial Data of Solution for Initial Value Problem of Fuzzy Multiterm Fractional Differential Equation
Authors: Choi Huichol , Sin Kinam , Pak Sunae , So Sungryol
Published: June 2019

In this paper, the fuzzy multiterm fractional differential equation involving Caputo-type fuzzy fractional derivative of order 0<α<1 is considered. The uniqueness of solution is established by using the contraction mapping principle and the existence of solution is obtained by Schauder fixed point theorem.
Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice
Authors: Tsai Hung-Cheng , Chang Fu-Pang , Li Tzu-Hao , Liu Chih-Wei , Huang Chia-Chang , Huang Shiang-Fen , Yang Ying-Ying , Lee Kuei-Chuan , Hsieh Yun-Cheng , Wang Ying-Wen , Lee Tzung-Yan , Huang Yi-Hsiang , Hou Ming-Chih , Lin Han-Chieh
Published: June 2019

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.
Identifying Potentially Avoidable Emergency Department Visits of Long-Term Care Hospital Residents in Korea: A Multicenter Retrospective Cohort Study
Authors: Kim Keon , Lee Dong Hoon , Yune Ho Young , Wee Jung Hee , Kim Duk Ho , Kim Eui Chung , Lim Jee Yong , Choi Seung Pil
Published: June 2019

The aims of this study were to investigate the reasons of transfers from long-term care hospitals (LTCHs) to emergency departments (EDs) of university hospitals in geriatric patients and to categorize the avoidable causes of these transfers. This retrospective multicenter study involved patients aged 65 years and older who were transferred from LTCHs to 5 EDs of university hospitals located in the metropolitan area of South Korea between January 2017 and December 2017. The expert panel reviewed and categorized the reason of transfers as avoidable or not. Moreover, we also investigated the number of patients with do-not-resuscitate (DNR) documents and the date these DNR documents were written. A total of 255,543 patients visited 5 EDs during the study period. Of these, 1,131 patients were from LTCHs. The number of potentially avoidable transfers was 168/1,131 (14.9%). The most common reason of avoidable transfers was noncritical diagnoses that could be assessed and managed in LTCHs (57.1%). There were 162 patients with DNR orders; of these, 12 had approved the DNR order before transfer. In conclusion, in Korea, potentially avoidable transfers could be reduced by managing noncritical diseases in LTCH and preparing advance care directives, including DNR orders, during admission to LTCH.
A Case-Based Reasoning Approach for Automatic Adaptation of Classifiers in Mobile Phishing Detection
Authors: Kyaw Zaw San , Vasupongayya Sangsuree
Published: June 2019

Currently, the smartphone contains lots of sensitive information. The increasing number of smartphone usage makes it more interesting for phishers. Existing phishing detection techniques are performed on their specific features with selected classifiers to get their best accuracy. An effective phishing detection approach is required to adapt the concept drift of mobile phishing and prevent degradation in accuracy. In this work, an adaptive phishing detection approach based on case-based reasoning technique is proposed to handle the concept drift challenge in phishing apps. Several experiments are conducted in order to demonstrate the design decision of our proposed model. The proposed model is evaluated with a large feature set containing 1,065 features from 10 different categories. These features are extracted from more than 10,000 android applications. Five combinations of features are created in order to mimic new real-world Android apps to evaluate our experiments. Moreover, a reduced feature set is also studied in this work in order to improve the efficiency of the proposed model. Both accuracy and efficiency of the proposed model are evaluated. The experimental results show that our proposed model achieves acceptable accuracy and efficiency for the phishing detection.
Neural Compensatory Response During Complex Cognitive Function Tasks in Mild Cognitive Impairment: A Near-Infrared Spectroscopy Study
Authors: Yoon Jin A. , Kong In Joo , Choi JongKwan , Baek Ji Yeong , Kim Eun Joo , Shin Yong-Il , Ko Myoug-Hwan , Shin Yong Beom , Shin Myung Jun
Published: June 2019

The present pilot study was aimed at conducting a comparative analysis of the level of activation in the prefrontal cortex among a normal elderly group and amnestic and nonamnestic mild cognitive impairment (MCI) groups and investigating the presence of neural compensatory mechanisms according to types of MCI and different cognitive tasks. We performed functional near-infrared spectroscopy (fNIRS) along with cognitive tasks, including two-back test, Korean color word Stroop test, and semantic verbal fluency task (SVFT), to investigate hemodynamic response and the presence of neural compensation and neuroplasticity in the prefrontal cortex of patients with amnestic and nonamnestic MCI compared with a healthy elderly group. During the two-back test, there was no significant difference in the bilateral region-of-interest (ROI) analysis in the three groups. During the Stroop test, right-sided hyperactivation compared to the left side during the task was shown in the nonamnestic MCI and normal groups with statistical significance. Mean acc∆HbO2  on the right side was highest in the nonamnestic MCI group (0.30 μM) followed by the normal group (0.07 μM) and the amnestic MCI group (-0.10 μM). Otherwise, intergroup ROI analysis of acc∆HbO2 in these activated right sides showed no significant difference. During the VFT test, there was no significant difference in the bilateral region-of-interest analysis in the three groups. The highest mean acc∆HbO2 was shown in the normal group (0.79 μM) followed by the nonamnestic MCI group (0.52 μM) and the amnestic MCI group (0.21 μM). Otherwise, there was no significant difference between groups. The hemodynamic response during fNIRS showed different findings according to MCI types and cognitive tasks. Among the three tasks, the Stroop test showed results that were suggestive of neural compensatory mechanisms in the prefrontal cortex in nonamnestic MCI.
Experimental Verification of Applying Active Control Method as Virtual Support for Relief Bridge
Authors: Shih Ming-Hsiang , Sung Wen-Pei
Published: June 2019

When natural disasters cause bridges to collapse, the delivery of rescue equipment and supplies to remote disaster areas is impeded and disaster relief efforts are thus delayed. In this study, to enhance and improve light bridges for disaster relief, a neutral equilibrium mechanism (NEM) is proposed to adjust the internal force of the bridge and reduce the deformation of the bridge. The NEM is installed at the center of a bridge to form a virtual bridge pier. A prototype of the NEM, composed of a pair of prestressed steel tendons, two pairs of anchor seats, a rotation cantilever arm mechanism, and a pair of radio‐controlled (RC) servos, is proposed to test and verify the control effect of a bridge with the NEM. Test and analysis results show the following: (1) The rotation angle of the cantilever arm can be rotated by the RC servo to appropriate angles to provide adequate upwards resultant force to balance the moving load. (2) The vertical displacement of the bridge can be controlled to close to zero by this proposed NEM. (3) The maximum vertical displacement at the midpoint of a bridge with the NEM control mechanism can be controlled to far below 1/400 of the span of the bridge required by the design criteria. (4) A bridge under the control of an NEM under a low‐speed moving load with various control gains achieves fine displacement reduction effects, but the displacement reduction effect for a high‐speed moving load with low control gain decreases. Test results also show that the bearing capacity of an existing bridge with an NEM can be increased and the weight of the bridge can be reduced. The effective span of a bridge can be increased without increasing the depth of the cross section. The feasibility and practicality of applying this proposed NEM to form a virtual pier of a bridge have been verified in this study.
A Comparative Genomic and Phylogenetic Analysis of the Origin and Evolution of the CCN Gene Family
Authors: Hu Kuan , Tao Yiming , Li Juanni , Liu Zhuang , Zhu Xinyan , Wang Zhiming
Published: June 2019

CCN gene family members have recently been identified as multifunctional regulators involved in diverse biological functions, especially in vascular and skeletal development. In the present study, a comparative genomic and phylogenetic analysis was performed to show the similarities and differences in structure and function of CCNs from different organisms and to reveal their potential evolutionary relationship. First, CCN homologs of metazoans from different species were identified. Then we made multiple sequence alignments, MEME analysis, and functional sites prediction, which show the highly conserved structural features among CCN metazoans. The phylogenetic tree was further established, and thus CCNs were found undergoing extensive lineage-specific duplication events and lineage-specific expansion during the evolutionary process. Besides, comparative analysis about the genomic organization and chromosomal CCN gene surrounding indicated a clear orthologous relationship among these species counterparts. At last, based on these research results above, a potential evolutionary scenario was generated to overview the origin and evolution of the CCN gene family.
A Phase I Dose Escalation Study of Once-Weekly Oral Administration of Docetaxel as ModraDoc001 Capsule or ModraDoc006 Tablet in Combination with Ritonavir
Authors: de Weger Vincent A. , Stuurman Frederik E. , Koolen Stijn L.W. , Moes Johannes J. , Hendrikx Jeroen J.M.A. , Sawicki Emilia , Thijssen Bas , Keessen Marianne , Rosing Hilde , Mergui-Roelvink Marja , Huitema Alwin D.R. , Nuijen Bastiaan , Beijnen Jos H. , Schellens Jan H.M. , Marchetti Serena
Published: June 2019

Purpose:

Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated.

Patients and Methods:

Patients with metastatic solid tumors were included. Dose escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Antitumor activity was assessed according to RECIST v1.0.

Results:

Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30 to 80 mg in combination with 100- or 200-mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1–2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration–time curve (AUC0–48) of docetaxel at the RP2D of once-weekly 60-mg ModraDoc001 capsule with 100-mg ritonavir was 1,000 ± 687 ng/mL/hour and for once-weekly 60-mg ModraDoc006 tablet with 100-mg ritonavir, the AUC0–48 was 1,790 ± 819 ng/mL/hour. Nine partial responses were reported as best response to treatment.

Conclusions:

Oral administration of once-weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60-mg ModraDoc with 100-mg ritonavir. Antitumor activity is considered promising.
PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage
Authors: Zhang Jinfang , Lee Yu-Ru , Dang Fabin , Gan Wenjian , Menon Archita Venugopal , Katon Jesse M. , Hsu Chih-Hung , Asara John M. , Tibarewal Priyanka , Leslie Nicholas R. , Shi Yang , Pandolfi Pier Paolo , Wei Wenyi
Published: June 2019

The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K–AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, governing efficient repair of DSBs partly through dephosphorylation of γH2AX. Of note, inhibiting NSD2-mediated methylation of PTEN, either through expressing methylation-deficient PTEN mutants or through inhibiting NSD2, sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor and DNA-damaging agents in both cell culture and in vivo xenograft models. Therefore, our study provides a novel molecular mechanism for PTEN regulation of DSB repair in a methylation- and protein phosphatase–dependent manner.

Significance:

NSD2-mediated dimethylation of PTEN is recognized by the 53BP1 tudor domain to facilitate PTEN recruitment into DNA-damage sites, governing efficient repair of DNA DSBs. Importantly, inhibiting PTEN methylation sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor combined with DNA-damaging agents in both cell culture and in vivo xenograft models.

This article is highlighted in the In This Issue feature, p. 1143
Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1
Authors: Ito Zensho , Kan Shin , Bito Tsuuse , Horiuchi Sankichi , Akasu Takafumi , Yoshida Sayumi , Kajihara Mikio , Hokari Atsushi , Saruta Masayuki , Yoshida Noriyuki , Kobayashi Masanori , Ohkusa Toshifumi , Shimodaira Shigetaka , Okamoto Masato , Sugiyama Haruo , Koido Shigeo
Published: June 2019

Background: We have developed a Wilms’ tumor 1 (WT1)-targeting dendritic cell (DC)-based cancer vaccine combined with standard chemotherapy for patients with advanced pancreatic ductal adenocarcinoma (PDA). Methods: We evaluated predictive markers of overall survival (OS) in PDA patients treated with multiple major histocompatibility complex class I/II-restricted, WT1 peptide-pulsed DC vaccinations (DC/WT1-I/II) in combination with chemotherapy. Throughout the entire period of immunochemotherapy, the plasma levels of soluble factors derived from granulocytes of 7 eligible PDA patients were examined. Moreover, systemic inflammatory response markers (neutrophil-to-lymphocyte ratio [NLR], monocyte-to-lymphocyte ratio [MLR], and granulocyte-to-lymphocyte ratio [GLR]) were assessed. In addition, cytoplasmic WT1 expression in PDA cells was examined. Results: Compared to the 4 non-super-responders (OS <1 year), the remaining 3 super-responders (OS ≥1 year) showed significantly decreased low plasma matrix metalloproteinase-9 levels throughout long-term therapy. The NLR, MLR, and GLR after 5 DC/WT1-I/II vaccinations and 3 cycles of gemcitabine were significantly lower in the super-responders than in the non-super-responders. Furthermore, the cytoplasmic WT1 expression in the PDA cells of super-responders was relatively weak compared to that in the PDA cells of non-super-responders. Conclusions: Prolonged low levels of a granulocyte-related systemic inflammatory response after the early period of therapy and low cytoplasmic WT1 expression in PDA cells may be markers predictive of OS in PDA patients receiving WT1-targeting immunochemotherapy.
Safety and Efficacy of Regional Citrate Anticoagulation during Plasma Adsorption Plus Plasma Exchange Therapy for Patients with Acute-on-Chronic Liver Failure: A Pilot Study
Authors: Ma Yuanji , Chen Fang , Xu Yan , Wang Ming , Zhou Taoyou , Lu Jiajie , Feng Ping , Wang Ying , Bai Lang , Tang Hong
Published: June 2019

Background: Patients with acute-on-chronic liver failure (ACLF) might be at risk for citrate accumulation during plasma adsorption plus plasma exchange (PE) therapy with regional citrate anticoagulation (RCA). Objectives: To assess the safety and efficacy of RCA during double plasma molecular adsorption system (DPMAS) plus PE therapy for patients with ACLF. Method: A prospective nonrandomized controlled pilot study was conducted at West China Hospital of Sichuan University. Patients with ACLF were enrolled to heparin anticoagulation (HA) group and RCA group. Serial blood samples were taken. Patients were followed up for 3 months. Results: Twenty-four patients with 94 sessions of HA and 28 patients with 106 sessions of RCA were enrolled. RCA method did not affect the therapeutic efficacy, the function of extracorporeal circulation, and the prognosis of these patients. The occurrences of citrate accumulation in RCA group were 0.0, 67.0, 100.0, 34.0, and 0.0% before DPMAS therapy, at the end of DPMAS therapy, immediately after PE therapy, 2 h after PE therapy, and the next morning, while that in HA group were 0.0, 0.0, 100.0, 7.4, and 0.0%, respectively. The occurrences of citrate accumulation at the end of DPMAS therapy and at 2 h after PE therapy in RCA group were much higher than that in HA group (67.0 vs. 0.0%, p = 0.000; 34.0 vs. 7.4%, p = 0.000, respectively). Although the trend of citrate accumulation in RCA group was much more obvious than that in HA group during and after DPMAS plus PE therapy (p = 0.000), the values on the next morning were similar between the 2 groups (p > 0.05). The main alteration of acid–base status was metabolic alkalosis with no difference between the 2 groups. Conclusions: RCA might be safe and effective in patients with ACLF receiving plasma adsorption plus PE therapy. RCA method might offer an alternative anticoagulation method for them.
Evaluation of Beta 2-Microglobulin, Cystatin C, and Lipocalin-2 as Renal Biomarkers for Patients with Fabry Disease
Authors: Braga Marion Coting , Fonseca Fernando Luiz Affonso , Marins Maryana Mara , Gomes Caio Perez , Bacci Marcelo Rodrigues , Martins Ana Maria , D’Almeida Vânia
Published: June 2019

Background: Since renal failure is one of the main causes of death in patients with Fabry disease (FD), renal follow-up is an important part of clinical monitoring in these patients. Despite its known limitations, serum creatinine is still the most widely used biomarker. While new renal biomarkers are described, their effectiveness has not yet been fully evaluated in relation to FD. Objectives: This study aimed to compare renal biomarkers commonly and rarely used in the evaluation of FD patients. Method: The usual biomarkers for renal monitoring (microalbuminuria, proteinuria, and creatinine) and some more rarely used (cystatin C, beta 2-microglobulin [β2M], neutrophil gelatinase-associated lipocalin/lipocalin-2) were quantified in the blood and/or urine samples of 40 FD patients, 39 controls without chronic kidney disease (CKD) paired by age and sex and 38 controls with CKD undergoing hemodialysis. Results: Significant statistical differences (p < 0.05) were observed for cystatin C and lipocalin-2 in plasma levels, for β2M and serum creatinine levels and by estimated glomerular filtration rate when compared FD patients and control group with CKD and for proteinuria and microalbuminuria in urine samples and for lipocalin-2 in plasma levels when compared FD patients and control group without CKD. Urine creatinine (UCreat), pH, and urine specific gravity did not present a significant statistical difference between groups. Conclusion: Considering serum creatinine as gold standard, all renal parameters evaluated, including receiver operating characteristic curve, indicated β2M as the best biomarker, followed by cystatin C, proteinuria and microalbuminuria, while the results for lipocalin-2 and UCreat do not indicate good predictors of renal impairment. It suggests that at least 2 altered biomarkers should be considered to characterize a renal alteration, thereby establishing a better therapeutic course for FD patients. If possible, along with serum creatinine, measurement of β2M or cystatin C for renal evaluation of Fabry’s patients should be considered.
Rac GTPase-Activating Protein 1 (RACGAP1) as an Oncogenic Enhancer in Esophageal Carcinoma
Authors: Yin Chengzeng , Toiyama Yuji , Okugawa Yoshinaga , Shigemori Tsunehiko , Yamamoto Akira , Ide Shozo , Kitajima Takahito , Fujikawa Hiroyuki , Yasuda Hiromi , Okita Yoshiki , Hiro Junichiro , Yoshiyama Shigeyuki , Ohi Masaki , Araki Toshimitsu , Yao Li , Kusunoki Masato
Published: June 2019

Purpose: Rac GTPase-activating protein 1 (RACGAP1) is associated with cell proliferation, and there is much evidence of its oncogenic role. This study investigated the clinical importance and functional role of RACGAP1 in esophageal carcinoma (EC). Methods: A total of 81 EC patients were enrolled in the study. We assessed the immunohistochemical score of EC tissues and adjacent normal esophageal mucosae, and then performed multiple cell function tests by means of in vitro experiments to elucidate the functional role of RACGAP1 using RNA interference technology in EC cell lines. Results: RACGAP1 was significantly overexpressed in EC tissues compared with the adjacent normal esophageal mucosae (p < 0.0001). Moreover, RACGAP1 overexpression was significantly correlated with poor overall survival (p = 0.032) and disease-free survival (p = 0.012) in EC patients. High RACGAP1 expression was also significantly correlated with the presence of lymphatic invasion (p = 0.012), vessel invasion (p = 0.003), and advanced TNM (tumor-node-metastasis) stage (p = 0.046) in EC patients. In vitro analysis demonstrated that RACGAP1 was involved in the proliferation, tumorigenicity, invasion, migration, and anoikis resistance in EC cells. Conclusions: RACGAP1 plays a pivotal role in EC development, suggesting that it could be used as an indicator of prognosis in EC patients.
Stool-Based miR-92a and miR-144* as Noninvasive Biomarkers for Colorectal Cancer Screening
Authors: Choi Hyun Ho , Cho Young-Seok , Choi Ji Hye , Kim Hyung-Keun , Kim Sung Soo , Chae Hiun-Suk
Published: June 2019

Objectives: Current noninvasive screening tests for colorectal cancer (CRC) have insufficient sensitivity. MicroRNA (miRNA) levels in stool have potential as markers for noninvasive screening of CRC. We evaluated the diagnostic value of stool miRNA levels and determined the optimal miRNA subtypes for detecting CRC. Methods: Stool samples were collected from 29 patients with CRC and 29 healthy controls. The stool levels of miR-21, miR-92a, miR-200c, miR-144*, miR-135a, miR-135b, miR-106a, and miR-17-3p were determined by real-time quantitative reverse transcription polymerase chain reaction. The sensitivity and specificity of the miRNAs for CRC were determined by receiver operating characteristics analysis. Results: Among the eight tested miRNAs, the mean stool levels of miR-21, miR-92a, miR-144*, and miR-17-3p differed significantly between the CRC group and the control group (p =0.014, 0.001, <0.001, and 0.008, respectively). The sensitivities and specificities of miR-21, miR-92, miR-144*, and miR-17-3p were 79.3 and 48.3%, 89.7 and 51.7%, 78.6 and 66.7%, and 67.9 and 70.8%, respectively. In a multivariate analysis, miR-92a and miR-144* were significantly associated with the presence of CRC (p = 0.03 and 0.011, respectively). Conclusions: The stool levels of miR-92a and miR-144* showed good sensitivity and fair specificity for detection of CRC, and thus may be useful as noninvasive biomarkers for this disease.
Trimming of Absorbable Plates and Screws through Smoothing by Multiple Sonic Activation Procedures Can Increase Local Tissue Reactions in Children with Cranial Fixations
Authors: Cho Sung Min  , Park Dong Ha , Yoon Soo Han , Koo Youn Moo  , Chang Young Lu
Published: June 2019

Objective: The aim of this paper was to investigate the local reactions due to the melting of absorbable plates and screws after trimming through smoothing by multiple sonic activation procedures (MSAP). Background: Drilling or smoothing by MSAP is performed for the trimming of the absorbable plates and screws for cranial fixation in children. Compared to drilling, smoothing by MSAP is suspected to more commonly cause local tissue reactions; thus, the issue was examined herein. Methods: For 90 children with smoothing by MSAP and 83 children with drilling procedures who underwent cranial fixation using absorbable plates and screws, the type, time of onset, and incidence of the local reactions were investigated. Results: Swelling was the most common reaction, followed by inflammatory reactions with itching, heating, skin-penetrating drainage, and pus formation. The mean time of onset of the local reaction was 10.0 ± 2.3 months after surgery. Local reactions occurred in 30% of the children in the group with smoothing by MSAP, and in 7.2% of the children in the group with drilling, showing a statistically significant difference between the two groups (p < 0.001). Conclusion: It was concluded that drilling rather than smoothing by MSAP to change the shapes of the absorbable plates and screws in cranial fixation can reduce the local reactions.
Current Status of Helicobacter pylori Diagnosis and Eradication Therapy in Japan Using a Nationwide Database
Authors: Deguchi Hisato , Uda Akihito , Murakami Kazunari
Published: June 2019

Background: Helicobacter pylori infection increases the risk of stomach cancer; therefore, eradication therapy is recommended for infected individuals. Although several methods are recommended for the diagnosis and therapy of H. pylori infection, their frequency and effectiveness have not been fully investigated in Japan. Methods: A nationwide claims database including >1.6 million patients (April 2008 – ­October 2016) in Japan was utilized. We analyzed the distribution of methods for H. pylori diagnosis and therapy, waiting period between eradication and diagnostic test, and success rate of primary therapy. Results: Data for 481,041 patients were extracted. After primary eradication therapy, urea breath test was used for >80% of diagnoses, and antibody measurement for 0.7%. The success rate of primary eradication was >80% for most diagnostic methods and 69.0% for antibody measurement; inappropriately-timed antibody measurement may have contributed to this disparity. The overall success rate of eradication therapy decreased from 2011 to 2014, but increased from 2015, coinciding with launch of the potassium-competitive acid blocker vonoprazan, which showed a higher success rate of eradication than proton-pump inhibitors. Conclusions: Diagnostic tests of H. pylori infection mostly followed Japanese Society for Helicobacter Research guidance, although some antibody measurements were timed inappropriately. Vonoprazan appears to increase the success rate of primary therapy.
Erroneously Analyzed F-Wave of Bradycardic Atrial Fibrillation as Ventricular Fibrillation for a Cardiac Arrest Patient
Authors: Watanabe Chikara , Nakajima Kento , Mori Kosuke , Gakumazawa Masayasu , Nakayama Naoki , Kato Makoto , Ogawa Fumihiro , Takahashi Kouhei , Iwashita Masayuki , Abe Takeru , Takeuchi Ichiro
Published: June 2019

The prognosis of out-of-hospital cardiac arrest has improved in Japan due to the increasing availability of automated external defibrillators. However, priority should be placed on specificity to not perform unnecessary waveforms rather than sensitivity to perform defibrillation on necessary waveforms. This report describes a case in which the f-wave of bradycardic atrial fibrillation was erroneously analyzed and defibrillated. Health care workers should be aware that the f-wave of bradycardic atrial fibrillation may be erroneously assessed as fine ventricular fibrillation; they should change it to the manual mode and respond as necessary.
Immuno-Oncological Treatment and Tumor Mass in Non-Small Cell Lung Cancer: Case-Control Analysis of Overall Survival in Routine Clinical Practice
Authors: Faehling Martin , Kopp Marcel , Schwenk Birgit , Fallscheer Sabine , Kramberg Sebastian , Eckert Robert
Published: June 2019

Background: Immuno-oncological (IO) therapies such as PD-1 and PD-L1 antibodies have been introduced in the treatment of advanced non-small cell lung cancer (NSCLC) since 2015 based on randomized trials showing unprecedented advantages in overall survival (OS) with hazard ratios (HRs) between 0.5 and 0.7. The impact of these treatments on OS in routine clinical practice and the role of tumor mass have not been studied. Methods: 557 consecutive patients with inoperable stage III or stage IV NSCLC diagnosed in our certified lung cancer center from 2006 to 2018 were included if they had received at least one line of systemic treatment. OS of immuno-oncologically treated patients (IO patients, n = 144) who received treatment with a PD-1 antibody (nivolumab [n = 77] or pembrolizumab [n = 51]) or a PD-L1 antibody (atezolizumab [n = 4] or durvalumab [n = 12]) was compared to historic controls treated before availability of IO treatment (n = 413) using case-control analysis. IO patients and historic controls were individually matched for stage, performance state, histology, smoking status, gender, age, and initial treatment mode (palliative vs. definitive radio-chemotherapy). Results: Case-control analysis of 91 matched pairs showed significantly longer OS in IO patients compared to historic controls (21.2 vs. 10.9 months, HR 0.526, CI 0.373–0.723). The benefit was more pronounced in patients with lower tumor stage (HR 0.48 [stage III], 0.40 [IVA], 0.63 [IVB]) or smaller tumor size (HR 0.38 [RECIST ≤57 mm], 0.40 [RECIST 58–94 mm], 0.59 [RECIST 95–141 mm], 0.75 [RECIST ≥142 mm]). Conclusions: IO patients showed significant benefit in OS with HRs comparable to those reported in phase III trials. The benefit tended to be greater in patients with lower tumor mass.
Exclusive Bee Venom Allergy: Risk Factors and Outcome of Immunotherapy
Authors: Rosman Yossi , Nashef Fatema , Cohen-Engler Anat , Meir-Shafrir Keren , Lachover-Roth Idit , Confino-Cohen Ronit
Published: June 2019

Introduction: Venom immunotherapy (VIT) is considered to be the gold-standard treatment for patients with Hymenoptera venom allergy. Data regarding VIT in bee venom (BV) allergic patients are scarce. Aim: The aim of this study was to evaluate the outcome of VIT in patients with exclusive BV allergy and to try to define risk factors for VIT-induced systemic reactions (VIT-ISR) and VIT failure. Methods: This is a retrospective study including data from all BV allergic patients that were treated by VIT in the Allergy Unit at the Meir Medical Center in the years 1995–2018. Results: Two hundred and forty-seven patients with exclusive BV allergy were included; 206 (83.4%) preferred to undergo rush buildup. Sixty-nine patients (27.9%) had at least 1 reaction during buildup, with the c-kit mutation being the only significant risk factor (100 vs. 28.9%, p = 0.02). Female gender (25.4 vs. 13.3%, p = 0.04), conventional buildup schedule (26.8 vs. 14.1%, p = 0.04), and c-kit mutation (100 vs. 16.8%, p < 0.01) but not tryptase level were found to be significantly more frequent in recurrent reactors. Females (20.3 vs. 9%, p = 0.03), patients with severe systemic reaction to the index sting (24.3 vs. 9.5%, p = 0.004), and c-kit mutation (66 vs. 12%, p = 0.05) but not tryptase level were found to be risk factors for severe systemic reactions. Conclusion: Despite the considerably high rate of VIT-ISR in patients with exclusive BV allergy, VIT can be performed safely and efficiently. C-kit mutation, and not basal serum tryptase level, seems to be a preferable biomarker for VIT-ISR in these patients.
Mechanisms of Nephrogenesis Revealed by Zebrafish Chemical Screen: Prostaglandin Signaling Modulates Nephron Progenitor Fate
Authors: Chambers Brooke E. , Wingert Rebecca A.
Published: June 2019

Nephron development involves the creation of discrete segment populations that are specialized to fulfill unique physiological roles. As such, renal function is reliant on the proper execution of segment patterning programs. Despite the central importance of nephron segmentation, the genetic mechanisms that regulate this process are far from understood, in large part due to the experimental complexities and cost of interrogating these events in the mammalian metanephros. For this reason, forward genetics utilizing phenotypic screening in the zebrafish pronephros provides an avenue to gain novel insights about the mechanisms of nephron segmentation in the vertebrate kidney. Discoveries from zebrafish can highlight possible conserved pathways and provide a useful starting point for reverse genetic analyses with other animal models or in vitro approaches. In this review, we discuss the results of a novel chemical screen using the zebrafish to identify segmentation regulators. Through this screen, we identified for the first time that prostaglandin signaling can modulate nephron segmentation, and that it is normally requisite during development to mitigate segment fate choice in the embryonic kidney. We briefly discuss how these discoveries relate to current knowledge about nephron segmentation. Finally, we explore the possible implications of these findings for understanding renal ontogeny and disease, and how this knowledge may be useful for ongoing research initiatives that are aimed at deciphering how to build or rebuild the human kidney.
Inhibition of miR-155 Ameliorates Acute Kidney Injury by Apoptosis Involving the Regulation on TCF4/Wnt/β-Catenin Pathway
Authors: Zhang Xiao-Bo , Chen Xiong , Li Dong-Jie , Qi Guan-Nan , Dai Yuan-Qing , Gu Jie , Chen Ming-Quan , Hu Sheng , Liu Zhen-Yu , Yang Zhi-Ming
Published: June 2019

Background: Acute kidney injury (AKI) is a complex clinical disorder with sudden decay in renal function. Ischemia-reperfusion injury (IRI) has been regarded as the main etiology for the occurrence of AKI. MicroRNAs have been consistently shown to be involved AKI. Objectives: We aimed to investigate the role of miR-155 in AKI and its underlying mechanism. Methods: Ischemia-reperfusion (I/R)-induced AKI rat model and hypoxia-reoxygeneration (H/R)-induced NRK-52E cell model were established. The concentrations of serum creatinine and blood urea nitrogen were measured to evaluate renal function. Hematoxylin and eosin staining and TUNEL assay were performed to assess the severity of kidney injury. Additionally, quantitative real-time-PCR and western blot analysis were subjected to determine the expression of miR-155, TCF4, and apoptosis-related proteins, respectively. Moreover, cell proliferation and apoptosis were evaluated by Cell Counting Kit-8, bromodeoxyuridine, and flow cytometry analyses, respectively. Luciferase reporter assay was used to validate the direct targeting of TCF4 with miR-155. The protein levels of TCF4 and its downstream proteins in cells were measured by western blot. Results: The expression level of miR-155 was upregulated in both I/R-induced AKI rat model and H/R-treated NRK-52E cells. Moreover, overexpression of miR-155 promoted H/R-induced NRK-52E cells apoptosis and suppressed cell proliferation, while inhibition of miR-155 expression exerted opposite effects. Additionally, TCF4 was identified as a target of miR-155, of which expression was downregulated both in vivo and in vitro. Furthermore, the activity of Wnt/β-catenin signaling pathway was promoted following overexpression of TCF4 in NRK-52E cells, and this effect was attenuated by the increasing miR-155 expression. Conclusion: We demonstrated that miR-155 exacerbated AKI involving the targeting and regulation of TCF4/Wnt/β-catenin signaling pathway, indicating a novel regulatory network and elucidating a potential target for IRI-induced AKI treatment.
Hepatocellular Carcinoma Occurrence/Recurrence after Direct-Acting Antivirals for Hepatitis C in Egyptian Cohort: Single-Center Experience
Authors: Lashen Sameh A. , Shamseya Mohammed M. , Madkour Marwa A.
Published: June 2019

Background: Conflicting data have been published about the risk of hepatocellular carcinoma (HCC) following direct-acting antivirals (DAAs). We investigated the incidence of HCC occurrence/recurrence after DAAs therapy. Patients and Methods: Retrospectively, we analyzed data of 392 patients with F3–4 fibrosis and cirrhosis treated by DAAs during the period from August 2015 to May 2018. In HCC-experienced patients, HCC treatment modality, and the duration between HCC management and DAAs initiation were recorded. In all patients, pretreatment clinicolaboratory evaluation, and imaging before, during and after DAAs were done. Results: De novo HCC occurred in 7.6% of naïve patients, while recurrence appeared in 28% of patients with previous HCC. Pretreatment alpha-fetoprotein was an independent predictor of HCC occurrence, while the time between HCC ablation and the beginning of DAAs was the only predictor of HCC recurrence (p < 0.001). Half of the patients who started DAAs before 6 months had HCC recurrence, while patients who started DAAs at ≥6 months had no recurrence (p< 0.0001). Conclusions: Although HCC occurrence after DAAs was not high, recurrence was apparently high. Pretreatment alpha-fetoprotein is a predictor for de novo HCC. The time between HCC ablation and DAAs was the strongest predictor of recurrence.
Osmotic and Nonosmotic Sodium Storage during Acute Hypertonic Sodium Loading
Authors: Adrogué Horacio J. , Mandayam Sreedhar , Tighiouart Hocine , Madias Nicolaos E.
Published: June 2019

Background: The Edelman equation has long guided the expected response of plasma [Na+] to changes in sodium, potassium, and water balance, but recent short-term studies challenged its validity. Plasma [Na+] following hypertonic NaCl infusion in individuals on low-sodium diet fell short of the Edelman predictions supposedly because sodium restriction caused progressive osmotic inactivation of 50% of retained sodium. Here, we examine the validity of this challenge. Methods: We evaluated baseline total body water (TBW) and Na+ space following acute hypertonic NaHCO3 infusion in dogs with variable sodium and potassium stores, including normal stores, moderate depletion (chronic HCl feeding), or severe depletion (diuretics and dietary NaCl deprivation). Results: TBW (percentage body weight) averaged 65.9 in normals, 62.6 in HCl-induced metabolic acidosis and moderate sodium and potassium depletion, and 57.6 in diuretic-induced metabolic alkalosis and severe sodium and potassium depletion (p < 0.02). Na+ space (percentage body weight) at 30, 60, and 90 min postinfusion averaged 61.1, 59.8, and 56.1, respectively, in normals (p = 0.49); 70.0, 74.4, and 72.1, respectively, in acidotic animals (p = 0.21); and 56.4, 55.1, and 54.2, respectively, in alkalotic animals (p = 0.41). Absence of progressive expansion of Na+ space in each group disproves progressive osmotic inactivation of retained sodium. Na+ space at each time point was not significantly different from baseline TBW in normal and alkalotic animals indicating that retained sodium remained osmotically active in its entirety. However, Na+ space in acidotic animals at all times exceeded by ∼16% baseline TBW (p < 0.01) signifying an early, but nonprogressive, osmotic inactivation of retained sodium, which we link to baseline bone-sodium depletion incurred during acid buffering. Conclusions: Our investigation affirms the validity of the Edelman construct in normal dogs and dogs with variable sodium and potassium depletion and, consequently, refutes the recent observations in human volunteers subjected to dietary NaCl restriction.
ДОСВІД ОРГАНІЗАЦІЇ ІНФЕКЦІЙНОГО КОНТРОЛЮ В ДИТЯЧІЙ ЛІКАРНІ
Authors: Uralbaieva T. S.
Published: June 2019

У статті наведено стратегію підвищення якості медичної допомоги через впровадження в практику охорони здоров’я системи інфекційного контролю.