bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED: Resibufogenin suppresses growth and metastasis through inducing caspase‐1‐dependent pyroptosis via ROS‐mediated NF‐κB suppression in non‐small cell lung cancer
Authors: Yin Hui , Liu Yan‐Ge , Li Fei , Wang Lun‐Qing , Zha Jian‐Hua , Xia Ying‐Chen , Yu Ben‐Tong , Wen Di‐Hao
Published: May 2020

The purpose of this study is to explore the antitumor properties of resibufogenin (RB) in non‐small cell lung cancer (NSCLC) and elucidate its underlying mechanism. A549 and H520 cells were treated with various concentrations of RB with or without NLRP3 inhibitor (MCC950), caspase‐1 inhibitor (VX765), or N‐acetyl‐l‐cysteine (an ROS scavenger). Cell counting kit‐8 and colony formation assays were conducted to determine cell viability. Cell invasion was detected by using the transwell assay. The release of lactate dehydrogenase (LDH) was determined by the LDH detection assay. The protein expression levels of related genes were measured by western blotting and immunohistochemistry. The reactive oxygen species (ROS) level was detected by using a 2,7‐dichlorodihydrofluorescein diacetate ROS Assay Kit. The in vivo effects of RB were evaluated in a xenograft mouse model. RB treatment reduced cell viability and invasion in a dose‐dependent manner. Furthermore, RB also enhanced pyroptosis levels in A549 and H520 cells, as indicated by the increased release of LDH and pyroptosis‐related proteins. Interestingly, we also found that the antiproliferative and antimetastatic effects of RB were alleviated by the blockade of pyroptosis using NLRP3 inhibitor MCC950. Further study demonstrated that RB induced pyroptosis in a caspase‐1‐dependent manner, as evidenced by the finding that VX765 effectively reversed the effects of RB on A549 and H520 cells. We also found that RB could trigger caspase‐1‐dependent pyroptosis through ROS‐mediated NF‐κB suppression. In summary, our findings provide a potential antitumor agent and a novel insight into the mechanism of RB treatment of NSCLC.
Superior Ion‐exchange Property of Amorphous Aluminosilicates Prepared by a Co‐precipitation Method
Authors: Hikichi Naomichi , Iyoki Kenta , Yanaba Yutaka , Ohara Koji , Okubo Tatsuya , Wakihara Toru
Published: May 2020

The development of inexpensive inorganic ion‐exchangers for the purification of environmental pollutants is a social demand. Amorphous aluminosilicates with a relatively high homogeneous Al environment are prepared by a feasible co‐precipitation method, i. e., mixing an acidic aluminum sulfate solution and basic sodium silicate solution, which exhibit excellent ion‐exchange selectivity for Cs+ and Sr2+. The Kd value for Sr2+ was comparable with that of zeolite 4A. The local structures and ion‐exchange behavior of the amorphous aluminosilicates are systematically investigated. The ion‐exchange property of the amorphous aluminosilicates can be tuned by changing the interaction between the exchangeable cation and the amorphous aluminosilicates. Also, the amorphous aluminosilicates can adsorb bulky cations that zeolites hardly adsorb due to the limitation of the miropore size of zeolites.
Harmful effects of high amounts of glucose on the immune system: An updated review
Authors: Shomali Navid , Mahmoudi Javad , Mahmoodpoor Ata , Zamiri Reza Eghdam , Akbari Morteza , Xu Huaxi , Shotorbani Siamak Sandoghchian
Published: May 2020

Release and storage of energy can be regulated by the metabolic parameter dependent on the central nervous system. Macrophages are one of the most professional antigen‐presenting cells that are formed by the accumulation of dead or damaged cells or in response to the infection, which has the main function of phagocytosis, secretion of cytokines, and presenting antigen to T cells. A proper immune response is needed for the production of effector cytokines along with comprehensive and rapid cell proliferation and growth. Activation of the immune system and immune cells is needed to increase glucose metabolism. When the immune system responds to pathogens, chemokines inform immune cells such as macrophages and T cells to travel to the infected area. Although glucose is vital for the proper function of immune cells and their proliferation, a high amount of glucose may lead to impaired function of the immune system and pathological conditions. However, a suitable amount of glucose is indispensable for the immune system, but its elevated amount leads to excessive proinflammatory cytokines production. In this study, we focused on the master regulatory role of glucose on the immune system.
Achiral and chiral analysis of duloxetine by chromatographic and electrophoretic methods, a review on the separation methodologies
Authors: Lupu Daniela , Hancu Gabriel
Published: May 2020

Duloxetine (DLX) is a widely used antidepressant drug belonging to the class of selective serotonin and norepinephrine reuptake inhibitors (SNRIs); its efficacy has been demonstrated in the treatment of not only major depressive disorders but also diabetic neuropathic pain, generalized anxiety disorder, fibromyalgia or stress urinary incontinence. It is a chiral substance and is used in therapy in the form of the enantiopure S‐DLX, which is twice as active as R‐DLX. Several methods have been published for the achiral and chiral determination of DLX in pharmaceuticals, biological materials and environmental samples, the majority using liquid chromatography and capillary electrophoresis coupled with different detection techniques (UV detection, fluorescence, mass spectrometry). The aim of the current review is to provide a systematic survey of the analytical techniques used for the determination of DLX from different matrices.
Teaching complex molecular simulation algorithms: Using self‐evaluation to tailor web‐based exercises at an individual level
Authors: Dahlen Oda , Lervik Anders , Aarøen Ola , Cabriolu Raffaela , Lyng Reidar , van Erp Titus S.
Published: May 2020

It is quite challenging to learn complex mathematical algorithms used in molecular simulations, stressing the importance of using the most advantageous teaching methods. Ideally, individuals should learn at their pace and deal with tasks fitting their levels. Web‐based exercises make it possible to tailor every small step of the learning process, but this requires continuous monitoring of the learner. Differentiation based on the scores after the first round of common tasks can be demotivating for all students, as they will experience the initial set of tasks as being either too easy or too hard. We designed two tests, a self‐monitoring test and a rapid test (RT) in which the students explained equations relating to the current topic. The first test was aimed to see if the students were able to evaluate their own level of knowledge, whereas the RT was aimed to find a fast way to determine the level of the students. We compared both tests with traditional measures of knowledge and used a relatively new method, which was originally designed for the analysis of molecular simulation data, to interpret the results. Based on this analysis, we concluded that self‐evaluation, rather than an RT, is a valuable tool to automatically steer individual students through a tree of web‐based exercises to match their skill levels and interests.
Cu−Zn Alloy Formation as Unfavored State for Efficient Methanol Catalysts
Authors: Frei Elias , Gaur Abhijeet , Lichtenberg Henning , Zwiener Leon , Scherzer Michael , Girgsdies Frank , Lunkenbein Thomas , Schlögl Robert
Published: May 2020

The active sites of Cu/ZnO‐based catalysts, commercially applied for the hydrogenation of CO2 or CO2‐rich synthesis gas, are still subject of current debates. Generally, the discussion is focused on the nature of the interfacial contact between Cu and ZnO, particularly whether it is rather of oxidic (Cu−ZnO) or alloying (Cu−Zn) character. We report on kinetic investigations on a Cu/ZnO : Al high performance catalyst activated at different temperatures. Incrementally increasing temperature under reductive conditions leads also to increased CuZn‐alloy formation, analyzed by in‐situ X‐ray diffraction, in‐situ X‐ray absorption spectroscopy and high resolution transmission electron microscopy. The combination of the catalytic data and the complementary characterization techniques provide valuable insights on the relevant reaction sites for CH3OH formation. Our results highlight the complexity of the interfacial contact with evidence for Cu−ZnO reaction sites and clarify the negative impact of CuZn alloy formation on the nature of the active site.
Cyclodextrin‐Based Organic Radical Contrast Agents for in vivo Imaging of Gliomas
Authors: Melone Lucio , Bach Alice , Lamura Gianrico , Canepa Fabio , Nivajärvi Riikka , Olsson Venla , Kettunen Mikko
Published: May 2020

Cyclodextrins (CDs), a class of cyclic oligosaccharides formed by α‐(1,4) linked glucopyranose units, were functionalized with (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) radicals to prepare water soluble supramolecular organic radical contrast agents (ORCAs) for the in vivo detection of glioma tumor in animal models. A first set of molecules (CDn1, n=6,7,8 is the number of both TEMPO and glucopyranose units) was studied by superconducting quantum interference devices (SQUID) magnetometry in order to define the role of the CD macrocycle on the effective magnetic moment (μeff). The μeff value increased from 3.982 μB(CD61) to 4.522 μB (CD81) but was limited by intramolecular antiferromagnetic (AF) interactions. A set of water‐soluble ORCAs (CDn8, n=6,7,8) was prepared by a sequence of thiol‐ene and Cu(I)‐catalyzed alkyne–azide “click” reactions. Their 1H water relaxivities r1 of these ORCAs were between 0.739 mM−1 s−1 (CD68) to 1.047 mM−1 s−1 (CD88) in D2O/H2O 9 : 1 (v : v) at 300 K. One of them (CD78) was tested on glioma‐bearing rats with reduced side effects and good relaxivity in vivo.
Organic Cages as Building Blocks for Mechanically Interlocked Molecules: Towards Molecular Machines
Authors: La Cognata Sonia , Miljkovic Ana , Mobili Riccardo , Bergamaschi Greta , Amendola Valeria
Published: May 2020

The research on systems able to perform controllable motions under external stimuli arises great interest in the scientific community. Over the years, a library of innovative devices has been produced, classified in different categories according to the molecular or supramolecular level of motion. This minireview aims to highlight some representative studies, in which organic cages are used as building blocks for mechanically interlocked molecules, and in which intramolecular motions are triggered by external input. However, the application of organic cages in the construction of molecular machines is hardly achieved. A good compromise must actually be reached, between flexibility and rigidity of the cage's framework for an effective control of the intra‐ and/or intermolecular motion in the final mechanical device. Our final goal is to stimulate researchers′ curiosity towards cage‐like molecules, so that they take on the challenge of converting a cage into a molecular machine.
Oral health‐related quality of life among young adults with cleft in northern Finland
Authors: Corcoran Mirjami , Karki Saujanya , Harila Virpi , Kyngäs Helvi , Luoto Anni , Ylikontiola Leena P. , Sándor George K. , Anttonen Vuokko
Published: May 2020

Objectives

This study aimed to examine Oral Health‐related Quality of Life (OHRQoL) among patients with cleft lip with or without palate (CLP) at their final scheduled follow‐up visit at the age of 18 years. Another aim was to investigate the motivation to attend multiple follow‐up appointments and the satisfaction with care given by the cleft team using inductive qualitative analysis.

Methods

This cross‐sectional study was conducted among the cohort of children born with CLP who had undergone treatment at the Oulu University Hospital Cleft Lip and Palate Centre, in northern Finland since 1995. OHRQoL was assessed using the validated Finnish version of the short form of the Oral Health Impact Profile (OHIP‐14). In addition to the OHIP‐14, two open‐ended questions were also included. These questions investigated the experience of each participant concerning their motivation to attend the Oulu University Hospital Cleft Lip and Palate Centre to receive complex treatments, and their satisfaction with care provided by the cleft team. Results were presented as proportions, means, and SD. Inductive content analysis method was performed for analysis of the open‐ended questions.

Results

A total of 63 patients with CLP participated in this study. More than half of the participants had cleft palate. More than half of the participants reported an impact on OHRQoL (OHIP‐14 score ≥ 3). All the participants with bilateral cleft lip and palate, three fourths of the participants with unilateral cleft lip and palate, and half of the participants with cleft palate reported impact on OHRQoL. Inductive content analysis showed that one fourth of the participants reported a good outcome as a motivation to attend cleft center despite of complex procedures. All the participants reported their appreciation of the cleft team.

Conclusions

Despite the comprehensive treatment received by the patients born with a CLP, they still experienced lower OHRQoL, especially physical pain and psychological discomfort were more pronounced. However, good outcome, support, and oral health care being a normal routine were the motivating factors to attend a long and demanding oral health care regimen.
Integreiddio’r cwricwlwm: yr heriau sy’n wynebu ysgolion cynradd ac uwchradd wrth ddatblygu cwricwlwm newydd yn y celfyddydau mynegiannol
Authors: Kneen Judith , Breeze Thomas , Davies‐Barnes Sian , John Vivienne , Thayer Emma
Published: May 2020

Mae integreiddio yn y cwricwlwm yn nodwedd mewn nifer o gwricwla newydd sydd wedi codi mewn gwahanol wledydd ers tua dechrau’r mileniwm. Mae hyn yn ymwneud yn bennaf â dileu’r ffiniau rhwng arbenigaethau pwnc traddodiadol, er mwyn gallu cynnig cyfleoedd dysgu mwy cyfannol a ‘chydgysylltiedig’. Mae’r astudiaeth hon yn tynnu ar brofiadau grŵp o athrawon cynradd ac uwchradd yng Nghymru a oedd yn cymryd rhan mewn gwaith i greu fframwaith ar gyfer cwricwlwm integredig i’r celfyddydau mynegiannol. Er bod yr athrawon yn rhannu’r uchelgais o sefydlu cwricwlwm sy’n rhoi statws uwch i’r celfyddydau, mae integreiddio’r cwricwlwm yn cynnig heriau mawr, yn enwedig o ran y ffordd y mae gwybodaeth pwnc yn cael ei deall a’i chyflwyno mewn cwricwlwm integredig. Mae’r athrawon yn delio mewn ffyrdd gwahanol ag integreiddio’r cwricwlwm, lle mae athrawon cynradd yn ffafrio dulltrawsddisgyblaetholsy’n rhoi blaenoriaeth i ddysgu a themâu a ysgogir gan y plentyn, a lle mae athrawon uwchradd yn dewis dulliauamlddisgyblaethol, lle mae’r themâu’n ddyfeisiau trefnu ond lle mae pynciau’n cael blaenoriaeth. Mae’r gwahaniaeth rhwng arferion yn awgrymu bod cysyniadau gwahanol o wybodaeth pwnc a meistrolaeth o fewn cwricwlwm integredig. Gan wneud defnydd yn benodol o gysyniadau Bernstein am ddisgyrsiau gwybodaeth, mae’r papur hwn yn awgrymu mai’r perygl mewn cwricwlwm integredig yw bod gwybodaeth ddisgyblaethol yn gwanhau. Er bod y papur hwn yn ymwneud â’r celfyddydau, mae modd cymhwyso’r negeseuon am integreiddio’r cwricwlwm yn fwy eang.
Detection of transformation zone cells in liquid‐based cytology and its comparison with conventional smears
Authors: Campaner Adriana Bittencourt , Fernandes Gustavo Leme
Published: May 2020

Background

To compare the differences between liquid‐based cytology (LBC) and conventional cytology in respect of the detection of transformation zone cells (TZC) by age group and to assess test performance by correlating results with cytological abnormalities.

Methods

A retrospective study assessing the results of cervical‐vaginal cytology smears collected at a private laboratory in São Paulo (Brazil) between January 2010 and December 2015.

Results

A total of 1 030 482 cytology tests were performed; of these, 3811 (0.36%) unsatisfactory samples were excluded. Cytology sampling in the patients studied was performed using the conventional technique in 394 879 (38.5%) cases and the liquid‐based techniques in 631 792 (61.5%) cases. The proportion of samples with TZC for interpretation was 73.2% (288 956 samples) in conventional cytology and 52.7% (333 115 samples) in LBC (P < .001). The presence of TZC rate declined in both groups with age, but was consistently lower for LBC (P < .001). The presence of endocervical and metaplastic cells was associated with higher high‐grade intraepithelial lesion detection rates.

Conclusion

Low representation of the transformation zone was found in the samples collected using the LBC technique, particularly in the over 50 age group. Conventional cytology was associated with a higher rate of detection of high‐grade lesions.
Schizophrenia‐associated gene dysbindin‐1 and tardive dyskinesia
Authors: Maes Miriam S. , Lu Justin Y. , Tiwari Arun K. , Freeman Natalie , de Luca Vincenzo , Müller Daniel J. , Voineskos Aristotle N. , Potkin Steven G. , Lieberman Jeffrey A. , Meltzer Herbert Y. , Remington Gary , Kennedy James L. , Zai Clement C.
Published: May 2020

Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long‐term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin‐1, encoded by the dystrobrevin‐binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three‐marker haplotypes to be associated with TD occurrence and TD severity (p < 0.05). These preliminary findings, if replicated in larger independent samples, would suggest that drugs targeting dysbindin‐1 may be an option in the prevention and treatment of TD.
Topography and disturbance influence trait‐based composition and productivity of adjacent habitats in a coastal system
Authors: Brown Joseph K. , Zinnert Julie C.
Published: May 2020

Coastal systems experience frequent disturbance and multiple environmental stressors over short spatial and temporal scales. Investigating functional traits in coastal systems has the potential to inform how variation in disturbance frequency and environmental variables influence differences in trait‐based community composition and ecosystem function. Our goals were to (1) quantify trait‐based communities on two barrier islands divergent in topography and long‐term disturbance response and (2) determine relationships between community trait‐based composition and ecosystem productivity. We hypothesized that locations documented with high disturbance would have habitats with similar environmental conditions and trait‐based communities, with the opposite relationship in low‐disturbance locations. Furthermore, we expected higher productivity and lower site‐to‐site variation with low disturbance. Functional traits, biomass, and environmental metrics (soil salinity, elevation, and distance to shoreline) were collected and analyzed for two habitat types (dune and swale) on two Virginia barrier islands. Our results show that trait‐based community composition differed among habitat types and was related to disturbance. Habitats exhibited more similarity on the high‐disturbance island in both trait‐based composition and environmental variables. Conversely, the low‐disturbance island habitats were more dissimilar. We found the habitat with the lowest disturbance had the highest ecosystem productivity and had trait‐based communities indicative of highly competitive environments, while the high‐disturbance trait‐based communities were influenced by traits that indicate rapid recovery and growth. Site‐to‐site variation was similar in all dune habitats but differed among inter‐island swale habitats that varied in disturbance. These results highlight the importance of incorporating trait‐based analyses when approaching questions about community structure and ecosystem productivity in disturbance‐mediated habitats, such as coastal systems.
Contemporary use of devices in chronic heart failure in the Netherlands
Authors: Raafs Anne G. , Linssen Gerard C.M. , Brugts Jasper J. , Erol‐Yilmaz Ayten , Plomp Jacobus , Smits Jeroen P.P. , Nagelsmit Michiel J. , Oortman Remko M. , Hoes Arno W. , Brunner‐LaRocca Hans‐Peter
Published: May 2020

Aims

Despite previous surveys regarding device implantation rates in heart failure (HF), insight into the real‐world management with devices is scarce. Therefore, we investigated device implantation rates in HF with reduced left ventricular ejection fraction (LVEF) in 34 Dutch centres.

Methods and results

A cross‐sectional outpatient registry was conducted in 6666 patients with LVEF < 50% and with information about device implantation available [74 (66–81) years of age; 64% male]. Patients were classified into conventional pacemakers (PM, n = 562), implantable cardioverter defibrillators (ICD, n = 1165), and cardiac resynchronization therapy with defibrillator function (CRT‐D, n = 885) or pacemaker function only (CRT‐P, n = 248), or no device (n = 3806). Centres were divided into ICD‐implanting and CRT‐implanting and referral centres. Overall, 17.5% had an ICD, 13.3% CRT‐D, 3.7% CRT‐P, and 8.4% PM. Of those with LVEF ≤ 30%, 42.5% had ICD or CRT‐D therapy. A large variation in implantation rates existed between centres: 3–51% for ICD therapy, 0.3–44% for CRT‐D therapy, 0–11% for CRT‐P therapy, and 0–25% PM therapy. Implantation centres showed higher implantation rates of ICD, CRT‐D, and CRT‐P compared with referral centres [36% vs. 25% for defibrillators (ICD or CRT‐D) and 17% vs. 9% for CRT devices (CRT‐D or CRT‐P), respectively, P < 0.001], independently of other factors. A large number of clinical factors were predictive for device usage. Among other, LVEF < 40% and male sex were independent positive predictors for ICD/CRT‐D use [odds ratio (OR) = 3.33, P < 0.001; OR = 1.87, P = 0.019, respectively]. Older age was independently associated with less ICD/CRT‐D (OR = 0.96 per year, P < 0.001) and more CRT‐P/PM use (OR = 1.03 per year, P = 0.006).

Conclusions

In this large Dutch HF registry, less than half of the patients with reduced LVEF received an ICD or CRT, even if LVEF was ≤30%, and a large variation between centres existed. Patients from implantation centres had more often ICD or CRT. More uniformity regarding guideline‐based use of device therapy in clinical practice is needed.
Nonlinear dynamic tests of a reinforced concrete frame building at different damage levels
Authors: Yousefianmoghadam Seyedsina , Song Mingming , Mohammadi Mohammad Ebrahim , Packard Brittany , Stavridis Andreas , Moaveni Babak , Wood Richard L.
Published: May 2020

This paper discusses the dynamic tests of a two‐story infilled reinforced concrete (RC) frame building using an eccentric‐mass shaker. The building, located in El Centro, CA, was substantially damaged prior to the tests due to the seismic activity in the area. During the testing sequence, five infill walls were removed to introduce additional damage states and to investigate the changes in the dynamic properties and the nonlinear response of the building to the induced excitations. The accelerations and displacements of the structure under the forced and ambient vibrations were recorded through an array of sensors, while lidar scans were obtained to document the damage. The test data provide insight into the nonlinear response of an actual building and the change of its resonant frequencies and operational shapes due to varying damage levels and changes of the excitation amplitude, frequency, and orientation.
The influence of Konjac glucomannan on the functional and structural properties of wheat starch
Authors: Zhang Ling , Zeng Lirong , Wang Xuan , He Juncheng , Wang Qiong
Published: May 2020

The aim of this study was to characterize the influence of Konjac glucomannan (KGM) on the functional and structural properties of wheat starch. Results showed that KGM significantly decreased the starch hydrolysis rate, with a lower level of rapidly digestible starch (RDS), and a higher content of slowly digestible starch (SDS). Besides, KGM decreased the content of leached amylose, while enhanced the swelling power, water‐holding capacity, freeze‐thaw stability, and paste clarity of wheat starch, which indicated a good improvement on the functional properties. Differential scanning calorimetry (DSC) and X‐ray diffraction patterns (XRD) manifested that the addition of KGM disrupted the original crystalline structures of wheat starch, which may result in the increased hydrolysis rate of starch. Interestingly, this did not consist with the decreased starch hydrolysis rate showed in the study. Moreover, FTIR results showed the existence of the interaction between KGM and starch. The morphological characterization demonstrated that the addition of KGM contributed to a more compact structure of freeze‐dried wheat starch. And KGM inhibited the expansion of starch granules and formed a barrier around the gelatinized starch. Therefore, the barrier around the starch granules and the interaction between KGM and starch were considered to be the important reasons that affected the starch digestibility.
Inactivation of Morganella morganii by high hydrostatic pressure combined with lemon essential oil
Authors: Kung Hsien‐Feng , Lee Yi‐Chen , Hwang Chiu‐Chu , Wu Ying‐Chuan , Hsieh Ching‐Yu , Tsai Yung‐Hsiang
Published: May 2020

The inactivation and damage of histamine‐forming bacterium, Morganella morganii, in phosphate buffer and tuna meat slurry by high hydrostatic pressure (HHP) alone or in combination with 0.2% lemon essential oil (LEO) treatments were studied using viability measurement and scanning electron microscopy (SEM). HHP alone or in combination with LEO treatments showed first‐order destruction kinetics to M. morganii during pressure holding period. The D values of M. morganii (200 to 600 MPa) in phosphate buffer ranged from 16.4 to 0.08 min, whereas those in tuna meat slurry ranged from 51.0 to 0.10 min, respectively. M. morganii in tuna meat slurry had higher D values and were more resistant to HHP treatments than in phosphate buffer. In addition, the D values of HHP in combination with LEO treatment were lower than those of HHP treatment alone at <400 MPa of pressure, indicating that it is more effective to inactivate M. morganii under the same pressure. The results showed the M. morganii at HHP in combination with LEO treatment was more susceptible to pressure treatment alone. HHP with or without LEO treatments can be used to inactivate M. morganii by causing disruption to bacterial cell membrane and cell wall as demonstrated by SEM micrographs.
Resting‐state and task‐based centrality of dorsolateral prefrontal cortex predict resilience to 1 Hz repetitive transcranial magnetic stimulation
Authors: Fitzsimmons Sophie M. D. D. , Douw Linda , van den Heuvel Odile A. , van der Werf Ysbrand D. , Vriend Chris
Published: May 2020

Repetitive transcranial magnetic stimulation (rTMS) is used to investigate normal brain function in healthy participants and as a treatment for brain disorders. Various subject factors can influence individual response to rTMS, including brain network properties. A previous study by our group showed that “virtually lesioning” the left dorsolateral prefrontal cortex (dlPFC; important for cognitive flexibility) using 1 Hz rTMS reduced performance on a set‐shifting task. We aimed to determine whether this behavioural response was related to topological features of pre‐TMS resting‐state and task‐based functional networks. 1 Hz (inhibitory) rTMS was applied to the left dlPFC in 16 healthy participants, and to the vertex in 17 participants as a control condition. Participants performed a set‐shifting task during fMRI at baseline and directly after a single rTMS session 1–2 weeks later. Functional network topology measures were calculated from resting‐state and task‐based fMRI scans using graph theoretical analysis. The dlPFC‐stimulated group, but not the vertex group, showed reduced setshifting performance after rTMS, associated with lower task‐based betweenness centrality (BC) of the dlPFC at baseline (p = .030) and a smaller reduction in task‐based BC after rTMS (p = .024). Reduced repeat trial accuracy after rTMS was associated with higher baseline resting state node strength of the dlPFC (p = .017). Our results suggest that behavioural response to 1 Hz rTMS to the dlPFC is dependent on baseline functional network features. Individuals with more globally integrated stimulated regions show greater resilience to rTMS effects, while individuals with more locally well‐connected regions show greater vulnerability.
Role of the Mammalian Target of Rapamycin Pathway in Liver Cancer: From Molecular Genetics to Targeted Therapies
Authors: Lu Xinjun , Paliogiannis Panagiotis , Calvisi Diego F. , Chen Xin
Published: May 2020

Primary liver cancers, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), are highly lethal tumors, with high worldwide frequency and few effective treatment options. The mammalian target of rapamycin (mTOR) complex is a central regulator of cell growth and metabolism that integrates inputs from amino acids, nutrients, and extracellular signals. The mTOR protein is incorporated into two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Specifically, mTORC1 regulates protein synthesis, glucose and lipid metabolism, and autophagy, whereas mTORC2 promotes liver tumorigenesis through modulating the adenine/cytosine/guanine family of serine/threonine kinases, especially the protein kinase B proteins. In human HCC and iCCA samples, genomics analyses have revealed the frequent deregulation of the mTOR complexes. Both in vitro and in vivo studies have demonstrated the key role of mTORC1 and mTORC2 in liver‐tumor development and progression. The first‐generation mTOR inhibitors have been evaluated for effectiveness in liver‐tumor treatment and have provided unsatisfactory results. Current research efforts are devoted to generating more efficacious mTOR inhibitors and identifying biomarkers for patient selection as well as for combination therapies. Here, we provide a comprehensive review of the mechanisms leading to a deregulated mTOR signaling cascade in liver cancers, the mechanisms whereby the mTOR pathway contributes to HCC and iCCA molecular pathogenesis, the therapeutic strategies, and the challenges to effectively inhibit mTOR in liver‐cancer treatment. Conclusion: Deregulated mTOR signaling significantly contributes to HCC and iCCA molecular pathogenesis. mTOR inhibitors, presumably administered in association with other drugs, might be effective against subsets of human liver tumors.
HBV‐Induced Increased N6 Methyladenosine Modification of PTEN RNA Affects Innate Immunity and Contributes to HCC
Authors: Kim Geon‐Woo , Imam Hasan , Khan Mohsin , Mir Saiful Anam , Kim Seong‐Jun , Yoon Seung Kew , Hur Wonhee , Siddiqui Aleem
Published: May 2020

Background and Aims

Epitranscriptomic modification of RNA has emerged as the most prevalent form of regulation of gene expression that affects development, differentiation, metabolism, viral infections, and most notably cancer. We have previously shown that hepatitis B virus (HBV) transcripts are modified by N6 methyladenosine (m6A) addition. HBV also affects m6A modification of several host RNAs, including phosphatase and tensin homolog (PTEN), a well‐known tumor suppressor. PTEN plays a critical role in antiviral innate immunity and the development of hepatocellular carcinoma (HCC). Reports have shown that PTEN controlled interferon regulatory factor 3 (IRF‐3) nuclear localization by negative phosphorylation of IRF‐3 at Ser97, and PTEN reduced carcinogenesis by inhibiting the phosphatidylinositol‐3‐kinase (PI3K)/AKT pathway.

Approach and Results

Here, we show that HBV significantly increases the m6A modification of PTEN RNA, which contributes to its instability with a corresponding decrease in PTEN protein levels. This is reversed in cells in which the expression of m6A methyltransferases is silenced. PTEN expression directly increases activated IRF‐3 nuclear import and subsequent interferon synthesis. In the absence of PTEN, IRF‐3 dephosphorylation at the Ser97 site is decreased and interferon synthesis is crippled. In chronic HBV patient biopsy samples, m6A‐modified PTEN mRNA levels were uniformly up‐regulated with a concomitant decrease of PTEN mRNA levels. HBV gene expression also activated the PI3K/AKT pathway by regulating PTEN mRNA stability in HCC cell lines.

Conclusions

The m6A epitranscriptomic regulation of PTEN by HBV affects innate immunity by inhibiting IRF‐3 nuclear import and the development of HCC by activating the PI3K/AKT pathway. Our studies collectively provide new insights into the mechanisms of HBV‐directed immune evasion and HBV‐associated hepatocarcinogenesis through m6A modification of the host PTEN mRNAs.
Respiratory infections regulated blood cells IFN‐β‐PD‐L1 pathway in pediatric asthma
Authors: Kölle Julia , Haag Patricia , Vuorinen Tytti , Alexander Kiefer , Rauh Manfred , Zimmermann Theodor , Papadopoulos Nikolaos G. , Finotto Susetta
Published: May 2020

Background

Respiratory infections, in general, and rhinovirus infection specifically are the main reason for asthma exacerbation in children and programmed cell death protein 1 ligand (PD‐L1) expression inhibits T cell responses.

Objective

Could the interferon (IFN) type I expression in peripheral blood mononuclear cells (PBMCs) improve disease exacerbation in pediatric asthma?

Results

Here we found increased level of PD‐L1 messenger RNA (mRNA) in total blood cells isolated from preschool children with virus‐induced asthma, with lower percentage of forced expiratory volume in 1 second and with high serum levels of the C‐reactive‐protein.

Conclusions and Clinical Relevance

These data indicate that, in the presence of infection in the airways of preschool children, worse asthma is associated with induced PD‐L1 mRNA expression in blood cells. Further, type I IFN, IFN‐β, a cytokine that is involved in the clearance of infections, was found to be associated with a better lung function in asthmatic children. These data suggest that improving peripheral blood IFN type I expression in PBMCs in pediatric asthma could improve disease exacerbation due to suppressing PD‐L1 expression in blood cells.
Comparison of the formation, adipogenic maturation, and retention of human adipose‐derived stem cell spheroids in scaffold‐free culture techniques
Authors: Fitzgerald Sarah J. , Cobb Jared S. , Janorkar Amol V.
Published: May 2020

While three‐dimensional spheroids outperform traditional two‐dimensional monolayer culture for human adipose‐derived stem cells (hASCs), there is not a consensus on the most successful method for enhancing their adipogenic differentiation and minimizing the loss of physiologically relevant, fatty spheroids during culture. To this end, we compared three culture methods, namely, elastin‐like polypeptide‐polyethyleneimine (ELP‐PEI) coated surfaces, ultra‐low attachment static culture, and suspension culture for their ability to form and retain productive hASC spheroids. The ELP‐PEI coatings used the ELP conjugated to two molecular weights of PEI (800 or 25,000 g/mol). FTIR spectroscopy, atomic force microscopy, and contact angle goniometry revealed that the ELP‐PEI coatings had similar chemical structures, surface topography, and hydrophobicity. Time‐lapse microscopy showed that increasing the PEI molecular weight resulted in smaller spheroids. Measurement of triglyceride content showed that the three methods induced comparable differentiation of hASCs toward the adipogenic lineage. DNA content and morphometric analysis revealed merging of spheroids to form larger spheroids in the ultra‐low attachment static culture and suspension culture methods. In contrast, the retention of hASC spheroid sizes and numbers with a regular spheroid size (~100 μm) were best atop the ELP‐PEI800 coatings. Overall, this research shows that the spheroid culture atop the ELP‐PEI coatings is a suitable cell culture model for future studies involving long‐term, three‐dimensional culture of mature adipocytes derived from hASCs.
Bone Microarchitecture Assessed by Trabecular Bone Score Is Independent of Mobility Level or Height in Pediatric Patients with Cerebral Palsy
Authors: Rehberg Mirko , Azim Manuela , Martakis Kyriakos , Winzenrieth Renaud , Hoyer-Kuhn Heike , Schoenau Eckhard , Semler Oliver , Duran Ibrahim
Published: May 2020

Bone strength and fracture risk do not only depend on bone density, but also on bone structure. The trabecular bone score (TBS) evaluates homogeneity of bone microarchitecture indirectly by measuring gray-level variations of two-dimensional (2D) DXA images. Although TBS is well-established for adults, there have been only few publications in pediatrics. In this monocentric retrospective analysis, we investigated TBS in children and adolescents with cerebral palsy (CP), a patient group vulnerable to low bone mineral mass due to impaired mobility. The influence of different parameters on TBS and areal BMD (aBMD) were evaluated, as well as the relationship between TBS and aBMD. We compared TBS values of our study population to a reference population. A total of 472 lumbar spine–dual-energy X-ray absorptiometry (LS-DXA) scans of children and adolescents with CP (205 female), aged between 4 and 18 years, were analyzed. The DXA-scans were part of the routine examination. The children had no records of fractures or specific bone diseases. Our study population with CP had similar TBS as the reference population. TBS did not increase with age until an inflection point at 10 years in females, and 12 years in males. Girls had significantly higher TBS than boys (p = .049) and pubertal girls aged 8 to 13 years had significantly higher TBS than prepubertal girls (p = .009). TBS standard deviation score for age (SDS-TBS) and aBMD Z-scores correlated weakly (p < .001; R = 0.276 [males], R = 0.284 [females]). Other than for aBMD Z-scores, SDS-TBS was not influenced by age-adjusted height Z-scores and there was no significant difference in SDS-TBS when grouped by mobility levels, using the Gross Motor Function Classification System (GMFCS). Our results indicate that children with CP have a similar homogeneous distribution of trabecular microarchitecture as controls. Puberty initiation appears to be essential for increase of TBS with age and for sex differences. TBS seems less influenced by body composition, height, and mobility than aBMD. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Equivalence of entropy balancing and the method of moments for matching‐adjusted indirect comparison
Authors: Phillippo David M. , Dias Sofia , Ades A. E. , Welton Nicky J.
Published: May 2020

Indirect comparisons are used to obtain estimates of relative effectiveness between two treatments that have not been compared in the same randomized controlled trial, but have instead been compared against a common comparator in separate trials. Standard indirect comparisons use only aggregate data, under the assumption that there are no differences in effect‐modifying variables between the trial populations. Population‐adjusted indirect comparisons aim to relax this assumption by using individual patient data (IPD) from one trial to adjust for differences in effect modifiers between populations. At present, the most commonly used approach is matching‐adjusted indirect comparison (MAIC), where weights are estimated that match the covariate distributions of the reweighted IPD to the aggregate trial. MAIC was originally proposed using the method of moments to estimate the weights, but more recently entropy balancing has been proposed as an alternative. Entropy balancing has an additional “optimality” property ensuring that the weights are as uniform as possible, reducing the standard error of the estimates. In this brief method note, we show that MAIC weights are mathematically identical whether estimated using entropy balancing or the method of moments. Importantly, this means that the standard MAIC (based on the method of moments) also enjoys the “optimality” property. Moreover, the additional flexibility of entropy balancing suggests several interesting avenues for further research, such as combining population adjustment via MAIC with adjustments for treatment switching or nonparametric covariate adjustment.
Association of Cervical Spondylosis With Peripheral Vertigo: A Case–Control Study
Authors: Yang Tzong‐Hann , Xirasagar Sudha , Cheng Yen‐Fu , Kuo Nai‐Wen , Lin Herng‐Ching
Published: May 2020

Objectives/Hypothesis

This study aimed to assess the association of prior cervical spondylosis (CS) with peripheral vertigo.

Study Design

Case–control study.

Methods

Data were retrieved from the Taiwan Longitudinal Health Insurance Database. A total of 2,570 patients who were newly diagnosed with peripheral vertigo were identified. We compared them with a 3:1 ratio of propensity score–matched patients, 7,710 comparison patients from the same dataset. We performed multivariate logistic regressions to estimate the odds ratio for prior CS occurrence among peripheral vertigo patients versus controls.

Results

Of 10,280 sample patients, 1,739 (16.92%) patients had CS prior to the index date. A significant difference in prior CS between peripheral vertigo patients and controls (19.49% vs. 16.06%, P < .001) was observed. Logistic regression analysis shows that the odds of prior CS was 1.285 for peripheral vertigo patients versus controls (95% confidence interval [CI]: 1.143‐1.446) after adjusting for age, sex, urbanization level, monthly income, geographic region, hyperlipidemia, diabetes, coronary heart disease, hypertension, and asthma. Prior CS with myelopathy was not associated with peripheral vertigo. Stratified analysis by age showed that the odds of CS were highest among patients with peripheral vertigo in the 45‐ to 64‐year‐old age group (1.442, 95% CI: 1.215‐1.712).

Conclusions

CS is associated with subsequent peripheral vertigo in the Taiwan population, with higher risk among those aged 45 to 64 years.

Level of Evidence

2b Laryngoscope, 131:E625–E630, 2021
Prevalence and Impact of Restrictive Lung Disease in Liver Transplant Candidates
Authors: DuBrock Hilary M. , Krowka Michael J. , Krok Karen , Forde Kimberly , Mottram Carl , Scanlon Paul , Al‐Naamani Nadine , Patel Mamta , McCormick Amber , Fallon Michael B. , Kawut Steven M.
Published: May 2020

We investigated the prevalence of spirometric restriction in liver transplantation (LT) candidates and the clinical impacts of restriction. We performed a cross‐sectional study within the Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) study, a multicenter prospective cohort study of patients being evaluated for LT. Patients with obstructive lung disease or missing spirometry or chest imaging were excluded. Patients with and without restriction, defined as a forced vital capacity (FVC) <70% predicted, were compared. Restriction prevalence was 18.4% (63/343). Higher Model for End‐Stage Liver Disease–sodium score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02‐1.11; P = 0.007), the presence of pleural effusions (OR, 3.59; 95% CI, 1.96‐6.58; P < 0.001), and a history of ascites (OR, 2.59; 95% CI, 1.26‐5.33; P = 0.01) were associated with the presence of restriction, though one‐third with restriction had neither pleural effusions nor ascites. In multivariate analysis, restriction was significantly and independently associated with lower 6‐minute walk distances (least squares mean, 342.0 [95% CI, 316.6‐367.4] m versus 395.7 [95% CI, 381.2‐410.2] m; P < 0.001), dyspnea (OR, 2.69; 95% CI, 1.46‐4.95; P = 0.002), and lower physical component summary Short Form 36 scores indicating worse quality of life (least squares mean, 34.1 [95% CI, 31.5‐36.7] versus 38.2 [95% CI, 36.6‐39.7]; P = 0.004). Lower FVC percent predicted was associated with an increased risk of death (hazard ratio, 1.16; 95% CI, 1.04‐1.27 per 10‐point decrease in FVC percent predicted; P = 0.01). Restriction and abnormal lung function are common in LT candidates; can be present in the absence of an obvious cause, such as pleural effusions or ascites; and is associated with worse exercise capacity, quality of life, and survival.
Nutrient availability in tropical caves influences the dynamics of microbial biomass
Authors: Paula Caio César Pires de , Bichuette Maria Elina , Seleghim Mirna Helena Regali
Published: May 2020

Few studies have evaluated the trophic level in tropical caves, and none related the microbial biomass dynamics in the immobilization of carbon and nitrogen. Here, four tropical caves of Terra Ronca State Park, Brazil, were studied: Angélica, São Bernardo, Terra Ronca I, and Terra Ronca II caves. Physical, chemical, and microbiological parameters (microbial biomass and respiration) were estimated in the dry and wet seasons. São Bernardo, Terra Ronca I, and Terra Ronca II caves presented higher nitrogen and microbial biomass nitrogen (MBN) values in the wet season than in the dry season. On the other hand, the Angélica cave showed larger amounts of nitrogen and lower MBN values in the dry season. These results indicate that caves can be adjusted in two ecological theories known as “stoichiometric decomposition” and “microbial nitrogen mining”—to the effects of nutrient availability on organic matter decomposition. The caves studied showed different environmental dynamics in relation to organic matter decomposition, which allows them to be considered unique and possess specific characteristics. Microbial biomass dynamics can be an important parameter to evaluate the availability of nutrients and ecological dynamics of the trophic network in subterranean environments.
Ropinirole Patch Versus Placebo, Ropinirole Extended‐Release Tablet in Advanced Parkinson's Disease
Authors: Hattori Nobutaka , Mochizuki Hideki , Hasegawa Kazuko , Nomoto Masahiro , Uchida Eiji , Terahara Takaaki , Okawa Koji , Fukuta Hiroyuki
Published: May 2020

Background

A dopamine agonist patch is an important treatment option for PD.

Objectives

A randomized, double‐blind, parallel‐group, placebo‐controlled trial was conducted to evaluate superiority of ropinirole hydrochloride patch over placebo and noninferiority to ropinirole hydrochloride extended‐release tablet.

Methods

PD patients using levodopa received ropinirole patch (up to 64 mg/d), ropinirole tablets (up to 16 mg/d), or placebo once‐daily (double‐dummy technique). The primary endpoint was the change from baseline in the total score for the UPDRS Part III (on state) at week 16.

Results

The change of the least squares mean (95% confidence interval) in the UPDRS Part III total score was –9.8 (–10.8 to –8.7) with ropinirole patch, –4.3 (–5.8 to –2.8) with placebo, and –10.1 (–11.2 to –9.1) with ropinirole tablet. The difference between the ropinirole patch and placebo groups was –5.4 (–7.3 to –3.6), demonstrating superiority of the patch over placebo. The difference between the ropinirole patch and tablet groups was 0.3 (–1.2 to 1.8). The upper limit of the 95% confidence interval was smaller than the noninferiority limit of 2.5, demonstrating noninferiority of ropinirole patch to ropinirole tablet. In all three groups, most adverse events were mild or moderate and there were no serious safety concerns.

Conclusions

Once‐daily ropinirole patch was effective in advanced PD patients, having demonstrated superiority over placebo and noninferiority to ropinirole tablet, without causing serious safety problems. Ropinirole patch can be an alternative option for PD patients. © 2020 International Parkinson and Movement Disorder Society