bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Genome Assemblies for Three Variants of the
Wolbachia
Endosymbiont of Drosophila melanogaster
Authors: Basting Preston J. , Bergman Casey M.
Published: November 2019

Here, we report genome assemblies for three strains of
Wolbachia pipientis
, assembled from unenriched, unfiltered long-read shotgun sequencing data of geographically distinct strains of
Drosophila melanogaster
. Our simple methodology can be applied to long-read data sets of other
Wolbachia
-infected species with limited
Wolbachia
-host lateral gene transfers to produce complete assemblies for this important model symbiont.
Complete Genome Sequences of Two Shiga Toxin-Producing Escherichia coli Strains Isolated from Crows
Authors: Carter Michelle Q. , Pham Antares , Carychao Diana K. , Cooley Michael B.
Published: November 2019

Escherichia coli
strains RM9088 and RM10410 were isolated from crows near a leafy greens-growing region in California in April and July 2009, respectively. Both strains carry genes encoding Shiga toxins and other virulence factors in enteric pathogens. Here, we report the complete genome sequences of RM9088 and RM10410.
Draft Genome Sequence of Agrobacterium tumefaciens Strain 1D1526
Authors: Huo Naxin , Gu Yong , McCue Kent F. , Alabed Diaa , Thomson James G.
Published: November 2019

This work reports the draft genome sequence of
Agrobacterium tumefaciens
strain 1D1526. The assembled genome is composed of a 2,881,823-bp circular chromosome, a 2,235,711-bp linear chromosome, and a 44,582-bp unassembled contig.
Draft Genome Sequence of
Methanobacterium
sp. Strain 34x, Reconstructed from an Enriched Electromethanogenic Biocathode
Authors: Ragab Ala’a , Shaw Dario R. , Katuri Krishna P. , Saikaly Pascal E.
Published: November 2019

A draft genome sequence of
Methanobacterium
sp. strain 34x was reconstructed from the metagenome of an enriched electromethanogenic biocathode operated in a microbial electrosynthesis (MES) reactor.
Methanobacterium
sp. strain 34x has 68.98% nucleotide-level genomic similarity with the closest related methanogen available with a whole-genome assembly,
Methanobacterium lacus
strain AL-21. This genome will provide insight into the functional potential of methanogens at the biocathodes of MES systems.
Draft Genome Sequence of the Symbiotically Competent Cyanobacterium
Nostoc
sp. Strain KVJ20
Authors: Halsør Marie-Josée H. , Liaimer Anton , Pandur Seila , Ræder Inger L. U. , Smalås Arne O. , Altermark Bjørn
Published: November 2019

Nostoc
sp. strain KVJ20 was isolated from the symbiotic organs of the liverwort
Blasia pusilla
. This cyanobacterium has been shown to have broad symbiotic competence, and bacterial extracts have inhibitory effects on cancer cell lines and microbes. An array of genes for the production of secondary metabolites is present.
Occurrence and Genomic Characterization of Two MCR-1-Producing Escherichia coli Isolates from the Same Mink Farmer
Authors: Zheng Beiwen , Xu Hao , Huang Chen , Yu Xiao , Guo Lihua , Han Huiming , Zhang Jing , Jiang Xiawei , Chen Chunlei , Xiao Yonghong
Published: November 2019

Colistin resistance is a real threat for both human and animal health. The mobile colistin resistance gene
mcr
has contributed to the persistence and transmission of colistin resistance at the interfaces of animals, humans, and ecosystems. Although
mcr
genes have usually been recovered from food animals, patients, and healthy humans, transmission of
mcr
genes at the animal-human interface remains largely unknown. This was the first study to isolate and characterize MCR-producing isolates from mink, as well as to report the coexistence of two different MCR-1 producers in the same farmer. The characterization and analysis of two MCR-1-producing
E. coli
isolates may have important implications for comprehension of the transmission dynamics of these bacteria. We emphasize the importance of improved multisectorial surveillance of colistin-resistant
E. coli
in this region.
How local context influences access to neuropsychological rehabilitation after acquired brain injury in South Africa
Authors: Joosub Noorjehan
Published: November 2019

The numbers of acquired brain injury (ABI) survivors in South Africa are increasing; however, facilities to provide neuropsychological rehabilitation are limited due to a lack of healthcare resources. The updated International Classification of Health, Functioning, and Disability (ICF) from the WHO emphasises how the context of an impairment influences the patient’s activity limitations and participation restrictions. This analysis examined South African contextual influences on the accessibility, quality and efficiency of neuropsychological rehabilitation interventions after ABI in South Africa. Three main contextual influences were identified, namely, socioeconomic disparities, sociocultural influences and discharge to underprepared communities. Systems thinking and inclusive models of healthcare are needed in low-income and middle-income countries, such as South Africa, where resource constraints necessitate creative and ecological forms of rehabilitation interventions after ABI. Contextual influences are vital to consider when designing neuropsychological rehabilitation interventions in order to improve the accessibility and relevance of these interventions and to ensure the effective utilisation of scarce healthcare resources.
The impact of oil sands process water matrix on the ozonation of naphthenic acids: from a model compound to a natural mixture
Authors: Qin Rui , Chelme-Ayala Pamela , Gamal El-Din Mohamed
Published: November 2019

Oil sands process water (OSPW) contains organics, inorganics, and particles. To understand and improve the ozonation performance, it is crucial to clarify the effect of inorganics and particles on the ozonation of OSPW organic compounds. In this study, OSPW containing only inorganic fraction (OSPW-IF) was obtained after the organics were adsorbed onto granular activated carbon. A model naphthenic acid (NA) compound, cyclohexanecarboxylic acid (CHA), was dissolved in OSPW-IF (CHA-OSPW-IF) and NaHCO3 buffer (CHA-Buffer). Ozonation of CHA-Buffer achieved higher CHA removal and lower utilized ozone dosages compared to CHA-OSPW-IF. Some inorganic ions present in OSPW (i.e., NH4+, HCO3−, and Cl−) caused a slight reduction of CHA degradation. Inorganics in OSPW inhibited the degradation of natural-occurring NAs while a negligible influence of particles on the ozonation of NAs was found. This research suggests that ozonation could be better utilized as an intermediate or post-treatment step in a treatment train for OSPW reclamation.
Global analysis of dark matter simplified models with leptophobic spin-one mediators using MasterCode
Authors: Bagnaschi E. , Costa J. C. , Sakurai K. , Borsato M. , Buchmueller O. , De Roeck A. , Dolan M. J. , Ellis J. R. , Flächer H. , Hahn K. , Heinemeyer S. , Lucio M. , Santos D. Martínez , Olive K. A. , Trifa S. , Weiglein G.
Published: November 2019

We report the results of a global analysis of dark matter simplified models (DMSMs) with leptophobic mediator particles of spin one, considering the cases of both vector and axial-vector interactions with dark matter (DM) particles and quarks. We require the DMSMs to provide all the cosmological DM density indicated by Planck and other observations, and we impose the upper limits on spin-independent and -dependent scattering from direct DM search experiments. We also impose all relevant LHC constraints from searches for monojet events and measurements of the dijet mass spectrum. We model the likelihood functions for all the constraints and combine them within the framework, and probe the full DMSM parameter spaces by scanning over the mediator and DM masses and couplings, not fixing any of the model parameters. We find, in general, two allowed regions of the parameter spaces: one in which the mediator couplings to Standard Model (SM) and DM particles may be comparable to those in the SM and the cosmological DM density is reached via resonant annihilation, and one in which the mediator couplings to quarks are $$\lesssim \, 10^{-3}$$≲10-3 and DM annihilation is non-resonant. We find that the DM and mediator masses may well lie within the ranges accessible to LHC experiments. We also present predictions for spin-independent and -dependent DM scattering, and present specific results for ranges of the DM couplings that may be favoured in ultraviolet completions of the DMSMs.
A controllable water transfer rate across a tandem carbon nanotube
Authors: Meng Xianwen , Li Yuan , Shen Ling
Published: November 2019

Water permeation across a carbon nanotube is important in carbon-based nanodevices. Water transfer rate is closely related to the radius of a carbon nanotube. It is hard to change water transfer rate by interior methods once the radius of the entrance of a carbon nanotube is chosen. In this paper, water transfer across a tandem carbon nanotube with a separation is investigated by molecular dynamics simulations. We find that water transfer rate experiences two different transfer behaviors: an increasing behavior and a decreasing behavior by changing the separation length. The result is important in designing a controllable carbon-based nanodevice.
Open Infected Seymour Fracture
Authors: Zolotov Alexander S.
Published: November 2019

One of the serious complications of Seymour fractures is infection. A 24-year-old male presented with the open infected distal phalanx fracture of the middle finger. Wound debridement, irrigation, use of antibiotics and external fixation with the aid of mini-Ilizarov provided a resolution to the infectious process and enabled us to achieve a stable osseous union in correct position.
Flavored e-liquids increase cytoplasmic Ca2+levels in airway epithelia
Authors: Rowell Temperance R. , Keating James E. , Zorn Bryan T. , Glish Gary L. , Shears Stephen B. , Tarran Robert
Published: November 2019

E-cigarettes are noncombustible, electronic nicotine-delivery devices that aerosolize an e-liquid, i.e., nicotine, in a propylene glycol-vegetable glycerin vehicle that also contains flavors. While the effects of nicotine are relatively well understood, more information regarding the potential biological effects of the other e-liquid constituents is needed. This is a serious concern, because e-liquids are available in >7,000 distinct flavors. We previously demonstrated that many e-liquids affect cell growth/viability through an unknown mechanism. Since Ca2+is a ubiquitous second messenger that regulates cell growth, we characterized the effects of e-liquids on cellular Ca2+homeostasis. To better understand the extent of this effect, we screened e-liquids for their ability to alter cytosolic Ca2+levels and found that 42 of 100 flavored e-liquids elicited a cellular Ca2+response. Banana Pudding (BP) e-liquid, a representative e-liquid from this group, caused phospholipase C activation, endoplasmic reticulum (ER) Ca2+release, store-operated Ca2+entry (SOCE), and protein kinase C (PKCα) phosphorylation. However, longer exposures to BP e-liquid depleted ER Ca2+stores and inhibited SOCE, suggesting that this e-liquid may alter Ca2+homeostasis by short- and long-term mechanisms. Since dysregulation of Ca2+signaling can cause chronic inflammation, ER stress, and abnormal cell growth, flavored e-cigarette products that can elicit cell Ca2+responses should be further screened for potential toxicity.
Hypothalamic AMPKα2 regulates liver energy metabolism in rainbow trout through vagal innervation
Authors: Conde-Sieira Marta , Capelli Valentina , Álvarez-Otero Rosa , Díaz-Rúa Adrián , Velasco Cristina , Comesaña Sara , López Miguel , Soengas José L.
Published: November 2019

Hypothalamic AMPK plays a major role in the regulation of whole body metabolism and energy balance. Present evidence has demonstrated that this canonical mechanism is evolutionarily conserved. Thus, recent data demonstrated that inhibition of AMPKα2 in fish hypothalamus led to decreased food intake and liver capacity to use and synthesize glucose, lipids, and amino acids. We hypothesize that a signal of abundance of nutrients from the hypothalamus controls hepatic metabolism. The vagus nerve is the most important link between the brain and the liver. We therefore examined in the present study whether surgical transection of the vagus nerve in rainbow trout is sufficient to alter the effect in liver of central inhibition of AMPKα2. Thus, we vagotomized (VGX) or not (Sham) rainbow trout and then intracerebroventricularly administered adenoviral vectors tagged with green fluorescent protein alone or linked to a dominant negative isoform of AMPKα2. The inhibition of AMPKα2 led to reduced food intake in parallel with changes in the mRNA abundance of hypothalamic neuropeptides [neuropeptide Y ( npy), agouti-related protein 1 ( agrp1), and cocaine- and amphetamine-related transcript ( cartpt)] involved in food intake regulation. Central inhibition of AMPKα2 resulted in the liver having decreased capacity to use and synthesize glucose, lipids, and amino acids. Notably, these effects mostly disappeared in VGX fish. These results support the idea that autonomic nervous system actions mediate the actions of hypothalamic AMPKα2 on liver metabolism. Importantly, this evidence indicates that the well-established role of hypothalamic AMPK in energy balance is a canonical evolutionarily preserved mechanism that is also present in the fish lineage.
Temporal but not spatial dysmetria relates to disease severity in FA
Authors: Corti Manuela , Casamento-Moran Agostina , Delmas Stefan , Bracksieck Samantha , Bowman Jessica , Meyer Blake , Norman Samantha , Subramony Sub , Christou Evangelos A.
Published: November 2019

Friedreich’s ataxia (FA) is an inherited disease that causes degeneration of the nervous system. Features of FA include proprioceptive and cerebellar deficits leading to impaired muscle coordination and, consequently, dysmetria in force and time of movement. The aim of this study is to characterize dysmetria and its association to disease severity. Also, we examine the neural mechanisms of dysmetria by quantifying the EMG burst area, duration, and time-to-peak of the agonist muscle. Twenty-seven individuals with FA and 13 healthy controls (HCs) performed the modified Functional Ataxia Rating Scale and goal-directed movements with the ankle. Dysmetria was quantified as position and time error during dorsiflexion. FA individuals exhibited greater time but not position error than HCs. Moreover, time error correlated with disease severity and was related to increased agonist EMG burst. Temporal dysmetria is associated to disease severity, likely due to altered activation of the agonist muscle.

NEW & NOTEWORTHY For the first time, we quantified spatial and temporal dysmetria and its relation to disease severity in Friedreich’s ataxia (FA). We found that FA individuals exhibit temporal but not spatial dysmetria relative to healthy controls. Temporal dysmetria correlated to disease severity in FA and was predicted from an altered activation of the agonist muscle. Therefore, these results provide novel evidence that FA exhibit temporal but not spatial dysmetria, which is different from previous findings on SCA6.
Interactions within and between parallel parietal-frontal networks involved in complex motor behaviors in prosimian galagos and a squirrel monkey
Authors: Stepniewska Iwona , Friedman Robert M. , Miller Daniel J. , Kaas Jon H.
Published: November 2019

Long-train intracortical microstimulation (ICMS) of motor (M1) and posterior parietal cortices (PPC) in primates reveals cortical domains for different ethologically relevant behaviors. How functional domains interact with each other in producing motor behaviors is not known. In this study, we tested our hypothesis that matching domains interact to produce a specific complex movement, whereas connections between nonmatching domains are involved in suppression of conflicting motor outputs to prevent competing movements. In anesthetized galagos, we used 500-ms trains of ICMS to evoke complex movements from a functional domain in M1 or PPC while simultaneously stimulating another mismatched or matched domain. We considered movements of different and similar directions evoked from chosen cortical sites distant or close to each other. Their trajectories and speeds were analyzed and compared with those evoked by simultaneous stimulation. Stimulation of two sites evoking same or complementary movements produced a similar but more pronounced movement or a combined movement, respectively. Stimulation of two sites representing movements of different directions resulted in partial or total suppression of one of these movements. Thus interactions between domains in M1 and PPC were additive when they were functionally matched across fields or antagonistic between functionally conflicting domains, especially in PPC, suggesting that mismatched domains are involved in mutual suppression. Simultaneous stimulation of unrelated domains (forelimb and face) produced both movements independently. Movements produced by the simultaneous stimulation of sites in domains of two cerebral hemispheres were largely independent, but some interactions were observed.

NEW & NOTEWORTHY Long trains of electrical pulses applied simultaneously to two sites in motor cortical areas (M1, PPC) have shown that interactions of functionally matched domains (evoking similar movements) within these areas were additive to produce a specific complex movement. Interactions between functionally mismatched domains (evoking different movements) were mostly antagonistic, suggesting their involvement in mutual suppression of conflicting motor outputs to prevent competing movements. Simultaneous stimulation of unrelated domains (forelimb and face) produced both movements independently.
Mirror neurons precede non-mirror neurons during action execution
Authors: Mazurek Kevin A. , Schieber Marc H.
Published: November 2019

Mirror neurons are thought to represent an individual’s ability to understand the actions of others by discharging as one individual performs or observes another individual performing an action. Studies typically have focused on mirror neuron activity during action observation, examining activity during action execution primarily to validate mirror neuron involvement in the motor act. As a result, little is known about the precise role of mirror neurons during action execution. In this study, during execution of reach-grasp-manipulate movements, we found activity of mirror neurons generally preceded that of non-mirror neurons. Not only did the onset of task-related modulation occur earlier in mirror neurons, but state transitions detected by hidden Markov models also occurred earlier in mirror neuron populations. Our findings suggest that mirror neurons may be at the forefront of action execution.

NEW & NOTEWORTHY Mirror neurons commonly are thought to provide a neural substrate for understanding the actions of others, but mirror neurons also are active during action execution, when additional, non-mirror neurons are active as well. Examining the timing of activity during execution of a naturalistic reach-grasp-manipulate task, we found that mirror neuron activity precedes that of non-mirror neurons at both the unit and the population level. Thus mirror neurons may be at the leading edge of action execution.
Differentiating Nonfunctional Paraganglioma of the Bladder from Urothelial Carcinoma of the Bladder: Pitfalls and Breakthroughs
Authors: Male Musa , Ye Tao , Tao Jin , Chen Zhi-qiang , Peng Ejun
Published: November 2019

Background. Although both nonfunctional paraganglioma of the bladder (NPB) and urothelial carcinoma of the bladder (UCB) are subtypes of bladder tumors, they are entirely different entities with distinct tissue origins and anatomical locations. However, NPB is frequently misdiagnosed as UCB chiefly due to the similarities in their clinical characteristics and cystoscopic features. This study aimed to compare the differences in their clinical characteristics and cystoscopic features. Patients and Methods. Between April 2007 and September 2017, 14 patients with NPB (NPB group) were retrieved from 2 centers, and 42 patients with new-onset UCB (UCB group) were randomly retrieved. Demographic, symptomatic, imaging, and cystoscopic data of patients in both groups were collected and compared. Results. NPB group comprised 7 males and 7 females, with a mean age of 43.1 ± 13.6 years. Compared with the UCB group, patients in the NPB group were significantly younger (p<0.001), less likely to be male (p<0.05), and to present with hematuria (p<0.01). However, no significant difference in maximum tumor diameter was observed between the 2 groups (p=0.609). Compared with the UCB group, cystoscopically, patients in the NPB group were significantly more likely to present with hypervascularization but less likely to present with hemorrhage, necrosis, calcification, pedunculation, and multilesion (p<0.05). No patients with NPB were clinically diagnosed correctly before cystoscopy. Of the 5 patients who underwent both cystoscopy and biopsy, 4 were diagnosed with NPB, while 1 remained undiagnosed. Of the remaining 9 patients who underwent cystoscopy only, 5 were diagnosed with nonepithelial tumor, and 4 were misdiagnosed with UCB. Conclusions. Age, sex, and hematuria may provide clues to differentiating NPB from UCB. Differences in cystoscopic features between NPB and UCB are of high diagnostic value. Cystoscopic biopsy should be considered in the preoperative diagnosis of NPB.
Investigation of Aerodynamic Stability of a Lightweight Dual‐Arm Power Transmission Line Inspection Robot under the Influence of Wind
Authors: Alhassan Ahmad Bala , Zhang Xiaodong , Shen Haiming , Jian Guo , Xu Haibo , Hamza Khaled
Published: November 2019

To efficiently transmit electric power to consumers, the power lines need to be inspected routinely for early fault detection. Thus, power line inspection robots are designed to replace the tedious and dangerous manual inspection using linemen or helicopters. However, most of the existing inspection robots are heavy, which make them slow and prone to external wind disturbance. This paper developed a lightweight dual‐arm robot and investigates its robustness to wind disturbance on a lab‐scale power line structure. The dynamic equations of the robot are derived using the Lagrangian equation for appropriate motor selection. Also, the components of the robot are designed to ensure low drag coefficient to wind flow, and the mechanism of the wind force on the robot‐line coupled system is presented. To study the real‐time impact of the wind, a wind speed of 4.5 m/s representing one of the windiest cities in China is considered as a case study. The experimental results for different wind directions, namely, 0°, 45°, and 90°, show that the maximum vibration is 8% higher than the normal vibration of the system in a controlled environment without wind. The results demonstrate that there is little influence of the wind on the system; hence, the robot has been successfully designed and can be applied for power line inspection.
Two Novel Variants in the ATRX Gene Associated with Variable Phenotypes
Authors: Hettiarachchi D. , Pathirana B. A. P. S. , Kumarasiri P. J. , Dissanayake V. H. W.
Published: November 2019

The X-linked alpha-thalassemia mental retardation (ATR-X) syndrome is a rare genetic condition caused by mutations in the X‐encoded gene ATRX. Here we describe two unrelated patients of Sri Lankan origin with novel missense variants in the ATRX gene: c.839C>T|p.Cys280Tyr and c.5369C>T|p.Ala1790Val. These two novel variants were associated with variable phenotypes which clinically resembled X-linked mental retardation-hypotonic facies syndrome and Smith-Fineman-Myers syndrome respectively. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe global developmental delay and intellectual disabilities.
Cushion Mechanism of Goat Hoof Bulb Tissues
Authors: Tian Weijun , Liu Hai , Zhang Qi , Su Bo , Xu Wei , Cong Qian
Published: November 2019

The hoof bulb sections of white goats were observed via scanning electron microscopy and stereomicroscopy in order to explore the cushion mechanism in the bulb tissue microstructures of hoofed animals. The hoof bulbs consisted of multilayer tissues, including an epidermal layer, a dermal layer, and subcutaneous tissues from outside to inside. A bionic model based on hoof bulb tissue composite structures was built with a normal model as the control. The microcosmic mechanics of the bulb tissues was analyzed via the finite element method. Simulations showed that when the bionic model was impacted by the top plates at the speed of 1-10 m/s, stress was concentrated in the epidermal layer and uniformly distributed in the dermal layer and dermal papillae, which effectively reduced the impact onto the ground. The cornified epidermal layer can resist the instant impact onto the ground, while the dermal papillae embedded in the dermal layer can store, release, and dissipate the impulsive energy, and the three parts synergically act in the cushion.
Multiagent Task Planning Based on Distributed Resource Scheduling under Command and Control Structure
Authors: Zhang Jie , Wang Gang , Song Yafei , Zhao Fangzheng , Wang Siyuan
Published: November 2019

For task planning of the command and control structure, the existing algorithms exhibit low efficiency and poor replanning quality under abnormal conditions. Given the requirements of the current accusation architecture, a distributed command and control structure model is built in this paper based on multiagents, which exploits the superiority of multiagents in achieving complex tasks. The concept of MultiAgent‐HTN is proposed based on the framework. The original hierarchical task network planning algorithm is optimized, the multiagent collaboration framework is redefined, and the coordination mechanism of local conflict is developed. With the classical resource scheduling problem as the experimental background, the proposed algorithm compared with the classical HTN algorithm is drawn. According to the experimental results, the proposed algorithm exhibits higher quality and higher efficiency than the existing algorithm and the space anomaly is significant in the course of processing. The planning is more efficient and the time is more complicated and superior in solving the same problem, and the algorithm exhibits good convergence and adaptability. In the conclusion, it is proved that the distributed command and control structure proposed in this paper exhibits high practicability in relevant fields and can solve the problem of distributed command and control structure in a multiagent scenario.
Developments in Platinum-Group Metals as Dual Antibacterial and Anticancer Agents
Authors: Odularu Ayodele T. , Ajibade Peter A. , Mbese Johannes Z. , Oyedeji Opeoluwa O.
Published: November 2019

Platinum-group (PG) complexes have been used as antibacterial and anticancer agents since the discovery of cisplatin. The science world still requires improvement on these complexes because of multidrug and antineoplastic resistances. This review observes discoverers and history of these platinum-group metals (PGMs), as well as their beneficial applications. The focus of this study was biological applications of PGMs in relation to human health. Sandwich and half-sandwich PGM coordination compounds and their metal nanoparticles give improved results for biological activities by enhancing efficient delivery of both antibacterial and anticancer drugs, as well as luminescent bioimaging (biomarkers) for biological identifications.
Infectious Trigger for Autoimmune Encephalitis: A Case Report and Literature Review
Authors: Sahar Najmus , Nurre Alexander Michael , Simon Ryan Q.
Published: November 2019

Herpes simplex virus 1 infection is a common cause of encephalitis (HSVE) in the United States. Post-HSVE development of N-methyl-D-aspartate receptor (NMDAR) antibodies resulting in autoimmune encephalitis is a rare complication, primarily affecting children and young adults. Anti-NMDAR develops 1–4 weeks after HSVE, manifesting as choreoathetosis and/or orofacial dyskinesia in children and psychiatric symptoms in young adults. We describe a case of a 61-year-old male who presented with agitation, behavioral changes, and confusion eight months after being treated for HSVE. Extensive investigation was unrevealing except for cerebrospinal fluid lymphocytic pleocytosis, a positive anti-NMDAR Ab titer 1 : 64, and imaging changes consistent with postviral encephalitis suggestive of HSV-induced anti-NMDAR encephalitis. Aggressive therapy resulted in limited success and persistent neurologic deficits. The unique features of this case are the old age of the patient and preceding HSVE which triggered this autoimmune process. Physicians should consider anti-NMDAR encephalitis in the differentials for relapsing patients after HSVE.
4-Hydroxy-Trans-2-Nonenal in the Regulation of Anti-Oxidative and Pro-Inflammatory Signaling Pathways
Authors: Sonowal Himangshu , Ramana Kota V.
Published: November 2019

Recent studies indicate that 4-hydroxy-trans-2-nonenal (HNE), a major oxidative stress triggered lipid peroxidation-derived aldehyde, plays a critical role in the pathophysiology of various human pathologies including metabolic syndrome, diabetes, cardiovascular, neurological, immunological, and age-related diseases and various types of cancer. HNE is the most abundant and toxicα,β-unsaturated aldehyde formed during the peroxidation of polyunsaturated fatty acids in a series of free radical-mediated reactions. The presence of an aldehyde group at C1, a double bond between C2 and C3 and a hydroxyl group at C4 makes HNE a highly reactive molecule. These strong reactive electrophilic groups favor the formation of HNE adducts with cellular macromolecules such as proteins and nucleic acids leading to the regulation of various cell signaling pathways and processes involved in cell proliferation, differentiation, and apoptosis. Many studies suggest that the cell-specific intracellular concentrations of HNE dictate the anti-oxidative and pro-inflammatory activities of this important molecule. In this review, we focused on how HNE could alter multiple anti-oxidative defense pathways and pro-inflammatory cytotoxic pathways by interacting with various cell-signaling intermediates.
Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review
Authors: Jayasinghe Chanika D. , Jayawardena Uthpala A.
Published: November 2019

Herbal remedies have been practiced by humans over centuries and therefore possess time-proven safety. However, it is imperative to evaluate the toxic effects of herbal medicine to confirm their safety, particularly when developing therapeutic leads. Use of laboratory animals such as rats, mice, and rabbits was considered as gold standard in herbal toxicity assessments. However, in the last few decades, the ethical consideration of using higher vertebrates for toxicity testing has become more contentious. Thus, possible alternative models entailing lower vertebrates such as zebrafish were introduced. The zebrafish embryotoxicity model is at the forefront of toxicology assessment due to the transparent nature of embryos, low cost, short cycle, higher fecundity, and genetic redundancy to the humans. Recently, its application has been extended to herbal toxicology. The present review intends to provide a comprehensive assembly of studies that applied the zebrafish embryo model for the assessment of herbal toxicity. A systematic literature survey was carried out in popular scientific databases. The literature search identified a total of 1014 articles in PubMed = 12, Scopus SciVerse® = 623, and Google Scholar = 1000. After screening, 25 articles were included in this review, and they were categorized into three groups in which the zebrafish embryotoxicity assay has been applied to investigate the toxicity of (1) polyherbal formulae/medical prescription (2 full texts), (2) crude extracts (12 full texts), and (3) phytocompounds/isolated constituents (11 full texts). These studies have investigated the toxicity of 6 polyherbal formulae, 16 crude extracts, and more than 30 phytocompounds/isolated constituents using the zebrafish embryotoxicity model. Moreover, this model has explicated the teratogenic effects and specific organ toxicities such as the kidney, heart, and liver. Furthermore, in some studies, the molecular mechanisms underlying the toxicity of herbal medicine have been elucidated. This comprehensive collection of scientific data solidifies the zebrafish embryo model as an effective model system for studying toxicological effects of a broad spectrum of herbal remedies. Henceforth, it provides a novel insight into the toxicity assessment of herbal medicine.
Outcome of Early-Stage Glottic Laryngeal Carcinoma Patients Treated with Radical Radiotherapy Using Different Techniques
Authors: Cetinayak Oguz , Dogan Ersoy , Kuru Ahmet , Akturk Nesrin , Aydin Barbaros , Umay Cenk , Er Ilhami , Akman Fadime
Published: November 2019

Purpose. The aim was to evaluate the treatment outcomes and prognostic characteristics of patients with early-stage glottic laryngeal carcinoma who underwent radical radiotherapy (RT) with different techniques. Patients and Methods. Radiotherapy was applied using the 2D conventional technique between 1991 and 2004 (130 patients), 3DCRT until 2014 (125 patients), and by VMAT until January 2017 (44 patients). Clinical T stages were 38 (12.7%) for Tis, 209 (69.9%) for T1, and 52 (17.4%) for T2. Radiotherapy technique and energy, anterior commissure involvement, and stage were analyzed as prognostic factors. Results. The median total dose was 66 (50–70) Gy, and median follow-up time was 72 (3–288) months; 5-year disease-specific survival (DSS) rates were 95.8%, 95.5%, and 88.6%, respectively, in Tis, T1, and T2 stages. In multivariate analyses, anterior commissure involvement was found significant for all survival and local control rates. The patients treated with VMAT technique had better local control and DSS rates. However, these results were not statistically significant. Conclusion. In early-stage laryngeal carcinomas, radical RT is a function sparing and effective treatment modality, regardless of treatment techniques.
A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells
Authors: Umeh-Garcia Maxine , Simion Catalina , Ho Pui-Yan , Batra Neelu , Berg Anastasia L. , Carraway Kermit L. , Yu Aiming , Sweeney Colleen
Published: November 2019

miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration, and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor miRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of miRNA mimics. Here, we take a novel approach to produce a miR-127 prodrug (miR-127PD), which we demonstrate is processed to mature, functional miR-127-3p in TNBC tumor cells. miR-127PD decreased the viability and motility of TNBC cells, sensitized TNBC cells to chemotherapy, and restricted the TNBC stem cell population. Furthermore, systemic delivery of miR-127PD suppressed tumor growth of MDA-MB-231 and MDA-MB-468 TNBC cells and spontaneous metastasis of MDA-MB-231 cells. In addition, CERK, NANOS1, FOXO6, SOX11, SOX12, FASN, and SUSD2 were identified as novel, functionally important targets of miR-127. In conclusion, our study demonstrates that miR-127 functions as a tumor and metastasis suppressor in TNBC and that delivery of miR-127 may hold promise as a novel therapy.

Significance:

Exogenous administration of miR-127, which is functionally activated in target cells, inhibits growth and spontaneous metastasis of triple-negative breast cancer.
Epigenetic Aging: More Than Just a Clock When It Comes to Cancer
Authors: Yu Ming , Hazelton William D. , Luebeck Georg E. , Grady William M.
Published: November 2019

The incidence of cancer, adjusted for secular trends, is directly related to age, and advanced chronologic age is one of the most significant risk factors for cancer. Organismal aging is associated with changes at the molecular, cellular, and tissue levels and is affected by both genetic and environmental factors. The specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood. DNA methylation, a prominent epigenetic mark, also changes over a lifetime as part of an “epigenetic aging” process. Here, we give an update and review of epigenetic aging, in particular, the phenomena of epigenetic drift and epigenetic clock, with regard to its implication in cancer etiology. We discuss the discovery of the DNA methylation–based biomarkers for biological tissue age and the construction of various epigenetic age estimators for human clinical outcomes and health/life span. Recent studies in various types of cancer point to the significance of epigenetic aging in tumorigenesis and its potential use for cancer risk prediction. Future studies are needed to assess the potential clinical impact of strategies focused on lowering cancer risk by preventing premature aging or promoting healthy aging.
MET Inhibition Elicits PGC1α-Dependent Metabolic Reprogramming in Glioblastoma
Authors: Zhang Yiru , Nguyen Trang T.T. , Shang Enyuan , Mela Angeliki , Humala Nelson , Mahajan Aayushi , Zhao Junfei , Shu Chang , Torrini Consuelo , Sanchez-Quintero Maria J. , Kleiner Giulio , Bianchetti Elena , Westhoff Mike-Andrew , Quinzii Catarina M. , Karpel-Massler Georg , Bruce Jeffrey N. , Canoll Peter , Siegelin Markus D.
Published: November 2019

The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy.

Significance:

c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.
Adding Indoximod to Hypofractionated Radiotherapy with Anti-PD-1 Checkpoint Blockade Enhances Early NK and CD8+ T-Cell–Dependent Tumor Activity
Authors: Watanabe Tsubasa , Gaedicke Simone , Guffart Elena , Firat Elke , Niedermann Gabriele
Published: November 2019

Purpose:

There is growing interest in combinations of immunogenic radiotherapy (RT) and immune checkpoint blockade, but clinical responses are still limited. Therefore, we tested the triple therapy with an inhibitor of the indoleamine 2,3-dioxygenase pathway, which like immune checkpoints, downregulates the antitumor immune response.

Experimental Design:

Triple treatment with hypofractionated RT (hRT) + anti-PD-1 antibody (αPD1) + indoximod was compared with the respective mono- and dual therapies in two syngeneic mouse models.

Results:

The tumors did not regress following treatment with hRT + αPD1. The αPD1/indoximod combination was not effective at all. In contrast, triple treatment induced rapid, marked tumor regression, even in mice with a large tumor. The effects strongly depended on CD8+ T cells and partly on natural killer (NK) cells. Numbers and functionality of tumor-specific CD8+ T cells and NK cells were increased, particularly early during treatment. However, after 2.5–3 weeks, all large tumors relapsed, which was accompanied by increased apoptosis of tumor-infiltrating lymphocytes associated with a non-reprogrammable state of exhaustion, terminal differentiation, and increased activation-induced cell death, which could not be prevented by indoximod in these aggressive tumor models. Some mice with a smaller tumor were cured. Reirradiation during late regression (day 12), but not after relapse, cured almost all mice with a large B16-CD133 tumor, and strongly delayed relapse in the less immunogenic 4T1 model, depending on CD8+ T cells.

Conclusions:

Our findings may serve as a rationale for the clinical evaluation of this triple-combination therapy in patients with solitary or oligometastatic tumors in the neoadjuvant or the definitive setting.
Organoid Cultures as Preclinical Models of Non–Small Cell Lung Cancer
Authors: Shi Ruoshi , Radulovich Nikolina , Ng Christine , Liu Ni , Notsuda Hirotsugu , Cabanero Michael , Martins-Filho Sebastiao N. , Raghavan Vibha , Li Quan , Mer Arvind Singh , Rosen Joshua C. , Li Ming , Wang Yu-Hui , Tamblyn Laura , Pham Nhu-An , Haibe-Kains Benjamin , Liu Geoffrey , Moghal Nadeem , Tsao Ming-Sound
Published: November 2019

Purpose:

Non–small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease.

Experimental Design:

Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment. Organoids were histologically and molecularly characterized by cytology and histology, exome sequencing, and RNA-sequencing analysis. Tumorigenicity was assessed through subcutaneous injection of organoids in NOD/SCID mice. Organoids were subjected to drug testing using EGFR, FGFR, and MEK-targeted therapies.

Results:

We have identified cell culture conditions favoring the establishment of short-term and long-term expansion of NSCLC organoids derived from primary lung patient and PDX tumor tissue. The NSCLC organoids recapitulated the histology of the patient and PDX tumor. They also retained tumorigenicity, as evidenced by cytologic features of malignancy, xenograft formation, preservation of mutations, copy number aberrations, and gene expression profiles between the organoid and matched parental tumor tissue by whole-exome and RNA sequencing. NSCLC organoid models also preserved the sensitivity of the matched parental tumor to targeted therapeutics, and could be used to validate or discover biomarker–drug combinations.

Conclusions:

Our panel of NSCLC organoids closely recapitulates the genomics and biology of patient tumors, and is a potential platform for drug testing and biomarker validation.
Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study
Authors: Mahalingam Devalingam , Wilkinson Grey A. , Eng Kevin H. , Fields Paul , Raber Patrick , Moseley Jennifer L. , Cheetham Karol , Coffey Matt , Nuovo Gerard , Kalinski Pawel , Zhang Bin , Arora Sukeshi Patel , Fountzilas Christos
Published: November 2019

Purpose:

Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell–inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective.

Patients and Methods:

A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies.

Results:

Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit.

Conclusions:

Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti–PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for pelareorep therapy warranting further investigation.
CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma
Authors: Xu Duo , Liang Shun-Qing , Yang Haitang , Bruggmann Rémy , Berezowska Sabina , Yang Zhang , Marti Thomas Michael , Hall Sean Ralph Robert , Gao Yanyun , Kocher Gregor J. , Schmid Ralph A. , Peng Ren-Wang
Published: November 2019

Malignant pleural mesothelioma (MPM) is an aggressive cancer with dismal prognosis, largely due to poor response rates to and rapid relapse after first-line pemetrexed (MTA)/cisplatin chemotherapy. A better understanding of the molecular mechanisms underlying chemotherapy sensitivity and duration represents a significant but still unmet clinical need. In this study, we reported on a kinome CRISPR/Cas9 knockout screen that identified several G2–M checkpoint kinases, including WEE1, whose loss of function sensitizes MPM cells to standard chemotherapy. We further showed that deregulation of the G2–M checkpoint contributes to chemotherapy resistance, and that WEE1 inhibition synergizes with cisplatin/MTA, leading to enhanced MPM cell death in vitro and potent antitumor effects in vivo. Mechanistically, WEE1 blockage overrides chemotherapy-induced G2–M cell-cycle arrest and promotes premature mitotic entry, which causes DNA damage accumulation and ultimately apoptosis. Our results suggest a new therapeutic combination for MPM, and support the application of CRISPR/Cas9-based functional genomics in identifying novel therapeutic targets to potentiate existing cancer therapies.