bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of the 2017 European LeukemiaNet classification for acute myeloid leukemia with NPM1 and FLT3‐internal tandem duplication genotypes
Authors: Boddu Prajwal C. , Kadia Tapan M. , Garcia‐Manero Guillermo , Cortes Jorge , Alfayez Mansour , Borthakur Gautam , Konopleva Marina , Jabbour Elias J. , Daver Naval G. , DiNardo Courtney D. , Naqvi Kiran , Yilmaz Musa , Short Nicholas J. , Pierce Sherry , Kantarjian Hagop M. , Ravandi Farhad
Published: December 2018

Background

The revised 2017 European LeukemiaNet (ELN) classification (ELN‐2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as the fms‐like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN‐2017 in comparison with ELN‐2010 in younger patients with AML has not been validated to date.

Methods

The authors performed a retrospective study on patients aged <60 years who received idarubicin plus cytarabine (IA)–based induction chemotherapy for newly diagnosed AML.

Results

According to ELN‐2017 criteria, the number of patients in the favorable (Fav), intermediate (Int), and adverse (Adv) risk categories was 192 patients (27%), 331 patients (46%), and 192 patients (27%), respectively. Overall survival probabilities at 5 years in the Fav, Int, and Adv groups were 57%, 37%, and 18%, respectively. In comparison, the 5‐year overall survival probabilities in the Fav (169 patients), intermediate (IR)‐1 (80 patients), IR‐2 (306 patients), and Adv (160 patients) ELN‐2010 categories were 59%, 32%, 40%, and 14%, respectively. Although ELN‐2010 historically distinguishes prognosis into IR‐1 and IR‐2 categories in younger patients, this difference was nullified in the current study cohort. When comparing patients with a low FLT3‐ITD AR with those with a high FLT3‐ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)‐mutated AML (P = .28) or wild‐type NPM1 (P = .35), and in those treated with IA alone (P = .79) or those treated with IA and a FLT3 inhibitor (P = .10).

Conclusions

The ELN‐2017 more accurately distinguishes prognosis in patients with newly diagnosed AML. The lack of prognostic significance for the FLT3‐ITD AR needs further evaluation in different treatment settings.
Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy
Authors: Saab Karim R. , Mooradian Meghan J. , Wang Daniel Y. , Chon Jeewon , Xia Cathy Y. , Bialczak Angelica , Abbate Kelly T. , Menzies Alexander M. , Johnson Douglas B. , Sullivan Ryan J. , Shoushtari Alexander N.
Published: December 2018

Background

Combined BRAF and MEK inhibition (BRAF‐MEK) is a standard therapy for patients with BRAF V600–mutant melanoma, but to the authors’ knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post–programmed cell death protein 1 (PD‐1) setting.

Methods

Patients with BRAF V600–mutant melanoma who received combined BRAF‐MEK after prior PD‐1–based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan‐Meier methods from the time of the initiation of BRAF‐MEK therapy.

Results

A total of 78 patients were identified as having received a BRAF‐MEK regimen at a median of 34 days after the last dose of PD‐1–based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty‐five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF‐MEK <90 days after the last dose of PD‐1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE‐related hospitalization. Among 55 BRAF‐naive patients, the median time receiving BRAF‐MEK therapy was 5.8 months and the median OS was 15.6 months.

Conclusions

The majority of patients receiving BRAF‐MEK inhibition after PD‐1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.
A randomized, double‐blind, placebo‐controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma
Authors: Jiang Chunling , Wang Huan , Xia Chaofei , Dong Qing , Chen En , Qiu Yang , Su Yong , Xie Honghui , Zeng Lei , Kuang Jie , Ao Fan , Gong Xiaochang , Li Jingao , Chen Tingtao
Published: December 2018

Background

The objective of this study was to evaluate the effect of a probiotic combination on the severity of oral mucositis (OM), which is a common, unpreventable complication induced by radiochemotherapy in patients with nasopharyngeal carcinoma who undergo concurrent radiochemotherapy (CCRT).

Methods

Eligible patients (n = 99) with locally advanced nasopharyngeal carcinoma who were undergoing CCRT were randomly assigned (2:1) to receive a probiotic combination or placebo during radiochemotherapy, and the incidence of severe OM (grade 3 or higher) was the primary endpoint.

Results

Patients taking the probiotic combination showed a significant reduction in the severity of OM. The incidences of grade 0, 1, 2, and 3 OM in the placebo group and the probiotic combination group were 0% and 12.07%, 0% and 55.17%, 54.29% and 17.24%, and 45.71% and 15.52%, respectively. Furthermore, CCRT greatly lowered the number of immune cells, whereas the probiotic combination markedly lowered the reduction rates of CD4+ T cells (76.59% vs 52.85%; P < .05), CD8+ T cells (62.94% vs 29.76%; P < .05), and CD3+ T cells (69.72% vs 45.49%; P < .05) in an A‐CCRT‐P (after treatment with radiotherapy plus chemotherapy plus the probiotic combination) group. High‐throughput sequencing results indicated that CCRT had obviously disturbed the intestinal diversity of patients in an A‐CCRT (after treatment with radiotherapy plus chemotherapy plus a placebo) group, whereas the probiotic combination distinctly restored the microbial diversity in the A‐CCRT‐P group toward that of healthy people and a B‐CCRT‐P (before the treatment of radiotherapy plus chemotherapy plus the probiotic combination) group.

Conclusions

A probiotic combination significantly enhances the immune response of patients and reduces the severity of OM through modification of gut microbiota.
Mediolateral and dorsoventral projection patterns of cutaneous afferents within transverse planes of the mouse spinal dorsal horn
Authors: Odagaki Kaoru , Kameda Hiroshi , Hayashi Toshihiro , Sakurai Masaki
Published: December 2018

The central projection patterns of cutaneous afferents from the forelimb and shoulder of mice were studied in the spinal dorsal horn after intracutaneous injection of AlexaFluor 488‐conjugated and/or 594‐conjugated cholera toxin subunit B (CTB). Based on their dermatomes, the following eight skin regions are thought to be innervated by spinal nerves from the sixth to eighth cervical spinal nerve roots: the dorsal surface of the shoulder, brachium, proximal forearm, distal forearm, hand, palmar surface of the second and third digits, and palm. The termination areas of afferents from the dorsal surface of the shoulder and forearm were narrow, distributed in a dorsoventral direction, and aligned in order from lateral to medial within the sixth to eighth cervical dorsal horns. By contrast, the termination areas of the palmar surface of the second and third digits largely overlapped. We also injected CTB into the dorsal surface of the hindlimb and pelvic regions. Skin regions there are thought to be innervated by nerves from the third to fifth lumbar spinal nerve roots. The observed projection patterns in the lumbar dorsal horn were similar to the cervical patterns. Injection of a mixture of CTB and wheat‐germ agglutinin‐conjugated horseradish peroxidase (WGA‐HRP), which are thought to label Aβ and Aδ/C fibers, respectively, showed segregated termination areas of CTB‐ and WGA‐HRP‐labeled afferents. Moreover, alignment of the termination areas was in the dorsoventral direction. These results suggest there is fine somatotopic (mediolateral axis) and modality‐specific (dorsoventral axis) organization within the spinal dorsal horn.
Ultrahigh field imaging of myelin disease models: Toward specific markers of myelin integrity?
Authors: Petiet Alexandra , Adanyeguh Isaac , Aigrot Marie‐Stéphane , Poirion Emilie , Nait‐Oumesmar Brahim , Santin Mathieu , Stankoff Bruno
Published: December 2018

Specific magnetic resonance imaging (MRI) markers of myelin are critical for the evaluation and development of regenerative therapies for demyelinating diseases. Several MRI methods have been developed for myelin imaging, based either on acquisition schemes or on mathematical modeling of the signal. They generally showed good sensitivity but validation for specificity toward myelin is still warranted to allow a reliable interpretation in an in vivo complex pathological environment. Experimental models of dys−/demyelination are characterized by various levels of myelin disorders, axonal damage, gliosis and inflammation, and offer the opportunity for powerful correlative studies between imaging metrics and histology. Here, we review how ultrahigh field MRI markers have been correlated with histology in these models and provide insights into the trends for future developments of MRI tools in human myelin diseases. To this end, we present the biophysical basis of the main MRI methods for myelin imaging based on T1, T2, water diffusion, and magnetization transfer signal, the characteristics of animal models used and the outcomes of histological validations. To date such studies are limited, and demonstrate partial correlations with immunohistochemical and electron microscopy measures of myelin. These MRI metrics also often correlate with axons, glial, or inflammatory cells in models where axonal degeneration or inflammation occur as potential confounding factors. Therefore, the MRI markers' specificity for myelin is still perfectible and future developments should improve mathematical modeling of the MR signal based on more complex systems or provide multimodal approaches to better disentangle the biological processes underlying the MRI metrics.
Analysis of serum macrophage migration inhibitory factor and D‐dopachrome tautomerase in systemic sclerosis
Authors: Vincent Fabien B , Lin Emily , Sahhar Joanne , Ngian Gene‐Siew , Kandane‐Rathnayake Rangi , Mende Rachel , Hoi Alberta Y , Morand Eric F , Lang Tali , Harris James
Published: December 2018

Objectives

Macrophage migration inhibitory factor (MIF) and D‐dopachrome tautomerase (DDT), members of the same cytokine superfamily, are linked to the pathogenesis of a number of inflammatory diseases. The aim of this study was to investigate their clinical relevance in systemic sclerosis (SSc).

Methods

Serum MIF and DDT were quantified in 105 SSc patients by ELISA and levels compared to healthy controls (HC) (47) and patients with systemic lupus erythematosus (SLE) (184). Clinical parameters included organ involvement, serum laboratory markers and results of pulmonary function tests, and overall disease activity assessed using the European Scleroderma Trials and Research group (EUSTAR) activity index.

Results

There was no significant difference in serum DDT concentrations between patients with SSc and HC. However, serum MIF was significantly increased in SSc compared to both HC and SLE cohorts. Serum MIF was increased in SSc patients with low forced vital capacity (FVC) and was also associated with the use of angiotensin II receptor blockers and beta blockers in SSc, confirmed after adjusting for the presence of systemic hypertension and low FVC. Serum DDT was significantly higher in SSc patients with low FEV1 and negatively correlated with EUSTAR score, particularly in patients with limited disease.

Conclusion

Although not significantly linked to specific clinical parameters, serum MIF was significantly higher in SSc patients than in HC and SLE patients, suggesting a fundamental role for MIF in SSc. DDT, while closely related to MIF, did not show a similar expression profile, suggesting functional differences between these molecules.
A stable and reliable data dissemination scheme based on intelligent forwarding in VANETs
Authors: Chahal Manisha , Harit Sandeep
Published: December 2018

Vehicular ad hoc networks (VANETs) have gained incredible attention because of their applications in safety, commercial uses, and traffic management. However, the dynamic topology changes caused by the high speed of vehicles raise many challenges for the effective data dissemination in vehicular applications. In this paper, with the objective to solve the problem of frequent disconnection during data delivery, we propose a novel, intelligent forwarding–based stable and reliable data dissemination scheme. First, link stability is described mathematically, by which vehicle chooses the next forwarding node. Then, a greedy algorithm is presented to transmit the data from source to destination. A separate recovery algorithm is also designed to resolve the intermediate link breakage problem. The performance of the proposed method is analyzed by performing extensive network and traffic simulations with respect to various indexes such as latency, packet delivery ratio (PDR), and throughput. Compared with the state‐of‐the‐art protocols, the proposed method under varying density improves the average PDR and throughput by 31.55% and 25.30%, respectively.
Investigation of properties influencing the impact resistance of calcium silicate masonry units
Authors: Rumplmayr Simon , Eden Wolfgang , Burtscher Wolfgang , Thienel Karl‐Christian
Published: December 2018

Calcium silicate masonry is characterized by a high loadbearing capacity. Despite the widespread use of calcium silicate masonry units as a building material in Germany, there have been no studies to specifically improve its resistance to bullet impact, which would result in a new, very specialized market segment for threatened infrastructure. Within the scope of a research project, fundamental knowledge was gained about the influence of manufacturing parameters on the impact resistance of calcium silicate masonry units. The investigations showed that both the type and proportion of coarse aggregate and the forming pressure play a decisive role. Based on these findings, calcium silicate masonry units can now be specifically optimized with regard to high impact resistance.
Multifunctional Mesoporous ZnO@BMMs with Strong Fluorescence and High Loading Capacity for Controlled Drug Delivery
Authors: Li Junfang , Sun Jihong , Bai Shiyang , Wu Xia , Xue Rensheng
Published: December 2018

Multifunctional mesoporous ZnO@BMMs were prepared via a facile and reliable post treatment, in which the influence of various parameters, including the amount of ZnCl2 doping, the different anions of the zinc salt, and the roasting temperature, on their structure, properties, and fluorescence performance were investigated by XRD, SEM, TEM, EDS, DLS, XPS, BET, PL, UV, and TGA/DTG. The drug loading and release performance was explored by using ibuprofen (IBU) as a model drug. The results showed that the ZnO@BMMs before drug‐loading and after drug release possessed not only ordered mesoporous structures, but also excellent luminescence, while the specific surface area decreased as the amount of Zn‐doping increased. The fluorescence profiles exhibited near band edge emission at 392 nm and defect of oxygen vacancy emission centered at 436 nm and 510 nm. The drug delivery behavior featured a high loading capacity (up to 250 mg/g) and good sustained release performance accompanied with strong fluorescence.
Substituted (E)‐2‐Methylene‐3,4‐cyclohexenones through Direct and Convenient Synthesis from Cyclohexenone‐MBH Alcohol in the Presence of DMAP
Authors: Ren Hong‐Xia , Song Xiang‐Jia , Wu Lin , Huang Zhi‐Cheng , Zou Ying , Li Xia , Chen Xiao‐Wen , Tian Fang , Wang Li‐Xin
Published: December 2018

An unexpected and effective DMAP catalyzed one‐step construction of 3,4‐cyclohexenone skeleton from simple and easily available cyclohexenone‐MBH alcohol has been disclosed. A series of substituted (E)‐2‐methylene‐3,4‐cyclohexenones have been effectively prepared in excellent yields (up to 93 %) under convenient reaction conditions. Succesful scale‐up preparation and synthetic transformations have demonstrated the potentials of this new protocol.
A design procedure for buildings equipped with energy dissipation devices using nonclassical damping and iso‐performance curves
Authors: de la Llera Juan C. , Muñoz Juan P. , Besa Juan J.
Published: December 2018

This article describes a design procedure for elastic buildings equipped with linear and nonlinear energy dissipating devices. The objective is to achieve a design that responds to a target building performance following a simple and robust step‐by‐step algorithm. The proposed procedure identifies first the modal significance of key design performance indicators and controls the modal properties by solving a singular two‐parameter eigenvalue problem. For that purpose, a new modal significance metric is proposed, and a target frequency shift and damping ratio for the complete structure are obtained from the so‐called iso‐performance design curves. The design algorithm employs linear‐equivalent stiffness and damping properties, which are then transformed into parameters characterizing inelastic force‐deformation constitutive models corresponding to physical devices. The design algorithm leads to an optimal damper distribution corresponding to the minimum global amount of supplemental equivalent damping needed to achieve a maximum modal perturbation. The design procedure is first demonstrated using a five‐story building example and then a real and complex 22‐story free‐plan building with two towers of rhomboid‐shape plan with a very singular dynamic behavior.
A 2-Tier standard method to test the toxicity of microplastics in marine water using Paracentrotus lividus and Acartia clausi larvae
Authors: Beiras Ricardo , Tato Tania , López-Ibáñez Sara
Published: December 2018

A 2-tier standardized protocol was designed to test the toxicity of microplastics to planktonic organisms. This approach uses sea urchin (Paracentrotus lividus) and copepod (Acartia clausi) larvae because they are common biological models in marine research, and standard methods for toxicity testing with regulatory applications are available. In Tier I, leachates obtained at a 100 to 1 liquid to solid ratio are tested, and toxic units are calculated using a probit dose–response model to quantify the toxicity of the plastics. In Tier II, which is conducted only if significant toxicity (> 1 toxic unit) is found in Tier I, particles less than 20 μm in size are tested at concentrations between 0.1 and 10 mg L−1, and a toxicity threshold suitable for ranking materials according to their toxicity is obtained from the 10% effect concentration (EC10) values. Results point to chemical additives as being responsible for the toxicity found in certain plastic materials. This process is suitable for both a priori identification of the hazard posed by plastic objects in the aquatic environment, and a posteriori assessment of environmental risk caused by microplastic pollution. The method also provides a quantitative procedure appropriate for ranking plastic materials according to their toxicity to aquatic organisms. Environ Toxicol Chem 2019;38:630–637. © 2018 SETAC

Abstract

Standard protocol for plastics’ toxicity testing including micronization of plastic objects, Tier I leachate test and calculation of toxic units (toxic units), and Tier II microparticle test and calculation of the toxicity threshold. EC10 = 10% effect concentration.
An accurate and robust HLLC‐type Riemann solver for the compressible Euler system at various Mach numbers
Authors: Xie Wenjia , Zhang Ran , Lai Jianqi , Li Hua
Published: December 2018

A simple, robust, and accurate HLLC‐type Riemann solver for the compressible Euler equations at various Mach numbers is built. To cure shock instability of the HLLC solver at strong shocks, a pressure‐control technique, which plays a role in limiting the propagation of erroneous pressure perturbation, is proposed. With an all Mach correction method for the compressible Euler system, the proposed method is further extended to compute flow problems at low Mach numbers. The proposed all Mach HLLC‐type scheme has been implemented and used to compute a variety of flow problems ranging from hypersonic compressible to low Mach incompressible flow regimes. Various numerical results demonstrate that the obtained all Mach HLLC‐type scheme is both accurate and stable for all speed ranges.
Early experience of transoral thyroidectomy: Comparison of robotic and endoscopic procedures
Authors: Tae Kyung , Lee Dong Won , Song Chang Myeon , Ji Yong Bae , Park Jung Hwan , Kim Dong Sun , Tufano Ralph P.
Published: December 2018

Background

The aim of this study was to evaluate the feasibility, safety, and early surgical outcomes of transoral thyroidectomy and to compare robotic and endoscopic procedures.

Methods

A total of 37 patients underwent robotic (23 cases) or endoscopic (14 cases) transoral thyroidectomy. We compared the outcomes of the two procedures.

Results

Of the 37 patients, 2 were converted to the robotic facelift approach as a result of an intraoperative CO2 embolism and inability to remove the tumor. The mean operative time was 172.8 ± 37.5 minutes. Transient recurrent laryngeal nerve palsy occurred in one case, and transient hypoparathyroidism in two cases. Most of patients were satisfied with the postoperative cosmesis. There were no significant differences between the robotic and endoscopic procedures, except for operative time, which was significantly longer in the robotic group.

Conclusion

Robotic and endoscopic transoral thyroidectomies are both feasible and safe in appropriate patients.
Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis
Authors: Clària Joan , Moreau Richard , Fenaille François , Amorós Alex , Junot Christophe , Gronbaek Henning , Coenraad Minneke J. , Pruvost Alain , Ghettas Aurélie , Chu‐Van Emeline , López‐Vicario Cristina , Oettl Karl , Caraceni Paolo , Alessandria Carlo , Trebicka Jonel , Pavesi Marco , Deulofeu Carme , Albillos Agustin , Gustot Thierry , Welzel Tania M. , Fernández Javier , Stauber Rudolf E. , Saliba Faouzi , Butin Noémie , Colsch Benoit , Moreno Christophe , Durand François , Nevens Frederik , Bañares Rafael , Benten Daniel , Ginès Pere , Gerbes Alexander , Jalan Rajiv , Angeli Paolo , Bernardi Mauro , Arroyo Vicente ,   for the CANONIC Study Investigators of the EASL Clif Consortium, Grifols Chair and the European Foundation for the Study of Chronic Liver Failure (EF Clif)
Published: December 2018

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute‐on‐chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28‐day follow‐up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short‐term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow‐up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow‐up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow‐up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.
Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice
Authors: Huck Ian , Gunewardena Sumedha , Espanol‐Suner Regina , Willenbring Holger , Apte Udayan
Published: December 2018

Hepatocyte nuclear factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4α in liver regeneration (LR) is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during LR. Western blotting analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels, accompanied with decreased target gene expression, within 1 hour after two‐thirds partial hepatectomy (post‐PH) in C57BL/6J mice. HNF4α protein expression did not recover to pre‐PH levels until day 3. Hepatocyte‐specific deletion of HNF4α (HNF4α‐KO [knockout]) in mice resulted in 100% mortality post‐PH, despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated that HNF4α‐KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by c‐Myc and cyclin D1 overexpression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation‐resistant HNF4α in hepatocytes delayed, but did not prevent, initiation of regeneration after PH. Finally, adeno‐associated virus serotype 8 (AAV8)‐mediated reexpression of HNF4α in hepatocytes of HNF4α‐KO mice post‐PH restored HNF4α protein levels, induced target gene expression, and improved survival of HNF4α‐KO mice post‐PH. Conclusion: In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of LR. These results indicate the role of HNF4α in LR and have implications for therapy of liver failure.
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features
Authors: Jiang Wu , Cai Mu‐Yan , Li Shi‐Yong , Bei Jin‐Xin , Wang Fang , Hampel Heather , Ling Yi‐Hong , Frayling Ian M. , Sinicrope Frank A. , Rodriguez‐Bigas Miguel A. , Dignam James J. , Kerr David J. , Rosell Rafael , Mao Mao , Li Ji‐Bin , Guo Yun‐Miao , Wu Xiao‐Yan , Kong Ling‐Heng , Tang Jing‐Hua , Wu Xiao‐Dan , Li Chao‐Feng , Chen Jie‐Rong , Ou Qing‐Jian , Ye Ming‐Zhi , Guo Feng‐Ming , Han Peng , Wang Qi‐Wei , Wan De‐Sen , Li Li , Xu Rui‐Hua , Pan Zhi‐Zhong , Ding Pei‐Rong ,   Written on behalf of AME Colorectal Cancer Cooperative Group
Published: December 2018

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.
NETS: Network estimation for time series
Authors: Barigozzi Matteo , Brownlees Christian
Published: December 2018

We model a large panel of time series as a vector autoregression where the autoregressive matrices and the inverse covariance matrix of the system innovations are assumed to be sparse. The system has a network representation in terms of a directed graph representing predictive Granger relations and an undirected graph representing contemporaneous partial correlations. A LASSO algorithm calledNETSis introduced to estimate the model. We apply the methodology to analyze a panel of volatility measures of 90 blue chips. The model captures an important fraction of total variability, on top of what is explained by volatility factors, and improves out‐of‐sample forecasting.
Has_circ_0055625 from circRNA profile increases colon cancer cell growth by sponging miR‐106b‐5p
Authors: Zhang Jian , Liu Hua , Zhao Ping , Zhou Hao , Mao Tao
Published: December 2018

Circular RNAs (circRNA) are endogenous noncoding RNAs and play important roles in cancer; however, the roles of circRNAs in colon cancer are far from clear. The circRNA expression profile in colon cancer tissues was analyzed by microarray. The data from microarray showed that there were 198 upregulated and 136 downregulated circRNAs in colon cancer tissues. Among the top 10 upregulated circRNAs, hsa_circ_0055625 (circ_0055625) was confirmed to be significantly upregulated in colon cancer tissues. Further analysis demonstrated that circ_0055625 might get involved in the pathogenesis of colon cancer by functioning as miRNA sponges and performed bioinformatics analysis of the predicted circ_0055625/miR‐106b‐5p (miR‐106b)/ITGB8 network. Moreover, we found that circ_0055625 expression was associated with pathological TNM stage and metastasis. These data indicated that circ_0055625/miR‐106b/ITGB8 played a role in promoting tumor growth and metastasis, which suggested that circ_0055625 was a potential biomarker of colon cancer.
LncRNA SNHG20 contributes to cell proliferation and invasion by upregulating ZFX expression sponging miR‐495‐3p in gastric cancer
Authors: Cui Ning , Liu Jun , Xia Hong , Xu Dong
Published: December 2018

Long noncoding RNAs (lncRNAs) exert key regulators in cancer development and progression. The functional significance of lncRNA small nucleolar RNA host gene 20 (SNHG20) was reported in gastric cancer (GC); however, the underlying molecular mechanism in GC development is largely unknown. Here, our results showed that the lncRNA SNHG20 expression was significantly higher in GC tissues compared with adjacent normal tissues by quantitative real‐time PCR (qRT‐PCR) analysis. Higher lncRNA SNHG20 expression was highly associated with tumor size and lymphatic metastasis of patients. Patients with higher lncRNA SNHG20 expression predicted a short disease‐free survival (DFS) and overall survival (OS). Furthermore, lncRNA SNHG20 expression negatively associated with miR‐495‐3p expression and regulated miR‐495‐3p expression. Function assays confirmed that lncRNA SNHG20 knockdown using RNA interference suppressed cell proliferation and invasion of GC by negatively regulating miR‐495‐3p expression. Moreover, we demonstrated that lncRNA SNHG20 inhibited zinc finger protein X‐linked (ZFX) expression by negatively miR‐495‐3p expression in GC cells. In vivo, the current study also indicated that lncRNA SNHG20 knockdown reduced the tumor growth by downregulating ZFX expression. Thus, our results implied that inhibition of SNHG20/miR‐495‐3p/ZFX axis may provide valuable target for GC treatment.
Hsa‐miRNA‐29a protects against high glucose‐induced damage in human umbilical vein endothelial cells
Authors: Huang Zhigang , Li Na , Shan Yi , Liang Chun
Published: December 2018

Sustained exposure to high glucose (HG) results in dysfunction of vascular endothelial cells. Hence, diabetic patients often suffer from secondary vascular damages, such as vascular sclerosis and thrombogenesis, which may eventually cause cardiovascular problems. Thus, elucidating how HG results in vascular endothelial cell damage and finding an approach for prevention are important to prevent and treat vascular damages in diabetic patients. In the current study, we first showed that 72‐hour exposure to HG‐decreased hsa‐miRNA‐29a and increased the expression of Bcl‐2 associated X protein (Bax), which subsequently inhibited Bcl‐2 and promoted the expression of apoptotic protease activating factor‐1 and activation of caspase‐3, thus directly triggering the mitochondrial apoptotic pathway in human umbilical vein endothelial cells (HUVECs). Study of the underlying mechanism showed that hsa‐miRNA‐29a/Bax plays an essential role in the decreased proliferation and increased apoptosis of HUVECs induced by HG, and overexpression of hsa‐miRNA‐29a effectively inhibits HG‐induced apoptosis and restores the proliferation and tube formation of HUVECs exposed to HG by inhibiting its target gene Bax. In short, our study demonstrates that hsa‐miRNA‐29a is a promising target for the prevention and treatment of vascular injury in diabetic patients.
Long noncoding RNA FOXD2‐AS1 promotes glioma malignancy and tumorigenesis via targeting miR‐185‐5p/CCND2 axis
Authors: Shen Fazheng , Chang Haigang , Gao Guojun , Zhang Bin , Li Xiangsheng , Jin Baozhe
Published: December 2018

Glioma is the most aggressive malignant tumor in the adult central nervous system. Abnormal long noncoding RNA (lncRNA) FOXD2‐AS1 expression was associated with tumor development. However, the possible role of FOXD2‐AS1 in the progression of glioma is not known. In the present study, we used in vitro and in vivo assays to investigate the effect of abnormal expression of FOXD2‐AS1 on glioma progression and to explore the mechanisms. FOXD2‐AS1 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of FOXD2‐AS1 was correlated with poor prognosis of glioma. Downregulation of FOXD2‐AS1 decreased cell proliferation, migration, invasion, stemness, and epithelial‐mesenchymal transition (EMT) in glioma cells and inhibited tumor growth in transplanted tumor. We also revealed that FOXD2‐AS1 was mainly located in cytoplasm and microRNA (miR)‐185‐5p both targeted FOXD2‐AS1 and CCND2 messenger RNA (mRNA) 3′‐untranslated region (3′‐UTR). miR‐185‐5p was downregulated in glioma tissue, cells, and sphere subpopulation. Downregulation of miR‐185‐5p was closely correlated with poor prognosis of glioma patients. In addition, miR‐185‐5p mimics decreased cell proliferation, migration, invasion, stemness, and EMT in glioma cells. CCND2 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of CCND2 was closely correlated with poor prognosis of glioma patients. CCND2 knockdown decreased cell proliferation, migration, invasion, and EMT in glioma cells. In glioma tissues, CCND2 expression was negatively associated with miR‐185‐5p, but positively correlated with FOXD2‐AS1. FOXD2‐AS1 knockdown and miR‐185‐5p mimics decreased CCND2 expression. Inhibition of miR‐185‐5p suppressed FOXD2‐AS1 knockdown‐induced decrease of CCND2 expression. Overexpression of CCND2 suppressed FOXD2‐AS1 knockdown‐induced inhibition of glioma malignancy. Taken together, our findings highlight the FOXD2‐AS1/miR‐185‐5p/CCND2 axis in the glioma development.
Astrocyte elevated gene‐1 induces autophagy in diabetic cardiomyopathy through upregulation of KLF4
Authors: Zhao Lichun , Zhang Qianhua , Liang Jie , Li Junxiu , Tan Xiaoming , Tang Nong
Published: December 2018

Background

Astrocyte elevated gene‐1 (AEG‐1), also known as metadherin, 3D3, and lysine‐rich carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) coisolated, has emerged as an important oncogene that is overexpressed in a variety of cancers. Previous studies revealed that AEG‐1 is also involved in multiple physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine, and Huntington's disease. However, the function of AEG‐1 in diabetic cardiomyopathy (DCM) has not been reported yet. Therefore, we conducted this study to characterize the potential role and mechanism of AEG‐1 in DCM rats.

Methods

DCM was induced by injections of streptozocin (STZ) in Wistar rats. Rats were randomized to be injected with lentivirus carrying AEG‐1 small interfering RNA. Haemodynamic changes of Wistar rats, assessment of cardiac weight index, and the expression of AEG‐1 and KLF4 were detected and compared among these three groups.

Results

The expressions of AEG‐1 and KLF4 in the STZ group were significantly elevated in cardiac tissues compared with the control group. Knockdown of AEG‐1 significantly increased the values of left ventricular ejection fraction, ±dp/dt
max, repressed autophagy, as well as upregulated the expression of KLF4.

Conclusions

Knockdown of AEG‐1 suppresses autophagy in DCM by downregulating the expression of KLF4. This study provide first‐notion evidence for the potential value of AEG‐1 as a therapeutic target for the treatment of the patients with DCM.
Space filling of permethylated β‐cyclodextrin by volatile hydrophobic and hydrophilic guests in polyethylene glycol
Authors: Onuchak Lyudmila A. , Kuraeva Yuliya G. , Evdokimova Maria A. , Golov Andrey A.
Published: December 2018

The inclusion of volatile organic compounds of various classes in the permethylated β‐cyclodextrin in an oligomeric solution of polyethylene glycol was investigated by inverse gas–liquid chromatography methods and by a stereochemical approach. It was established that the “guest–host” complexation process is influenced by the geometrical structure of the guest molecules, their chirality, and entropy factors.
CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review
Authors: Farhood Bagher , Najafi Masoud , Mortezaee Keywan
Published: December 2018

CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune‐resistance. Cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8
+ T cell‐mediated antitumor immune responses. Thus, CD8
+ T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8
+ T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4
+ T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so‐called infiltrated–inflamed [I–I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8
+ T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death‐1 receptor (PD‐1)–ligand (PD‐L1) and CTL‐associated antigen 4 (CTLA‐4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8
+ T cells and renewing their priming, respectively, and thereby eliminating antigen‐expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.
From Secondary to Postsecondary: Charting an Engineering Career and Technical Education Pathway
Authors: Gottfried Michael A. , Plasman Jay Stratte
Published: December 2018

Background

As a whole, the percentage of undergraduates pursuing degrees in science, technology, engineering, and mathematics (STEM) fields has remained constant, a trend of particular concern in the field of engineering. One potential solution for increasing the number of students completing engineering degrees in postsecondary education (PSE), and perhaps closing the gender gap in this area as well, might be through completion of engineering career and technical education (E‐CTE) coursework in high school.

Purpose/Hypothesis

This study explores the following questions: What are the characteristics of students who take E‐CTE in high school and the high schools offering these courses? How does E‐CTE in high school connect to engineering degrees in PSE? Does any relationship observed differ by gender?

Design/Method

This study utilizes the Education Longitudinal Study of 2002 (ELS) to respond to these research questions. ELS provides a rich array of student and school variables including complete high school and PSE transcripts. The study uses probit regression and a random intercepts model to determine completion of the following engineering outcomes: declared engineering major, AA/AS, BA/BS, MA/MS, and PhD/Doctoral/Professional.

Results

This study found that the engineering gender gap is evident in high school, that there are observed connections between E‐CTE in high school and all levels of degree except for AA/AS, and that there is a clear difference across genders as women benefitted more from E‐CTE in connection to completion of an engineering BA/BS than men.

Conclusions

This study documents an engineering gender gap in high school and finds that participation in E‐CTE can encourage completion of an engineering degree as well as potentially narrowing the engineering gender gap.
Shared Resources: Engineering Students' Emerging Group Understanding of Thermodynamic Work
Authors: Cao Ying , Koretsky Milo D.
Published: December 2018

Background

We have developed several interactive virtual laboratories (IVLs) based on a sequence of agent‐based molecular simulations designed to target specific threshold concepts to help students learn thermodynamics. We previously analyzed learning in the IVLs from a cognitive perspective, seeking to repair students' misconceptions; however, that perspective provided limited information for iteratively improving the IVLs.

Purpose

In this study, we shift to a sociocultural perspective to identify student learning resources activated during their engagement in the Thermodynamic Work IVL. We seek to identify the productive social and environmental triggers through which students develop conceptual ideas using technology in a social setting.

Method

We conducted emergent lexical coding on a cohort of 187 students' textual responses as they completed the IVL in a studio setting. We then analyzed the discursive and technology interactions of four students from different groups using video recordings.

Results

Coding results show distributions of students' activated resources. Almost all of the students demonstrated productive ideas, and almost all also revealed opportunities to learn more. Through the detailed studies, we illustrate the moment‐by‐moment interactions of students with one another and with technology to describe how they activate and share resources. These interactions are conceptualized and illustrated through the construct of shared resources. We relate shared resources to processes of knowledge co‐construction and knowledge transfer, and discuss implications for instructional practice and educational technology design.

Conclusions

The resources framework helps us recognize productive ideas in students' evolving understanding of thermodynamic work. Shared resources allows for elaboration of the interwoven cognitive and social aspects of learning.
Quantitation of cobalt in Chinese tea by surface‐enhanced Raman spectroscopy in combination with the spectral shape deformation quantitative theory
Authors: Liu Qing , Chen Zeng‐Ping , Shi Cai‐Xia , Chen Yao , Yu Ru‐Qin
Published: December 2018

A surface‐enhanced Raman spectroscopy (SERS) method for the quantification of Co2+ in Chinese tea was developed in this contribution. SERS‐enhancing substrates with a high selectivity for Co2+ were prepared by attaching 2‐(bis (pyridin‐2‐ylmethyl)amino)ethane‐1‐thiol onto the surfaces of Ag nanoparticles. A calibration model based on the spectral shape deformation quantitative theory was derived to address the poor reproducibility problem in SERS assays due to the practical impossibility in controlling the number and distribution of “hot spots” on or close to the surface of enhancing substrates. The proposed SERS platform was applied to the quantification of Co2+ in Chinese tea samples and achieved quite satisfactory quantitative results. The average relative deviation between the quantitative results of the proposed SERS platform and those of inductively coupled plasma mass spectrometry was about 6.0%. It is therefore reasonable to expect that the proposed SERS platform can be a competitive alternative for the quantification of Co2+ in food samples.
Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling
Authors: Zheng Hailun , Yang Lehe , Kang Yanting , Chen Min , Lin Shichong , Xiang Youqun , Li Caleb , Dai Xuanxuan , Huang Xiaoying , Liang Guang , Zhao Chengguang
Published: December 2018

Several studies have implicated the feedback activation of signal transducer and activator of transcription 3 (STAT3) as a new cancer drug‐resistance mechanism and linked it to the failure of epidermal growth factor receptor (EGFR)‐targeted therapies. In this study, we discovered that Alantolactone, a natural sesquiterpene lactone, potently inhibited human pancreatic cancer cells and suppressed constitutively activated STAT3. In contrast, Alantolactone had little effect on the EGFR pathway. Moreover, combination of Alantolactone and an EGFR inhibitor, Erlotinib or Afatinib, demonstrated a remarkable synergistic anti‐cancer effect against pancreatic cancer cells both in vitro and in vivo. Our results suggested that Alantolactone could sensitize human pancreatic cancer cells to EGFR inhibitors possibly through down‐regulating the STAT3 signaling. Alantolactone, when combined with other EGFR targeted agents, could be further developed as a potential therapy for pancreatic cancer.