bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mesoproterozoic Baoban Complex, South China: A missing fragment of western Laurentian lithosphere
Authors: Xu Ya-Jun , Cawood Peter A. , Zhang Hang-Chuan , Zi Jian-Wei , Zhou Jin-Bo , Li Li-Xing , Du Yuan-Sheng
Published: November 2019

New age data for the Baoban Complex, South China establishes that it lay outboard of western Laurentia in the early Mesoproterozoic but was not part of the Cathaysia Block, with which it is traditional linked, until the mid-Paleozoic. Our geochronology data for detrital zircon and authigenic monazite grains from metasedimentary rocks indicate accumulation between ca. 1.55 Ga and 1.45 Ga for the Gezhencun succession of the Baoban Complex and ca. 1.45 Ga and 1.30 Ga for the Ewenling succession. The former unit is dominated by detrital zircon populations between 1900 Ma and 1500 Ma with two peaks at 1780 Ma and 1580 Ma. The Ewenling succession has detrital zircon peaks at 1720 Ma and 1450 Ma. Newly discovered gneissic granites were emplaced at 1550 Ma and intruded by 1450 Ma leucogranite dykes that are coeval with 1460–1430 Ma bimodal magmatism. The whole Baoban Complex was metamorphosed over the range of 1.3–0.9 Ga based on ages of authigenic zircon and monazite.

Depositional ages of metasedimentary rocks are coeval with successions of the Belt-Purcell Basin, western Laurentia. Detrital zircon from the two regions have similar age populations and Lu-Hf compositions, and display a synchronous provenance shift at ca. 1.45 Ga. Basement lithologies on Hainan Island range in age from ca. 1.55–1.43 Ga and underwent metamorphism during 1.3–0.9 Ga. This is younger than basement rocks on the mainland of the Cathaysia Block in South China, suggesting the two regions are spatially unrelated at this time and hence the Mesoproterozoic record of the island cannot constrain the location of the Cathaysia Block in the Nuna and Rodinia supercontinents.
Contribution to differential diagnosis of sarcoidosis and disseminated tuberculosis
Authors: Hansen Kamille Carstens , Jensen-Fangel Søren , Hønge Bo Langhoff
Published: November 2019

A previously healthy 54-year-old ethnically Danish man was referred to the Department of Infectious Diseases at Aarhus University Hospital after an unexpected detection ofMycobacterium tuberculosisDNA in his lungs. Further examination revealed widespread dissemination of the tuberculosis (TB) to brain, mastoid, urinary and gastrointestinal tract. Thirteen months earlier, the patient was orchiectomised due to recurring inflammation of the right testicle. Three and a half months prior to admission to our department the patient started immunosuppressive therapy with steroids due to radiological and histological findings in the lungs that were interpreted as sarcoidosis (SA). This treatment is likely to be co-responsible for the pronounced dissemination of the TB. The patient was Bacillus Calmette-Guérin (BCG)-vaccinated as a child and had no apparent risk factors for TB apart from travelling in TB-endemic countries until 10 years before falling ill. Screening for latent TB was not performed prior to starting steroid treatment.
Internet based vestibular rehabilitation with and without physiotherapy support for adults aged 50 and older with a chronic vestibular syndrome in general practice: three armed randomised controlled trial
Authors: van Vugt Vincent A , van der Wouden Johannes C , Essery Rosie , Yardley Lucy , Twisk Jos W R , van der Horst Henriëtte E , Maarsingh Otto R
Published: November 2019

Objective

To investigate the clinical effectiveness and safety of stand alone and blended internet based vestibular rehabilitation (VR) in the management of chronic vestibular syndromes in general practice.

Design

Pragmatic, three armed, parallel group, individually randomised controlled trial.

Setting

59 general practices in the Netherlands.

Participants

322 adults aged 50 and older with a chronic vestibular syndrome.

Interventions

Stand alone VR comprising a six week, internet based intervention with weekly online sessions and daily exercises (10-20 minutes a day). In the blended VR group, the same internet based intervention was supplemented by face-to-face physiotherapy support (home visits in weeks 1 and 3). Participants in the usual care group received standard care from a general practitioner, without any restrictions.

Main outcome measures

The primary outcome was vestibular symptoms after six months as measured by the vertigo symptom scale-short form (VSS-SF range 0-60, clinically relevant difference ≥3 points). Secondary outcomes were dizziness related impairment, anxiety, depressive symptoms, subjective improvement of vestibular symptoms after three and six months, and adverse events.

Results

In the intention-to-treat analysis, participants in the stand alone and blended VR groups had lower VSS-SF scores at six months than participants in the usual care group (adjusted mean difference −4.1 points, 95% confidence interval −5.8 to −2.5; and −3.5 points, −5.1 to −1.9, respectively). Similar differences in VSS-SF scores were seen at three months follow-up. Participants in the stand alone and blended VR groups also experienced less dizziness related impairment, less anxiety, and more subjective improvement of vestibular symptoms at three and six months. No serious adverse events related to online VR occurred during the trial.

Conclusion

Stand alone and blended internet based VR are clinically effective and safe interventions to treat adults aged 50 and older with a chronic vestibular syndrome. Online VR is an easily accessible form of treatment, with the potential to improve care for an undertreated group of patients in general practice.

Trial registration

Netherlands Trial Register NTR5712.
Emerging role of clinical mass spectrometry in pathology
Authors: Fung Angela W.S. , Sugumar Vijithan , Ren Annie He , Kulasingam Vathany
Published: November 2019

Mass spectrometry-based assays have been increasingly implemented in various disciplines in clinical diagnostic laboratories for their combined advantages in multiplexing capacity and high analytical specificity and sensitivity. It is now routinely used in areas including reference methods development, therapeutic drug monitoring, toxicology, endocrinology, paediatrics, immunology and microbiology to identify and quantify biomolecules in a variety of biological specimens. As new ionisation methods, instrumentation and techniques are continuously being improved and developed, novel mass spectrometry-based clinical applications will emerge for areas such as proteomics, metabolomics, haematology and anatomical pathology. This review will summarise the general principles of mass spectrometry and specifically highlight current and future clinical applications in anatomical pathology.
Equality of opportunity is linked to lower mortality in Europe
Authors: Gugushvili Alexi , Kaiser Caspar
Published: November 2019

Background

This study investigates if intergenerational equality of opportunity is linked to mortality in 30 European countries. Equality of opportunity may lead to greater returns on health investments and, consequently, improved health outcomes. In turn, a perceived lack of fairness in the distribution of life chances and limited possibilities for upward intergenerational mobility can cause anxiety among individuals and gradually compromise their health.

Methods

We used information on 163 467 individuals’ and their parents’ Socio-Economic Index of Occupational Status from a large survey data set—the European Social Survey—to generate three complementary measures of equality of opportunity. We then linked these to administrative data on total, gender-specific and cause-specific mortality rates assembled by Eurostat from the national statistical offices.

Results

We found that lower equality of opportunity, measured by the attainment of individuals from the lowest and highest quartiles of socioeconomic status and by the overall intergenerational correlation in socioeconomic status, was related to higher mortality rates, particularly in relation to diseases of the nervous system and the sense organs, diseases of the respiratory system and external causes of mortality. Our measures of equality of opportunity were more consistently linked with mortality of men than women.

Conclusion

Equality of opportunity may be an important explanation of mortality that warrants further research. Measures that aim at facilitating intergenerational social mobility can be justified not only via normative considerations of equality of opportunity but also in terms of individuals’ chances to enjoy healthy lives.
Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice
Authors: McCann Emily P , Fifita Jennifer A , Grima Natalie , Galper Jasmin , Mehta Prachi , Freckleton Sarah E , Zhang Katharine Y , Henden Lyndal , Hogan Alison L , Chan Moi Fat Sandrine , Wu Sharlynn SL , Jagaraj Cyril J , Berning Britt A , Williams Kelly Louise , Twine Natalie A , Bauer Denis , Piguet Olivier , Hodges John , Kwok John B J , Halliday Glenda M , Kiernan Matthew C , Atkin Julie , Rowe Dominic B , Nicholson Garth A , Walker Adam K , Blair Ian P , Yang Shu
Published: November 2019

Objective

Since the first report ofCHCHD10gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation inCHCHD10has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia.

Methods

Whole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation inCHCHD10. CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology.

Results

No causal, novel or disease-associated variants inCHCHD10were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease.

Conclusions

Genetic variation inCHCHD10is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.
Presumptive antibiotics in tube thoracostomy for traumatic hemopneumothorax: a prospective, Multicenter American Association for the Surgery of Trauma Study
Authors: Cook Alan , Hu Chengcheng , Ward Jeanette , Schultz Susan , Moore III Forrest O"Dell , Funk Geoffrey , Juern Jeremy , Turay David , Ahmad Salman , Pieri Paola , Allen Steven , Berne John
Published: November 2019

Background

Thoracic injuries are common in trauma. Approximately one-third will develop a pneumothorax, hemothorax, or hemopneumothorax (HPTX), usually with concomitant rib fractures. Tube thoracostomy (TT) is the standard of care for these conditions, though TTs expose the patient to the risk of infectious complications. The controversy regarding antibiotic prophylaxis at the time of TT placement remains unresolved. This multicenter study sought to reconcile divergent evidence regarding the effectiveness of antibiotics given as prophylaxis with TT placement.

Methods

The primary outcome measures of in-hospital empyema and pneumonia were evaluated in this prospective, observational, and American Association for the Surgery of Trauma multicenter study. Patients were grouped according to treatment status (ABX and NoABX). A 1:1 nearest neighbor method matched the ABX patients with NoABX controls. Multilevel models with random effects for matched pairs and trauma centers were fit for binary and count outcomes using logistic and negative binomial regression models, respectively.

Results

TTs for HPTX were placed in 1887 patients among 23 trauma centers. The ABX and NoABX groups accounted for 14% and 86% of the patients, respectively. Cefazolin was the most frequent of 14 antibiotics prescribed. No difference in the incidence of pneumonia and empyema was observed between groups (2.2% vs 1.5%, p=0.75). Antibiotic treatment demonstrated a positive but non-significant association with risk of pneumonia (OR 1.61; 95% CI: 0.86~3.03; p=0.14) or empyema (OR 1.51; 95% CI: 0.42~5.42; p=0.53).

Conclusion

There is no evidence to support the routine use of presumptive antibiotics for post-traumatic TT to decrease the incidence of pneumonia or empyema. More investigation is necessary to balance optimal patient outcomes and antibiotic stewardship.

Level of evidence

II Prospective comparative study
Constraints on barotropic dark energy models by a new phenomenological q(z) parameterization
Authors: Román-Garza Jaime , Verdugo Tomás , Magaña Juan , Motta Verónica
Published: November 2019

In this paper, we propose a new phenomenological two parameter parameterization of q(z) to constrain barotropic dark energy models by considering a spatially flat Universe, neglecting the radiation component, and reconstructing the effective equation of state (EoS). This two free-parameter EoS reconstruction shows a non-monotonic behavior, pointing to a more general fitting for the scalar field models, like thawing and freezing models. We constrain the q(z) free parameters using the observational data of the Hubble parameter obtained from cosmic chronometers, the joint-light-analysis Type Ia Supernovae (SNIa) sample, the Pantheon (SNIa) sample, and a joint analysis from these data. We obtain, for the joint analysis with the Pantheon (SNIa) sample a value of q(z) today, $$q_0=-0.51\begin{array}{c} +0.09 \\ -0.10 \end{array}$$q0=-0.51+0.09-0.10, and a transition redshift, $$z_t=0.65\begin{array}{c} +0.19 \\ -0.17 \end{array}$$zt=0.65+0.19-0.17 (when the Universe change from an decelerated phase to an accelerated one). The effective EoS reconstruction and the $$\omega '$$ω′–$$\omega $$ω plane analysis point towards a transition over the phantom divide, i.e. $$\omega =-1$$ω=-1, which is consistent with a non parametric EoS reconstruction reported by other authors.
FRACTAL STOKES’ THEOREM BASED ON INTEGRALS ON FRACTAL MANIFOLDS
Authors: WU JUNRU , WANG CHENGYUAN
Published: November 2019

In this paper, with the Hausdorff measure, the Hausdorff integral on fractal sets with one or lower dimension is firstly introduced via measure theory. Then the definition of the integral on fractal sets in [Formula: see text] is given. With the variable substitution theorem in the Riemann integral generalized to the integral on fractal sets, the integral on fractal manifolds is defined. As a result, with the generalization of Gauss’ theorem, Stokes’ theorem is generalized to the integral on fractal manifolds in [Formula: see text].
ANALYTICAL SOLUTIONS FOR PERMEABILITY OF A THREE-DIMENSIONAL FRACTAL-LIKE TREE NETWORK MODEL WITH FRACTURES HAVING VARIABLE WIDTHS
Authors: LIU RICHENG , YU LIYUAN , GAO YANG , HE MING , JIANG YUJING
Published: November 2019

This study proposed analytical solutions for permeability of a fractal-like tree network model with fractures having variable widths, which has not been reported before, if any. This model is more realistic with natural fracture networks than the traditional constant width fracture network models. The results show that considering fracture width variations decreases the permeability. Taking the fracture width ratio that equals to 0.6 and the total number of branching levels that equals to 30 as an example, the permeability decreases by more than three orders of magnitude with respect to that of a constant width fracture network model. The fracture length ratio plays a more significant role in permeability when it is larger than 0.8 than that is less than 0.8. The permeability is more sensitive to the fracture aperture ratio that is less than 0.8. When the total number of branching levels is large (i.e. 30), the permeability changes significantly (i.e. more than three orders of magnitude); whereas when the total number of branching levels is small (i.e. 5), the permeability varies in a small range (i.e. less than one order of magnitude). When taking into account the relationships among fracture length ratio, fracture aperture ratio and fracture width ratio, the parameters can be easily obtained and analytical solutions for permeability can also be easily derived. The empirical function for predicting critical hydraulic gradient is proposed, which can be used to estimate whether the fluid flow is within the linear flow regime and whether the proposed analytical solutions are applicable in the present study.
COMPLEXITY-BASED ANALYSIS OF THE RELATION BETWEEN TOOL WEAR AND MACHINE VIBRATION IN TURNING OPERATION
Authors: KIEW CHAI LIP , BRAHMANANDA AKSHAYEN , ISLAM KH. TAUHID , LEE HAO NAM , VENIER SAMUEL ANTHONY , SARAAR ASHIR , NAMAZI HAMIDREZA
Published: November 2019

Tool wear is an important issue that happens in all machining operations when the tool exerts forces on the workpiece. Therefore, engineers should choose the optimum values for machining parameters and conditions to reduce the amount of tool wear and increase its life. Machine vibration is one of the factors that highly affects tool wear. Since both tool wear and machine vibration signal have complex structures, in this research we employ fractal theory to find out their relation. In this paper, we analyze the relation between tool wear and machine vibration signal in different experiments where the depth of cut, feed rate and spindle speed change. The obtained results showed that tool wear and machine vibration signal are related to each other in case of variations of depth of cut and feed rate in different experiments, where both fractal structures get more complex by the increment of these machining parameters. The obtained method of analysis in this research can be potentially applied to other machining operations in order to link the machine vibration to the structure of tool wear.
ANALYSIS OF THE RELATION BETWEEN FRACTAL STRUCTURES OF MACHINED SURFACE AND MACHINE VIBRATION SIGNAL IN TURNING OPERATION
Authors: KIEW CHAI LIP , BRAHMANANDA AKSHAYEN , ISLAM KH. TAUHID , LEE HAO NAM , VENIER SAMUEL ANTHONY , SARAAR ASHIR , NAMAZI HAMIDREZA
Published: November 2019

Investigating about the machined surface is an important issue in every machining operation. One of the factors that affect the quality of machined surface is the vibration of machine that is caused by different parameters such as the spindle speed. Therefore, the analysis of the relation between the machine vibration and surface quality of machined surface is very important. In this research, we analyze the relation between the machined surface and machine vibration from the complexity point of view. For this purpose, we employ fractal analysis. We investigate the variations of fractal structure of vibration signal collected from lathe machine versus the variations of fractal structure of the machined surface, for different depths of cut, feed rates and spindle speeds. Based on the obtained results, the variations of fractal structures of machined surface and vibration signal show a similar trend with the variations of depth of cut and feed rate, where by the increment of depth of cut and feed rate, vibration signal and machined surface get more complex. However, the obtained results in the case of variation of spindle speed do not show a consistent trend between variations of fractal structures of vibration signal and machined workpiece. The obtained method in this research can be applied to other machining operations in order to analyze the relation between the complexities of machine vibration and machined surface.
NUMERICAL INVESTIGATION OF THREE-DIMENSIONAL HAUSDORFF DERIVATIVE ANOMALOUS DIFFUSION MODEL
Authors: CAI WEI , WANG FAJIE
Published: November 2019

The Hausdorff derivative has been recognized as an efficient tool to characterize anomalous diffusion phenomena. This paper makes the first attempt to numerically investigate three-dimensional Hausdorff derivative diffusion equation by the method of fundamental solutions. The fundamental solution of the three-dimensional Hausdorff derivative diffusion equation is closely related to scaling transform and non-Euclidean Hausdorff fractal distance. The used method, as a meshless technique, is simple, accurate and efficient for solving the partial differential equations with fundamental solutions. Three numerical experiments have been conducted to reveal the effectiveness and rationality of Hausdorff derivative anomalous diffusion models with various temporal and spatial fractal orders, as well as the accuracy of the developed methodology.
Use and misuse of electrochemical impedance spectroscopy in PEFC research
Authors: Boillat Pierre , Gubler Lorenz , Büchi Felix N. , Schmidt Thomas J.
Published: November 2019

In this presentation, two important pitfalls ocuring during the analysis of electrochemical impedance spectra (EIS) of polymer electrolyte fuel cells (PEFCs) are discussed. Based on very simple considerations, some commonly found interpretation statements are identified as wrong. A comprehensive review of the papers published during the year 2018 using EIS in PEFC research show that such wrong statements are not occasional, but frequently occurring in the peer reviewed literature. At the end of the presentation, solution are proposed to increase the awareness to the risks of wrong EIS interpretations.
The gut microbiota is a major regulator of androgen metabolism in intestinal contents
Authors: Colldén Hannah , Landin Andreas , Wallenius Ville , Elebring Erik , Fändriks Lars , Nilsson Maria E. , Ryberg Henrik , Poutanen Matti , Sjögren Klara , Vandenput Liesbeth , Ohlsson Claes
Published: November 2019

Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.
Preparation of Superhydrophobic Multiscale Films for Oil-Water Separation in a Harsh Environment
Authors: Li Depeng , Fan Jinyang , Chen Jie , Jiang Deyi
Published: November 2019

The problem of oil-water separation regarding oil-containing brine has been of much concern when using the oil pad water dissolution method to construct salt cavern reservoirs. In this paper, oil-water separation materials with micro-nano hierarchical structure were prepared on different metal substrates using chemical etching and electrophoretic deposition. And hydrophobic materials with a single micro/nano structure were also prepared; then, the surfaces were hydrophobized by various low surface energy modifiers. Thereafter, we analyzed and compared the surface morphology, chemical composition, and wettability of all the materials and found that brine contact angles on hierarchical structure surfaces were above 160° while the diesel was completely diffused. Furthermore, preparation parameters affecting the surface morphology and wettability of micro-nano composite structures were explored. Meanwhile, it was found that the surface of prepared composite structure could still maintain super-hydrophobic/lipophilic properties after exposure in air for 6 months, sliding 60 cm on sandpaper, or immersion in diesel/brine for 48 h. Moreover, the composite structure surface displayed improved corrosion resistance with corrected self-corrosion potential and lower corrosion current density. It was equally observed that the studied materials could be better adapted to the actual context of salt cavern reservoir construction and thus have great application prospects.
Superparamagnetic Clustering of Diabetes Patients Raman Spectra
Authors: González-Solís J. L. , Torres-González L. A. , Villafán-Bernal J. R.
Published: November 2019

In this paper, we present a different way to the standard methods to classify Raman spectra whose grouping process is based on a phenomenon of clustering observed in nature at the atomic level and correctly described by the statistical physics model known as the Potts model, which represents the interacting spins on a crystalline lattice. This clustering method is known as the super paramagnetic clustering (SPC), which allows identifying hierarchical structures in data banks. In this novel method, we assigned a Potts spin to each data point (Raman spectrum) and introduced an interaction between neighboring points whose coupling strength is a decreasing function of the distance between the nearest neighboring sites. We found a hierarchical tree structure in our data bank of Raman spectra allowing us to discriminate between the spectra from control and diabetes patients. The sensitivity and specificity of the diabetes detection technique by Raman spectroscopy were calculated directly because the SPC method achieves an accurate determination of the members of each cluster. As a cross-check, SPC results were compared with published results of multivariate analysis, observing excellent agreements; however, the SPC method allows determining the members of all identified clusters explicitly.
Identifying Mutually Exclusive Gene Sets with Prognostic Value and Novel Potential Driver Genes in Patients with Glioblastoma
Authors: Gao Qian , Cui Yan , Shen Yanan , Li Yanyan , Gao Xue , Xi Yanfeng , Wang Tong
Published: November 2019

The pathogenesis and prognosis of glioblastoma (GBM) remain poorly understood. Mutual exclusivity analysis can distinguish driver genes and pathways from passenger ones. The purpose of this study was to identify mutually exclusive gene sets (MEGSs) that have prognostic value and to detect novel driver genes in GBM. The genomic alteration profile and clinical information were derived from The Cancer Genome Atlas, and the MEGSA method was used to identify the MEGS. Next, we performed survival analysis and constructed a risk prediction model for prognostic stratification. Leave-one-out cross-validation and permutation test were used to evaluate its performance. Finally, we identified 21 statistically significant MEGSs. We found that the MEGS in the RB pathway was significantly associated with poor prognosis, after adjusting for age and gender (HR = 1.837, 95% CI: 1.192–2.831). Based on the risk prediction model, 208 (80.9%) and 49 (19.1%) patients were assigned to high- and low-risk groups, respectively (log-rank: p<0.001, adjusted p=0.001). Additionally, we found that SPTA1, a novel gene involved in the MEGS, was mutually exclusive with members of cell cycle, P53, and RB pathways. In conclusion, the MEGS in the RB pathway had considerable clinical value for GBM prognostic stratification. Mutated SPTA1 may be involved in GBM development.
Shaking Table Tests on Sliding Displacements of Loess Slope under Coupling Effect of Rainfall and Earthquake
Authors: Yin Xiaojun , Wang Lanmin
Published: November 2019

Shaking table tests were performed to investigate whether the coupling effect of rainfall and earthquake induces the loess slope instability. The loess slope model was made by using the similarity ratio based on a real slope. Artificial rainfall was carried out, and then seismic waves were loaded step by step to adopt a large shaking table of 4∗6 m. The displacement in x, y, and z directions and absolute displacement of loess slope (ux, uy, uz, and ua) were measured to use the XTDIC displacement test system in 50 s when the seismic waves at peak acceleration were loaded to 600 gal, 700 gal, 800 gal, 976 gal, and 1300 gal, respectively. The results showed that the acceleration of one point was much larger than the other. ua occurred when seismic waves were loaded to 700 gal, and uamax was obtained when seismic waves were loaded to 1300 gal finally. The umax would reach in 20∼25 s, which was the period of amplitude peak. The theoretical value was larger than the test value for the critical seismic acceleration coefficient. Loess liquefaction appeared along the slope top under 976 gal loading condition. The change of displacement in y direction is the main reason for the curve trajectory of the sliding block, and the displacement differences of adjacent measuring points are the main reason for the formation of the sliding block. This study can provide a theoretical basis for loess slope design and risk management.
Successful Use of Ertapenem for the Treatment of Enterobacter cloacae Complex Infection of the Central Nervous System (CNS)
Authors: Shah Sunish , McManus Dayna , Topal Jeffrey E.
Published: November 2019

A 55-year-old female with a past medical history of cocaine use and hypertension was admitted for intracranial hemorrhage requiring right decompressive craniotomy with duraplasty. Due to persistent fevers, a head CT scan obtained on day 28 of hospitalization identified a low-density subgaleal fluid collection overlying the duraplasty. Aspiration of this collection was sent for culture which grew 2+ Enterobacter cloacae complex susceptible to sulfamethoxazole-trimethoprim (SMX-TMP), gentamicin, ciprofloxacin, and ertapenem. Based on these results, the patient was transitioned from empiric vancomycin and ceftazidime to SMX-TMP and metronidazole. Despite treatment with SMX-TMP and metronidazole, aspirated subgaleal collection cultures remained positive for E. cloacae. Intrathecal gentamicin was therefore added; however, repeat subgaleal culture collections remained persistently positive. Given the persistently positive subgaleal culture collections, the patient was transitioned from SMX-TMP and metronidazole to ertapenem. After transition to ertapenem, subgaleal cultures were sterilized and the patient’s infection was resolved. This report suggests ertapenem may be a viable option for central nervous system infections; however, further study is needed.
Aseptic Meningitis as an Immune-Related Adverse Event after Pembrolizumab
Authors: Lima Gian , Kahn Adriana , Sama Shashank , Savage Jacqueline
Published: November 2019

Introduction. The management of patients with advanced malignancies is challenging, although recent advances with immunotherapy have shown better outcomes. Pembrolizumab has been associated with a variety of immune-related side effects, but the occurrence of aseptic meningitis is rare. Case. A 55-year-old male with a history of metastatic lung adenocarcinoma previously treated with pembrolizumab presented with persistent severe headaches and photophobia. Subsequent workup with cerebrospinal fluid analysis showed elevated opening pressure, increased nucleated cells with 30% lymphocytes, elevated protein levels, and normal glucose levels. The patient was started on high doses of IV steroids and progressed with significant improvement of his symptoms. Discussion. Given the rarity of this side effect, this case is a reminder that immune checkpoint inhibitors can cause aseptic meningitis and its early recognition is important for initiation of therapy with steroids and prompt discontinuation of the immunotherapy agent.
Association between MicroRNA-4669 Polymorphism and Ischemic Stroke in a Korean Population
Authors: Hong Seoung-Jin , Kim Su Kang , Yun Dong Hwan , Chon Jinmann , Park Hae Jeong
Published: November 2019

Recent studies have explored the association between single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) and ischemic stroke (IS). In particular, the associations of rs2910164 (miRNA-146A), rs11614913 (miRNA-196A2), and rs3746444 (miRNA-499A) were intensively studied in IS. In this study, we investigated the associations between SNPs in miRNAs and IS including rs2910164, rs11614913, and rs3746444 in a Korean population. For a pilot study, we selected 19 SNPs in pre-miRNA region (including mature miRNA region) and genotyped in 140 IS patients and 240 control subjects using the Fluidigm Dynamic Array. Our pilot study showed a weak association of rs79402775 in miRNA-933 (p=0.044) and a relatively strong association of rs35196866 in miRNA-4669 (p=0.016) with IS. From the pilot study, we selected rs79402775, rs35196866, and rs7202008 (miRNA-2117; p=0.055) as candidate miRNA SNPs on IS and further genotyped these SNPs in 264 IS patients and 455 control subjects using direct sequencing. In addition, we further analyzed the associations of rs2910164, rs11614913, and rs3746444 that have been intensively studied in previous studies. In the further analysis, we found the significant association between rs35196866 and IS (p=0.0014 in additive model and p=0.00015 in dominant model; p=0.00037 in allele frequency analysis). However, the association between rs2910164, rs11614913, rs3746444, rs79402775, and rs7202008 and IS was not shown. These results suggest that miRNA-4669 may be involved in the susceptibility of IS.
Does Tumour Contrast Retention on CT Immediately Post Chemoembolization Predict Tumour Metabolic Response on FDG-PET in Patients with Hepatic Metastases from Colorectal Cancer?
Authors: Tan K. T. , Rakheja R. , Plewes C. , Mondal P. , Lim H. , Ahmed S. , Lee E. , Otani R. , Luo Y. , Shaw J.
Published: November 2019

Purpose. The exact mechanism of action of chemoembolization with drug eluting beads loaded with irinotecan (DEBIRI) in colorectal cancer is undetermined. Posttreatment tumour contrast retention often seen on CT immediately post procedure is of indeterminate significance. This study is aimed at assessing if metabolic response on PET-CT can be related to posttreatment tumour contrast retention. Materials and Methods. In this retrospective study, a total of 17 patients with a total of 55 marker lesions were recruited. Results. The area of tumour contrast retention can be matched to a hypometabolic area on subsequent PET-CT in over 36 lesions (65.5%). Out of the 55 lesions, a total of 38 marker lesions in 11 patients who also had pre-DEBIRI PET-CT were analyzed for disease response. 10 out of 10 lesions that had a complete response on PET-CT were found to demonstrate contrast retention throughout the tumour. 12 out of 13 (92.3%) tumours that had a partial metabolic response on PET-CT were found to demonstrate contrast uptake in the hypometabolic area only. In the 15 lesions that had progression/no response, 13 (86.6%) demonstrated no relationship between tumour contrast retention and tumour response. There was a significant correlation between contrast retention and disease response (P<0.001). Conclusion. Our study showed that PET-CT response can be associated with post embolization contrast retention. The data suggests blood stasis, for which tumour contrast retention is a surrogate marker, is important for the PET-CT metabolic response. The authors propose that tumour contrast retention is an important embolization endpoint in DEBIRI.
Adipose-Derived Mesenchymal Stem Cells Promote M2 Macrophage Phenotype through Exosomes
Authors: Heo June Seok , Choi Youjeong , Kim Hyun Ok
Published: November 2019

Accumulating evidence has shown that the paracrine factors derived from mesenchymal stem cells (MSCs) are capable of regulating the immune system via interaction with various immune cells. In this study, adipose-derived MSCs (AdMSCs) and human peripheral blood monocytes (PBMCs) were isolated and cultured to examine the effects of MSC-induced macrophages (iMΦ) on inflammation and immune modulation. Indirect coculture with MSCs increased the expression of arginase-1 and mannose receptor (CD206), markers of activated M2 macrophages, in the PBMCs demonstrating that MSC-secreted factors promoted M2-MΦ polarization. Additionally, iMΦ exhibited a similar higher inhibitory effect on the growth of activated T cells compared to that in the other groups (AdMSCs only, AdMSCs plus iMΦ), implying that iMΦ can play a sufficient functional role. Interestingly, the population of FoxP3 Treg cells significantly increased when cocultured with iMΦ, suggesting that iMΦ have an immunomodulatory effect on the Treg cells through the modulation of the FoxP3 expression. Notably, iMΦ expressed high levels of immunosuppressive and anti-inflammatory cytokines, namely IL-10 and TSG-6. Furthermore, we confirmed that the AdMSC-derived exosomes modulated macrophage polarization by upregulating the expression of M2 macrophage markers. Conclusively, our results suggest that iMΦ play a significant role in regulating the immunomodulatory- and inflammatory-mediated responses. Thus, iMΦ may be used as a novel stem cell-based cell-free therapy for the treatment of immune-mediated inflammatory disorders.
Immune Checkpoint Inhibitor Induced Diabetes Mellitus Treated with Insulin and Metformin: Evolution of Diabetes Management in the Era of Immunotherapy
Authors: Alrifai Taha , Ali Faisal Shaukat , Saleem Sameer , Ruiz Diana Carolina Miranda , Rifai Dana , Younas Sundas , Qureshi Faisal
Published: November 2019

Immune checkpoint inhibitors (ICPIs) are a breakthrough therapy in oncology and have been approved by the Food and Drug Administration for the treatment of several malignancies. ICPIs have been reported to cause immune-mediated damage of islet cells leading to ICPI-induced type 1 diabetes mellitus (T1DM). These reports described patients presenting with severe diabetic ketoacidosis (DKA). We present a case of a 69-year-old Caucasian male with type 2 diabetes suffering from non-small cell lung cancer and undergoing treatment with pembrolizumab, an anti-programmed cell death protein-1 antibody, who presented to our emergency department with complaints of nausea, vomiting, polyuria, and polydipsia. He was found to have high anion gap metabolic acidosis with ketosis and elevated blood glucose levels consistent with DKA. Lab workup was consistent with T1DM. Despite being on a tailored insulin regimen, his blood glucose remained elevated, necessitating the addition of metformin to his regimen which effectively controlled his blood glucose.
Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Authors: Gale Molly , Li Yao , Cao Jian , Liu Zongzhi Z. , Holmbeck Marissa A. , Zhang Meiling , Lang Sabine M. , Wu Lizhen , Do Carmo Mariana , Gupta Swati , Aoshima Keisuke , DiGiovanna Michael P. , Stern David F. , Rimm David L. , Shadel Gerald S. , Chen Xiang , Yan Qin
Published: November 2019

Acquired resistance to HER2-targeted therapies occurs frequently in HER2+ breast tumors and new strategies for overcoming resistance are needed. Here, we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function. Resistant cells were sensitive to inhibition of ATP synthase by oligomycin A, and knockdown of ATP5J or ATP5B, components of ATP synthase complex, rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin A with trastuzumab led to regression of trastuzumab-resistant tumors in vivo. In conclusion, we identify a novel vulnerability of cells with acquired resistance to HER2-targeted antibody therapies and reveal a new therapeutic strategy to overcome resistance.

Significance:

These findings implicate ATP synthase as a novel potential target for tumors resistant to HER2-targeted therapies.
Heparanase and Chemotherapy Synergize to Drive Macrophage Activation and Enhance Tumor Growth
Authors: Bhattacharya Udayan , Gutter-Kapon Lilach , Kan Tal , Boyango Ilanit , Barash Uri , Yang Shi-Ming , Liu JingJing , Gross-Cohen Miriam , Sanderson Ralph D. , Shaked Yuval , Ilan Neta , Vlodavsky Israel
Published: November 2019

The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized, encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here, we focused on the cross-talk between macrophages, chemotherapy, and heparanase and the combined effect on tumor progression. Macrophages were markedly activated by chemotherapeutics paclitaxel and cisplatin, evidenced by increased expression of proinflammatory cytokines, supporting recent studies indicating that chemotherapy may promote rather than suppress tumor regrowth and spread. Strikingly, cytokine induction by chemotherapy was not observed in macrophages isolated from heparanase-knockout mice, suggesting macrophage activation by chemotherapy is heparanase dependent. paclitaxel-treated macrophages enhanced the growth of Lewis lung carcinoma tumors that was attenuated by a CXCR2 inhibitor. Mechanistically, paclitaxel and cisplatin activated methylation of histone H3 on lysine 4 (H3K4) in wild-type but not in heparanase-knockout macrophages. Furthermore, the H3K4 presenter WDR5 functioned as a molecular determinant that mediated cytokine induction by paclitaxel. This epigenetic, heparanase-dependent host-response mechanism adds a new perspective to the tumor-promoting functions of chemotherapy, and offers new treatment modalities to optimize chemotherapeutics.

Significance:

Chemotherapy-treated macrophages are activated to produce proinflammatory cytokines, which are blunted in the absence of heparanase.
IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition
Authors: Treffers Louise W. , ten Broeke Toine , Rösner Thies , Jansen J.H. Marco , van Houdt Michel , Kahle Steffen , Schornagel Karin , Verkuijlen Paul J.J.H. , Prins Jan M. , Franke Katka , Kuijpers Taco W. , van den Berg Timo K. , Valerius Thomas , Leusen Jeanette H.W. , Matlung Hanke L.
Published: November 2019

Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen–targeting mAbs is mediated—at least partially—by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPα. We and others have previously demonstrated that inhibiting CD47–SIRPα interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies both in vivo and in vitro. IgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47–SIRPα on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47–SIRPα interactions further enhances destruction of IgA antibody–opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPα inhibition proved to be effective in eradicating cancer cells in vivo. In a syngeneic in vivo model, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPα blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47–SIRPα checkpoint inhibition. These findings provide a basis for targeting CD47–SIRPα interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients.
Sphingosine-1-Phosphate Receptor Modulator, FTY720, Improves Diastolic Dysfunction and Partially Reverses Atrial Remodeling in a Tm-E180G Mouse Model Linked to Hypertrophic Cardiomyopathy
Authors: Ryba David M. , Warren Chad M. , Karam Chehade N. , Davis Robert T. , Chowdhury Shamim A.K. , Alvarez Manuel G. , McCann Maximilian , Liew Chong Wee , Wieczorek David F. , Varga Peter , Solaro R. John , Wolska Beata M.
Published: November 2019

Background:

Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM.

Methods:

We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm;
P
<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6];
P
=0.004) as assessed by echocardiography.

Results:

Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca
2+
-responsiveness (pCa
50
=6.15±0.11 [n=13] versus 6.24±0.06 [n=14];
P
=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180G mice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis.

Conclusions:

This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca
2+
-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.