bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of Bacterial Signal Recognition Particle at a Single Molecule Level
Authors: Mayer Benjamin , Schwan Meike , Oviedo-Bocanegra Luis M. , Bange Gert , Thormann Kai M. , Graumann Peter L.
Published: April 2021

We have studied the localization and dynamics of bacterial Ffh, part of the SRP complex, its receptor FtsY, and of ribosomes in the Gamma-proteobacterium Shewanella putrefaciens. Using structured illumination microscopy, we show that ribosomes show a pronounced accumulation at the cell poles, whereas SRP and FtsY are distributed at distinct sites along the cell membrane, but they are not accumulated at the poles. Single molecule dynamics can be explained by assuming that all three proteins/complexes move as three distinguishable mobility fractions: a low mobility/static fraction may be engaged in translation, medium-fast diffusing fractions may be transition states, and high mobility populations likely represent freely diffusing molecules/complexes. Diffusion constants suggest that SRP and FtsY move together with slow-mobile ribosomes. Inhibition of transcription leads to loss of static molecules and reduction of medium-mobile fractions, in favor of freely diffusing subunits, while inhibition of translation appears to stall the medium mobile fractions. Depletion of FtsY leads to aggregation of Ffh, but not to loss of the medium mobile fraction, indicating that Ffh/SRP can bind to ribosomes independently from FtsY. Heat maps visualizing the three distinct diffusive populations show that while static molecules are mostly clustered at the cell membrane, diffusive molecules are localized throughout the cytosol. The medium fast populations show an intermediate pattern of preferential localization, suggesting that SRP/FtsY/ribosome transition states may form within the cytosol to finally find a translocon.
Prevalence and Genetic Analysis of Chromosomal mcr-3/7 in Aeromonas From U.S. Animal-Derived Samples
Authors: Wang Yan , Hou Naxin , Rasooly Reuven , Gu Yongqiang , He Xiaohua
Published: April 2021

The prevalence of mcr-positive bacteria in 5,169 domestic animal-derived samples collected by USDA Food Safety and Inspection Service between October 2018 and May 2019 was investigated. A procedure including enriched broth culture and real-time PCR targeting mcr-1 to mcr-8 were used for the screening. Fifteen positive isolates were identified, including one plasmid-borne mcr-1-positive Escherichia coli strain, EC2492 (reported elsewhere) and 14 mcr-3/7-positive strains from poultry (1), catfish (2), and chicken rinse (11) samples, resulting in an overall prevalence of mcr-positive bacteria 0.29% in all meat samples tested. Analysis of 16S rRNA and whole genome sequences revealed that all 14 strains belonged to Aeromonas. Data from phylogenetic analysis of seven housekeeping genes, including gyrB, rpoD, gyrA, recA, dnaJ, dnaX, and atpD, indicated that nine strains belonged to Aeromonas hydrophila and five strains belonged to Aeromonas jandaei. Antimicrobial tests showed that almost all mcr-positive strains exhibited high resistance to colistin with MICs ≥ 128mg/L, except for one A. jandaei strain, which showed a borderline resistance with a MIC of 2 mg/L. A segment containing two adjacent mcr-3 and mcr-3-like genes was found in two A. hydrophila and one A. jandaei strains and a variety of IS-like elements were found in the flanking regions of this segment. A mcr-3-related lipid A phosphoethanolamine transferase gene was present in all 14 Aeromonas strains, while an additional mcr-7-related lipid A phosphoethanolamine transferase gene was found in 5 A. jandaei strains only. In addition to mcr genes, other antimicrobial resistance genes, including blaOXA–12/OXA–724, aqu-2, tru-1, cepS, cphA, imiH, ceph-A3, ant(3″)-IIa, aac(3)-Via, and sul1 were observed in chromosomes of some Aeromonas strains. The relative high prevalence of chromosome-borne mcr-3/7 genes and the close proximity of various IS elements to these genes highlights the need for continued vigilance to reduce the mobility of these colistin-resistance genes among food animals.
Whole-Killed Blood-Stage Vaccine: Is It Worthwhile to Further Develop It to Control Malaria?
Authors: Cai Jingjing , Chen Suilin , Zhu Feng , Lu Xiao , Liu Taiping , Xu Wenyue
Published: April 2021

Major challenges have been encountered regarding the development of highly efficient subunit malaria vaccines, and so whole-parasite vaccines have regained attention in recent years. The whole-killed blood-stage vaccine (WKV) is advantageous as it can be easily manufactured and efficiently induced protective immunity against a blood-stage challenge, as well as inducing cross-stage protection against both the liver and sexual-stages. However, it necessitates a high dose of parasitized red blood cell (pRBC) lysate for immunization, and this raises concerns regarding its safety and low immunogenicity. Knowledge of the major components of WKV that can induce or evade the host immune response, and the development of appropriate human-compatible adjuvants will greatly help to optimize the WKV. Therefore, we argue that the further development of the WKV is worthwhile to control and potentially eradicate malaria worldwide.
Proteomic Analysis on Anti-Proliferative and Apoptosis Effects of Curcumin Analog, 1,5-bis(4-Hydroxy-3-Methyoxyphenyl)-1,4-Pentadiene-3-One-Treated Human Glioblastoma and Neuroblastoma Cells
Authors: Lee Yee Qian , Rajadurai Pathmanathan , Abas Faridah , Othman Iekhsan , Naidu Rakesh
Published: April 2021

Curcumin analogs with excellent biological properties have been synthesized to address and overcome the poor pharmacokinetic profiles of curcumin. This study aims to investigate the cytotoxicity, anti-proliferative, and apoptosis-inducing ability of curcumin analog, MS13 on human glioblastoma U-87 MG, and neuroblastoma SH-SY5Y cells, and to examine the global proteome changes in these cells following treatment. Our current findings showed that MS13 induced potent cytotoxicity and anti-proliferative effects on both cells. Increased caspase-3 activity and decreased bcl-2 concentration upon treatment indicate that MS13 induces apoptosis in these cells in a dose- and time-dependent manner. The label-free shotgun proteomic analysis has defined the protein profiles in both glioblastoma and neuroblastoma cells, whereby a total of nine common DEPs, inclusive of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), alpha-enolase (ENO1), heat shock protein HSP 90-alpha (HSP90AA1), Heat shock protein HSP 90-beta (HSP90AB1), Eukaryotic translation initiation factor 5A-1 (EFI5A), heterogenous nuclear ribonucleoprotein K (HNRNPK), tubulin beta chain (TUBB), histone H2AX (H2AFX), and Protein SET were identified. Pathway analysis further elucidated that MS13 may induce its anti-tumor effects in both cells via the common enriched pathways, “Glycolysis” and “Post-translational protein modification.” Conclusively, MS13 demonstrates an anti-cancer effect that may indicate its potential use in the management of brain malignancies.
Quantitative Immunohistochemistry to Measure Regional Expression of Nurr1 in the Brain and the Effect of the Nurr1 Heterozygous Genotype
Authors: Kummari Evangel , Guo-Ross Shirley X. , Partington Heath S. , Nutter Jennifer Makenzie , Eells Jeffrey B.
Published: April 2021

The transcription factor Nurr1 is a member of the steroid hormone nuclear receptor superfamily. Ablation of Nurr1 expression arrests mesencephalic dopamine neuron differentiation while attenuation of Nurr1 in the subiculum and hippocampus impairs learning and memory. Additionally, reduced Nurr1 expression has been reported in patients with Parkinson’s disease and Alzheimer’s disease. In order to better understand the overall function of Nurr1 in the brain, quantitative immunohistochemistry was used to measure cellular Nurr1 protein expression, across Nurr1 immunoreactive neuronal populations. Additionally, neuronal Nurr1 expression levels were compared between different brain regions in wild-type mice (+/+) and Nurr1 heterozygous mice (+/−). Regional Nurr1 protein was also investigated at various time points after a seizure induced by pentylenetetrazol (PTZ). Nurr1 protein is expressed in various regions throughout the brain, however, a wide range of Nurr1 expression levels were observed among various neuronal populations. Neurons in the parietal and temporal cortex (secondary somatosensory, insular, auditory, and temporal association cortex) had the highest relative Nurr1 expression (100%) followed closely by the claustrum/dorsal endopiriform cortex (85%) and then subiculum (76%). Lower Nurr1 protein levels were found in neurons in the substantia nigra pars compacta and ventral tegmental area (39%) followed by CA1 (25%) and CA3 (19%) of the hippocampus. Additionally, in the parietal and temporal cortex, two distinct populations of high and medium Nurr1 expressing neurons were observed. Comparisons between +/− and +/+ mice revealed Nurr1 protein was reduced in +/− mice by 27% in the parietal/temporal cortex, 49% in the claustrum/dorsal endopiriform cortex, 25% in the subiculum, 33% in substantia nigra pars compacta, 22% in ventral tegmental area, and 21% in CA1 region of the hippocampus. Based on these data, regional mechanisms appear to exist which can compensate for a loss of a Nurr1 allele. Following a single PTZ-induced seizure, Nurr1 protein in the dentate gyrus peaked around 2 h and returned to baseline by 8 h. Since altered Nurr1 expression has been implicated in neurologic disorders and Nurr1 agonists have showed protective effects, understanding regional protein expression of Nurr1, therefore, is necessary to understand how changes in Nurr1 expression can alter brain function.
Genetic Depletion of BDNF Impairs Extinction Learning of a Spatial Appetitive Task in the Presence or Absence of the Acquisition Context
Authors: Méndez-Couz Marta , Krenzek Beate , Manahan-Vaughan Denise
Published: April 2021

Brain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent and independent learning, as well as hippocampus-dependent learning. Extinction learning comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. The participation of BDNF in memory processing is experience-dependent. For example, BDNF has been associated with synaptic plasticity needed for spatial learning, and it is involved in acquisition and extinction learning of fear conditioning. However, little is known about its role in spatial appetitive extinction learning. In this study, we evaluated to what extent BDNF contributes to spatial appetitive extinction learning in the presence (ABA) or absence (AAA) of exposure to the acquisition context. Daily training, of BDNF+/−-mice or their wildtype (WT) littermates, to reach acquisition criterion in a T-maze, resulted in a similar performance outcome. However, extinction learning was delayed in the AAA, and impaired in the ABA-paradigm compared to performance in WT littermates. Trial-by-trial learning analysis indicated differences in the integration of the context into extinction learning by BDNF+/−-mice compared to WT littermates. Taken together, these results support an important role for BDNF in processes that relate to information updating and retrieval that in turn are crucial for effective extinction learning.
Prosthetic Embodiment and Body Image Changes in Patients Undergoing Bionic Reconstruction Following Brachial Plexus Injury
Authors: Sturma Agnes , Hruby Laura A. , Boesendorfer Anna , Pittermann Anna , Salminger Stefan , Gstoettner Clemens , Politikou Olga , Vujaklija Ivan , Farina Dario , Aszmann Oskar C.
Published: April 2021

Brachial plexus injuries with multiple-root involvement lead to severe and long-lasting impairments in the functionality and appearance of the affected upper extremity. In cases, where biologic reconstruction of hand and arm function is not possible, bionic reconstruction may be considered as a viable clinical option. Bionic reconstruction, through a careful combination of surgical augmentation, amputation, and prosthetic substitution of the functionless hand, has been shown to achieve substantial improvements in function and quality of life. However, it is known that long-term distortions in the body image are present in patients with severe nerve injury as well as in prosthetic users regardless of the level of function. To date, the body image of patients who voluntarily opted for elective amputation and prosthetic reconstruction has not been investigated. Moreover, the degree of embodiment of the prosthesis in these patients is unknown. We have conducted a longitudinal study evaluating changes of body image using the patient-reported Body Image Questionnaire 20 (BIQ-20) and a structured questionnaire about prosthetic embodiment. Six patients have been included. At follow up 2.5–5 years after intervention, a majority of patients reported better BIQ-20 scores including a less negative body evaluation (5 out of 6 patients) and higher vital body dynamics (4 out of 6 patients). Moreover, patients described a strong to moderate prosthesis embodiment. Interestingly, whether patients reported performing bimanual tasks together with the prosthetic hand or not, did not influence their perception of the prosthesis as a body part. In general, this group of patients undergoing prosthetic substitution after brachial plexus injury shows noticeable inter-individual differences. This indicates that the replacement of human anatomy with technology is not a straight-forward process perceived in the same way by everyone opting for it.
Extracellular ATP-Induced Alterations in Extracellular H+ Fluxes From Cultured Cortical and Hippocampal Astrocytes
Authors: Choi Ji-in Vivien , Tchernookova Boriana K. , Kumar Wasan , Kiedrowski Lech , Goeke Calla , Guizzetti Marina , Larson John , Kreitzer Matthew A. , Malchow Robert Paul
Published: April 2021

Small alterations in the level of extracellular H+ can profoundly alter neuronal activity throughout the nervous system. In this study, self-referencing H+-selective microelectrodes were used to examine extracellular H+ fluxes from individual astrocytes. Activation of astrocytes cultured from mouse hippocampus and rat cortex with extracellular ATP produced a pronounced increase in extracellular H+ flux. The ATP-elicited increase in H+ flux appeared to be independent of bicarbonate transport, as ATP increased H+ flux regardless of whether the primary extracellular pH buffer was 26 mM bicarbonate or 1 mM HEPES, and persisted when atmospheric levels of CO2 were replaced by oxygen. Adenosine failed to elicit any change in extracellular H+ fluxes, and ATP-mediated increases in H+ flux were inhibited by the P2 inhibitors suramin and PPADS suggesting direct activation of ATP receptors. Extracellular ATP also induced an intracellular rise in calcium in cultured astrocytes, and ATP-induced rises in both calcium and H+ efflux were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin. Replacement of extracellular sodium with choline did not significantly reduce the size of the ATP-induced increases in H+ flux, and the increases in H+ flux were not significantly affected by addition of EIPA, suggesting little involvement of Na+/H+ exchangers in ATP-elicited increases in H+ flux. Given the high sensitivity of voltage-sensitive calcium channels on neurons to small changes in levels of free H+, we hypothesize that the ATP-mediated extrusion of H+ from astrocytes may play a key role in regulating signaling at synapses within the nervous system.
Inhibitory Circuits in the Basolateral Amygdala in Aversive Learning and Memory
Authors: Perumal Madhusoothanan B. , Sah Pankaj
Published: April 2021

Neural circuits in the basolateral amygdala (BLA) play a pivotal role in the learning and memory formation, and processing of emotionally salient experiences, particularly aversive ones. A diverse population of GABAergic neurons present in the BLA orchestrate local circuits to mediate emotional memory functions. Targeted manipulation of GABAergic neuronal subtypes has shed light on cell-type specific functional roles in the fear learning and memory, revealing organizing principles for the operation of inhibitory circuit motifs in the BLA.
Circadian Rhythm Disorders and Corresponding Functional Brain Abnormalities in Young Female Nurses: A Preliminary Study
Authors: Wu Xiaoli , Bai Fan , Wang Yunlei , Zhang Lu , Liu Lixu , Chen Yudong , Li Hanzhi , Zhang Tong
Published: April 2021

Objective: Shift work is associated with a decrease in melatonin level and perturbation of the circadian rhythm; however, it is unknown if these lead to functional brain changes. In this study, we investigated whether circadian rhythm disorders caused by shift work are related to changes in brain functional connectivity (FC) and regional homogeneity (ReHo) using whole-brain resting-state functional magnetic resonance imaging (fMRI).

Methods: This prospective case-control study included nine female night shift nurses and nine age-matched female day work nurses with normal sleep rhythms. To assess sleep quality and mood, participants were asked to complete questionnaires. Serum melatonin and cortisol levels were measured. ReHo of whole-brain resting-state function and seed-based FC of the bilateral hypothalamus were compared between groups. Variables that differed significantly between groups were used to examine the association between questionnaire scores and hormone levels and fMRI data.

Results: The night shift nurses had significantly lower sleep quality and melatonin levels; lower ReHo activation in the bilateral cerebellar hemisphere and higher ReHo in the bilateral occipital lobe and left parietal lobe; and higher FC from the hypothalamus to the right cingulate gyrus, right putamen, and vermis than did the day shift nurses. Activation of the right cerebellar hemisphere left superior parietal gyrus, and the right superior occipital gyrus was correlated with sleep quality scores. Moreover, activation of the right cerebellar hemisphere (r = 0.583, P = 0.011) was correlated with melatonin levels, and higher sleepiness scores were associated with stronger FC between the hypothalamus and vermis (r = 0.501, P = 0.034).

Conclusions: Circadian rhythm disorder caused by night shift work can lead to a decrease in sleep quality and melatonin level, as well as a series of changes in brain FC and ReHo.
Vector Phase Analysis Approach for Sleep Stage Classification: A Functional Near-Infrared Spectroscopy-Based Passive Brain–Computer Interface
Authors: Arif Saad , Khan Muhammad Jawad , Naseer Noman , Hong Keum-Shik , Sajid Hasan , Ayaz Yasar
Published: April 2021

A passive brain–computer interface (BCI) based upon functional near-infrared spectroscopy (fNIRS) brain signals is used for earlier detection of human drowsiness during driving tasks. This BCI modality acquired hemodynamic signals of 13 healthy subjects from the right dorsolateral prefrontal cortex (DPFC) of the brain. Drowsiness activity is recorded using a continuous-wave fNIRS system and eight channels over the right DPFC. During the experiment, sleep-deprived subjects drove a vehicle in a driving simulator while their cerebral oxygen regulation (CORE) state was continuously measured. Vector phase analysis (VPA) was used as a classifier to detect drowsiness state along with sleep stage-based threshold criteria. Extensive training and testing with various feature sets and classifiers are done to justify the adaptation of threshold criteria for any subject without requiring recalibration. Three statistical features (mean oxyhemoglobin, signal peak, and the sum of peaks) along with six VPA features (trajectory slopes of VPA indices) were used. The average accuracies for the five classifiers are 90.9% for discriminant analysis, 92.5% for support vector machines, 92.3% for nearest neighbors, 92.4% for both decision trees, and ensembles over all subjects’ data. Trajectory slopes of CORE vector magnitude and angle: m(|R|) and m(∠R) are the best-performing features, along with ensemble classifier with the highest accuracy of 95.3% and minimum computation time of 40 ms. The statistical significance of the results is validated with a p-value of less than 0.05. The proposed passive BCI scheme demonstrates a promising technique for online drowsiness detection using VPA along with sleep stage classification.
Neurophysiological Synchrony Between Children With Severe Physical Disabilities and Their Parents During Music Therapy
Authors: Samadani Ali , Kim Song , Moon Jae , Kang Kyurim , Chau Tom
Published: April 2021

Although physiological synchronization has been associated with the level of empathy in emotionally meaningful relationships, little is known about the interbrain synchrony between non-speaking children with severe disabilities and their familial caregivers. In a repeated measures observational study, we ascertained the degree of interbrain synchrony during music therapy in 10 child-parent dyads, where the children were non-speaking and living with severe motor impairments. Interbrain synchrony was quantified via measurements of spectral coherence and Granger causality between child and parent electroencephalographic (EEG) signals collected during ten 15-min music therapy sessions per dyad, where parents were present as non-participating, covert observers. Using cluster-based permutation tests, we found significant child-parent interbrain synchrony, manifesting most prominently across dyads in frontal brain regions within β and low γ frequencies. Specifically, significant dyadic coherence was observed contra-laterally, between child frontal right and parental frontal left regions at β and lower γ bands in empathy-related brain areas. Furthermore, significant Granger influences were detected bidirectionally (from child to parent and vice versa) in the same frequency bands. In all dyads, significant increases in session-specific coherence and Granger influences were observed over the time course of a music therapy session. The observed interbrain synchrony suggests a cognitive-emotional coupling during music therapy between child and parent that is responsive to change. These findings encourage further study of the socio-empathic capacity and interpersonal relationships formed between caregivers and non-speaking children with severe physical impairments.
Chronic Ethanol Exposures Leads to a Negative Affective State in Female Rats That Is Accompanied by a Paradoxical Decrease in Ventral Hippocampus Excitability
Authors: Bach Eva C. , Morgan James W. , Ewin Sarah E. , Barth Samuel H. , Raab-Graham Kimberly F. , Weiner Jeffrey L.
Published: April 2021

Alcohol use disorder (AUD) differentially impacts men and women and a growing body of evidence points to sex-dependent adaptations in a number of brain regions. In a prior study, we explored the effect of a chronic intermittent ethanol exposure (CIE) model of AUD on neuronal and molecular adaptations in the dorsal and ventral domains of the hippocampus (dHC and vHC, respectively) in male rats. We found the vHC to be particularly sensitive to CIE, showing an increase in neuronal excitability and synaptic proteins associated with augmented excitation. These findings were accompanied by a CIE-dependent increase in anxiety-like behaviors. To explore sex-dependent adaptations in the hippocampus, we conducted a similar study in female rats. CIE-treated female rats showed a relatively modest increase in anxiety-like behaviors along with a robust increase in depressive-like measures. Despite both sexes showing clear evidence of a negative affective state following CIE, the vHC of females showed a decrease, rather than an increase, in neuronal excitability. In line with the reduced sensitivity to neural adaptations in the dHC of male rats, we were unable to identify any functional changes in the dHC of females. The functional changes of the vHC in female rats could not be explained by altered expression levels of a number of proteins typically associated with changes in neuronal excitability. Taken together, these findings point to sex as a major factor in CIE-dependent hippocampal adaptations that should be explored further to better understand possible gender differences in the etiology and treatment of AUD.
Extrasynaptic Communication
Authors: De-Miguel Francisco F. , Leon-Pinzon Carolina , Torres-Platas Susana G. , del-Pozo Vanessa , Hernández-Mendoza Guillermo A. , Aguirre-Olivas Dilia , Méndez Bruno , Moore Sharlen , Sánchez-Sugía Celeste , García-Aguilera Marco Antonio , Martínez-Valencia Alejandro , Ramírez-Santiago Guillermo , Rubí J. Miguel
Published: April 2021

Streams of action potentials or long depolarizations evoke a massive exocytosis of transmitters and peptides from the surface of dendrites, axons and cell bodies of different neuron types. Such mode of exocytosis is known as extrasynaptic for occurring without utilization of synaptic structures. Most transmitters and all peptides can be released extrasynaptically. Neurons may discharge their contents with relative independence from the axon, soma and dendrites. Extrasynaptic exocytosis takes fractions of a second in varicosities or minutes in the soma or dendrites, but its effects last from seconds to hours. Unlike synaptic exocytosis, which is well localized, extrasynaptic exocytosis is diffuse and affects neuronal circuits, glia and blood vessels. Molecules that are liberated may reach extrasynaptic receptors microns away. The coupling between excitation and exocytosis follows a multistep mechanism, different from that at synapses, but similar to that for the release of hormones. The steps from excitation to exocytosis have been studied step by step for the vital transmitter serotonin in leech Retzius neurons. The events leading to serotonin exocytosis occur similarly for the release of other transmitters and peptides in central and peripheral neurons. Extrasynaptic exocytosis occurs commonly onto glial cells, which react by releasing the same or other transmitters. In the last section, we discuss how illumination of the retina evokes extrasynaptic release of dopamine and ATP. Dopamine contributes to light-adaptation; ATP activates glia, which mediates an increase in blood flow and oxygenation. A proper understanding of the workings of the nervous system requires the understanding of extrasynaptic communication.
Natural Phytochemicals in Bladder Cancer Prevention and Therapy
Authors: Xia Yong , Chen Ruijiao , Lu Guangzhen , Li Changlin , Lian Sen , Kang Taek-Won , Jung Young Do
Published: April 2021

Phytochemicals are natural small-molecule compounds derived from plants that have attracted attention for their anticancer activities. Some phytochemicals have been developed as first-line anticancer drugs, such as paclitaxel and vincristine. In addition, several phytochemicals show good tumor suppression functions in various cancer types. Bladder cancer is a malignant tumor of the urinary system. To date, few specific phytochemicals have been used for bladder cancer therapy, although many have been studied in bladder cancer cells and mouse models. Therefore, it is important to collate and summarize the available information on the role of phytochemicals in the prevention and treatment of bladder cancer. In this review, we summarize the effects of several phytochemicals including flavonoids, steroids, nitrogen compounds, and aromatic substances with anticancer properties and classify the mechanism of action of phytochemicals in bladder cancer. This review will contribute to facilitating the development of new anticancer drugs and strategies for the treatment of bladder cancer using phytochemicals.
NGFR Increases the Chemosensitivity of Colorectal Cancer Cells by Enhancing the Apoptotic and Autophagic Effects of 5-fluorouracil via the Activation of S100A9
Authors: Chen Hao , Huang Jintuan , Chen Chunyu , Jiang Yingming , Feng Xingzhi , Liao Yi , Yang Zuli
Published: April 2021

Colorectal cancer (CRC) is currently the third leading cause of cancer-related deaths worldwide, and 5-fluorouracil (5-FU)-based chemotherapies serve as important adjuvant therapies before and after surgery for CRC. However, the efficacy of CRC chemotherapy is limited by chemoresistance, and therefore the discovery of novel markers to indicate chemosensitivity is essential. Nerve growth factor receptor (NGFR), a cell surface receptor, is involved in cell death and survival. Our previous study indicated that NGFR acts as a tumor suppressor, and high expression is associated with better outcomes in patients receiving 5-FU-based adjuvant chemotherapy after surgery. The aim of this study was to investigate the effect of NGFR on the chemotherapeutic response in CRC. Chemosensitivity was investigated using DLD1 and HCT8 cells after NGFR transfection. Apoptosis was investigated by flow cytometry. Autophagy was assessed using GFP-LC3B transient transfection. Gene expression was measured using an mRNA microarray. Beclin-1 and Bcl-2 protein expressions were assessed by western blot. NGFR and S100 calcium-binding protein A9 (S100A9) expressions in CRC patients were investigated by immunohistochemistry. The results showed that the half maximal inhibitory concentration of NGFR-transfected cells was lower than that of controls in DLD1 and HCT8 cells after 5-FU treatment, and cell viability was lower than in empty-vector cells. Tumor sizes were also smaller than in empty-vector cells in vivo. The percentages of apoptotic and autophagic cells were higher in NGFR-transfected cells. NGFR elevated the expression of S100A9 after 5-FU treatment. The combination of Bcl-2 and Beclin-1 was significantly suppressed by overexpressed NGFR. Five-year overall and disease-free survival in NGFR+/S100A9+ patients was better than in NGFR−/S100A9− patients. This study’s findings suggest that NGFR may serve as a marker predicting CRC patients’ chemosensitivity.
Baicalein Induces Apoptosis of Pancreatic Cancer Cells by Regulating the Expression of miR-139-3p and miR-196b-5p
Authors: Ma Danhui , Chen Sinuo , Wang Heming , Wei Jiayi , Wu Hao , Gao Hong , Cheng Xinlai , Liu Taotao , Luo Shi-Hua , Zhao Yicheng , Song Guangqi
Published: April 2021

Pancreatic cancer is a common malignant tumor with a high incidence and mortality rate. The prognosis of patients with pancreatic cancer is considerably poor due to the lack of effective treatment in clinically. Despite numerous studies have revealed that baicalein, a natural product, is responsible for suppressing multiple cancer cells proliferation, motility and invasion. The mechanism by which baicalein restraining pancreatic cancer progression remains unclear. In this study, we firstly verified that baicalein plays a critical role in inhibiting pancreatic tumorigenesis in vitro and in vivo. Then we analyzed the alteration of microRNAs (miRNAs) expression levels in Panc-1 cells incubated with DMSO, 50 and 100 μM baicalein by High-Throughput sequencing. Intriguingly, we observed that 20 and 39 miRNAs were accordingly up- and down-regulated through comparing Panc-1 cells exposed to 100 μM baicalein with the control group. Quantitative PCR analysis confirmed that miR-139-3p was the most up-regulated miRNA after baicalein treatment, while miR-196b-5p was the most down-regulated miRNA. Further studies showed that miR-139-3p induced, miR-196b-5p inhibited the apoptosis of Panc-1 cells via targeting NOB1 and ING5 respectively. In conclusion, we demonstrated that baicalein is a potent inhibitor against pancreatic cancer by modulating the expression of miR-139-3p or miR-196b-5p.
Efficacy of Liver Resection for Single Large Hepatocellular Carcinoma in Child-Pugh A Cirrhosis: Analysis of a Nationwide Cancer Registry Database
Authors: Hong Suk Kyun , Lee Kwang-Woong , Hong Su young , Suh Sanggyun , Hong Kwangpyo , Han Eui Soo , Lee Jeong-Moo , Choi YoungRok , Yi Nam-Joon , Suh Kyung-Suk
Published: April 2021

Background

Therapeutic strategies and good prognostic factors are important for patients with single large hepatocellular carcinoma (HCC). This retrospective study aimed to identify the prognostic factors in patients with single large HCC with good performance status and Child-Pugh A cirrhosis using a large national cancer registry database and to recommend therapeutic strategies.

Methods

Among 12139 HCC patients registered at the Korean Primary Liver Cancer Registry between 2008 and 2015, single large (≥ 5 cm) HCC patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 and Child-Pugh score A were selected.

Results

Overall, 466 patients were analyzed. The 1-,2-,3-, and 5-year survival rates after initial treatment were 84.9%, 71.0%, 60.1%, and 51.6%, respectively, and progression-free survival rates were 43.6%, 33.0%, 29.0%, and 26.8%, respectively. Platelet count < 100 × 109/L (P < 0.001), sodium level < 135 mmol/L (P = 0.002), maximum tumor diameter ≥ 10 cm (P = 0.001), and treatment other than resection (transarterial therapy vs. resection: P < 0.001, others vs. resection: P = 0.002) were significantly associated with poorer overall survival; sodium < 135 mmol/L (P = 0.015), maximum tumor diameter ≥ 10 cm (P < 0.001), and treatment other than resection (transarterial therapy vs. resection: P < 0.001, others vs. resection: P = 0.001) were independently associated with poorer progression-free survival.

Conclusion

Resection as an initial treatment should be considered when possible, even in patients with single large HCC with good performance status and mild cirrhosis. Caution should be exercised in patients with low platelet level (< 100 × 109/L), low serum sodium level (< 135 mmol/L), and maximum tumor diameter ≥ 10 cm.
Case Report: A Case of Trimethoprim/Sulfamethoxazole-Triggered Hypotensive Shock: Cytokine Release Syndrome Related to Immune Checkpoint Inhibitors and Drug-Induced Hypersensitivity Syndrome
Authors: Urasaki Tetsuya , Ono Makiko , Mochizuki Toshiaki , Takeda Koichi , Nishizawa Aya , Fukagawa Eri , Fujiwara Motohiro , Komai Yoshinobu , Kitano Shigehisa , Yuasa Takeshi , Yonese Junji , Takahashi Shunji
Published: April 2021

Currently, only a few reports exist on the cytokine release syndrome (CRS) as one of the severe immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Notably, it is very rare that grade 4 CRS related to ICI therapy overlaps with the drug-induced hypersensitivity syndrome (DiHS). A 46-year old woman with metastatic kidney cancer had grade 3 interstitial pneumonitis induced by four cycles of combination therapy of anti-programmed death-1 and anti-cytotoxic T lymphocyte-4 antibodies after right cytoreductive nephrectomy. Prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) was started concomitantly with prednisolone therapy to treat the interstitial pneumonitis. She developed hypotensive shock when reducing the dosage of prednisolone, and required intubation and ventilation using vasopressors at the intensive care unit. She subsequently exhibited prominent leukocytosis and an increased level of C-reactive protein, suggesting markedly increased cytokine levels. Interestingly, facial edema and erythema increased in association with pyrexia, leukocytosis, liver dysfunction, and renal failure, suggesting that she developed DiHS. She received hemodialysis three times, a plasma exchange, and anti-interleukin-6 therapy to treat severe renal dysfunction, a thrombotic thrombocytopenic purpura-suspected condition, and possible grade 4 CRS, respectively. Although these therapies did not elicit sufficient effects, high-dose administration of intravenous immunoglobulin was successful. With steroid mini-pulse therapy and the subsequent administration of prednisolone, she recovered successfully. To the best of our knowledge, this is the first report that ICIs and TMP/SMX can induce hypotensive shock accompanied with CRS and DiHS during immunosuppressive therapy for an irAE. Importantly, the prophylactic administration of TMP/SMX should be performed cautiously to avoid severe drug reactions such as CRS or DiHS.
Outcome of Very Premature Newborn Receiving an Early Second Dose of Surfactant for Persistent Respiratory Distress Syndrome
Authors: Greiner Eva , Wittwer Apolline , Albuisson Eliane , Hascoët Jean-Michel
Published: April 2021

Background:Infants presenting respiratory distress syndrome (RDS) not responding to surfactant often receive a second instillation. Few studies evaluated the consequences of this second administration. This study aimed at determining the outcome of infants presenting persistent RDS and receiving an early second dose of surfactant.

Methods:Infants below 32 weeks' gestation who received a second dose of 100mg/kg of surfactant within the first 72 h of life, were retrospectively involved in this 42 months' study. They were matched to two controls receiving a single dose of 200mg/Kg based upon gender and gestational age.

Results:52/156 infants receiving two doses (Group 2-doses) were significantly more often SGA [22 (42%) vs. 21 (20%)p= 0.04] and outborn [29 (56%) vs. 13 (12%)p= 0.001]. They had received antenatal corticos teroid therapy less often [26 (50%) vs. 89 (86%)p= 0.001] and presented more severe RDS based upon FiO2 level, oxygenation index and radiography. Group 2-doses survival was lower (65.4% vs. 79.6 %p< 0.1) but surviving infants did not have different morbidity than controls.

Discussion:Premature newborn receiving a second dose of surfactant had adverse antenatal characteristics, presented more severe RDS and only partially responded to the first dose. Outcomes of surviving infants who received 2 doses of surfactant were comparable to others.
Ultrasound Monitoring of Umbilical Catheters in the Neonatal Intensive Care Unit—A Prospective Observational Study
Authors: Sobczak Alina , Dudzik Aleksandra , Kruczek Piotr , Kwinta Przemko
Published: April 2021

Introduction:Umbilical catheterization provides a quick yet demanding central line that can lead to complications seen nowhere else. The aim of our study was to determine whether the repeated ultrasound scanning can influence the catheterization time, prevent some of the catheter-related complications, support the decision-making process and allow prolonged catheterization in patients without an alternative central access route.

Methods:A prospective observational study was performed in a tertiary neonatal intensive care unit. A total of 129 patients and 194 umbilical catheters (119 venous and 75 arterial) were analyzed with a total of 954 scans. Ultrasound screening consisted of 1) assessing the catheter tip, location, movability, and surface and 2) analyzing the catheter trajectory. The outcome variables were defined as 1) catheter dislocation and 2) associated thrombosis.

Results:Dislocation of catheter throughout the whole catheterization period was observed in 68% (81/119) of UVCs and 23% (17/75) of UACs. Thrombotic complications were observed in 34.5% (41/119) of UVCs and 12% (9/75) of UACs. 1/3 of UAC-associated thrombi were visible only after catheter removal. 51% (61/119) of UVC patients and 8% (6/75) of UAC patients made a clinical decision regarding the obtained catheter image.

Conclusion:Bedside ultrasound imaging of catheters supports the decision-making process related to the catheterization duration, shortening the time if abnormalities are detected and allowing a safer prolonged UC stay when an alternative central line cannot be inserted.
Timing, Dosage, and Adherence of Antiretroviral Therapy and Risk of Osteoporosis in Patients With Human Immunodeficiency Virus Infection in Taiwan: A Nested Case-Control Study
Authors: Chiu Mu-Lin , Liang Wen-Miin , Li Ju-Pi , Cheng Chi-Fung , Chiou Jian-Shiun , Ho Mao-Wang , Wu Yang-Chang , Lin Ting-Hsu , Liao Chiu-Chu , Huang Shao-Mei , Tsai Fuu-Jen , Lin Ying-Ju
Published: April 2021

The progression of acquired immunodeficiency syndrome is delayed in patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART). However, long-term ART is associated with adverse effects. Osteoporosis is one of the adverse effects and is a multifactorial systemic skeletal disease associated with bone fragility and an increased risk of fracture. We performed a longitudinal, comprehensive, nested case-control study to explore the effect of ART on the risk of osteoporosis in 104 osteoporotic and 416 non-osteoporotic patients with HIV infection at their average age about 29 years old in Taiwan. Patients with history of ART, current exposure to ART, higher cumulative defined daily doses (DDDs), or higher ART adherence were at a higher risk of osteoporosis (p < 0.05). Patients receiving nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine-lamivudine combination, lamivudine-abacavir combination, and abacavir alone) and protease inhibitor (PI)-containing regimen (lopinavir-ritonavir combination, ritonavir, and atazanavir) had a higher risk of osteoporosis (p < 0.05). Especially, patients receiving high doses of the PIs lopinavir-ritonavir combination had an increased risk of osteoporosis (p < 0.05). In conclusion, history of ART, current exposure to ART, higher cumulative DDDs, and higher ART adherence were associated with an increased risk of osteoporosis. Furthermore, NRTI- and PI-containing regimens and high doses of PIs lopinavir-ritonavir combination may be associated with an increased risk of osteoporosis in patients with HIV infection in Taiwan.
Intermittent Hypoxic Preconditioning: A Potential New Powerful Strategy for COVID-19 Rehabilitation
Authors: Cai Ming , Chen Xuan , Shan Jieling , Yang Ruoyu , Guo Qi , Bi Xia , Xu Ping , Shi Xiangrong , Chu Lixi , Wang Liyan
Published: April 2021

COVID-19 is a highly infectious respiratory virus, which can proliferate by invading the ACE2 receptor of host cells. Clinical studies have found that the virus can cause dyspnea, pneumonia and other cardiopulmonary system damage. In severe cases, it can lead to respiratory failure and even death. Although there are currently no effective drugs or vaccines for the prevention and treatment of COVID-19, the patient’s prognosis recovery can be effectively improved by ameliorating the dysfunction of the respiratory system, cardiovascular systems, and immune function. Intermittent hypoxic preconditioning (IHP) as a new non-drug treatment has been applied in the clinical and rehabilitative practice for treating chronic obstructive pulmonary disease (COPD), diabetes, coronary heart disease, heart failure, hypertension, and other diseases. Many clinical studies have confirmed that IHP can improve the cardiopulmonary function of patients and increase the cardiorespiratory fitness and the tolerance of tissues and organs to ischemia. This article introduces the physiological and biochemical functions of IHP and proposes the potential application plan of IHP for the rehabilitation of patients with COVID-19, so as to provide a better prognosis for patients and speed up the recovery of the disease. The aim of this narrative review is to propose possible causes and pathophysiology of COVID-19 based on the mechanisms of the oxidative stress, inflammation, and immune response, and to provide a new, safe and efficacious strategy for the better rehabilitation from COVID-19.
Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization
Authors: Yang Hong-Xia , Sun Jia-Huan , Yao Ting-Ting , Li Yuan , Xu Geng-Rui , Zhang Chuang , Liu Xing-Chao , Zhou Wei-Wei , Song Qiu-Hang , Zhang Yue , Li Ai-Ying
Published: April 2021

Myocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, Gentianella amarella subsp. acuta (Michx.) J.M.Gillett (G. acuta) is a kind of tea used to prevent cardiovascular diseases. Bellidifolin (BEL) is an active xanthone molecule from G. acuta that protects against myocardial damage. However, the effects and mechanisms of BEL on myocardial fibrosis have not been reported. In vivo, BEL dampened isoprenaline (ISO)-induced cardiac structure disturbance and collagen deposition. In vitro, BEL inhibited transforming growth factor (TGF)-β1-induced cardiac fibroblast (CF) proliferation. In vivo and in vitro, BEL decreased the expression of α-smooth muscle actin (α-SMA), collagen Ⅰ and Ⅲ, and inhibited TGF-β1/Smads signaling. Additionally, BEL impeded p38 activation and NR4A1 (an endogenous inhibitor for pro-fibrogenic activities of TGF-β1) phosphorylation and inactivation in vitro. In CFs, inhibition of p38 by SB203580 inhibited the phosphorylation of NR4A1 and did not limit Smad3 phosphorylation, and blocking TGF-β signaling by LY2157299 and SB203580 could decrease the expression of α-SMA, collagen I and III. Overall, both cell and animal studies provide a potential role for BEL against myocardial fibrosis by inhibiting the proliferation and phenotypic transformation of CFs. These inhibitory effects might be related to regulating TGF-β1/Smads pathway and p38 signaling and preventing NR4A1 cytoplasmic localization.
Boosting Akt Pathway by Rupatadine Modulates Th17/Tregs Balance for Attenuation of Isoproterenol-Induced Heart Failure in Rats
Authors: Ahmed Lamiaa A. , Mohamed Ahmed F. , Abd El-Haleim Enas A. , El-Tanbouly Dalia M.
Published: April 2021

Disruption of Th17/Tregs homeostasis plays a crucial role in governing the immune response during myocardial fibrosis and its progression to heart failure. The present study aimed to assess for the first time the possible protection afforded by rupatadine against isoproterenol-induced heart failure in rats. It also explored the role of PI3k/Akt as a possible mechanistic pathway, through which rupatadine could modulate Th17/Tregs balance to display its effect. Isoproterenol (85 and 170 mg/kg/day) was injected subcutaneously for 2 successive days, respectively and rupatadine (4 mg/kg/day) was then given orally for 14 days with or without wortmannin (PI3K/Akt inhibitor). Rupatadine succeeded to completely ameliorate isoproterenol-induced cardiac dysfunction as demonstrated by improvements of electrocardiographic and echocardiographic measurements. Moreover, rupatadine prevented the marked elevation of PAF and oxidative stress in addition to Th17 promoting cytokines (IL-6, IL-23, and TGF-β). Accordingly, rupatadine prevented Th17 stimulation or expansion as indicated by increased Foxp3/RORγt ratio and decreased production of its pro-inflammatory cytokine (IL-17). Rupatadine treatment mitigated isoproterenol-induced activation of STAT-3 signaling and the imbalance in p-Akt/total Akt ratio affording marked decrease in atrogin-1 and apoptotic biomarkers. Finally, this therapy was effective in averting cardiac troponin loss and reverting the histological alterations as assessed by myocardial fibrosis and hypertrophy grading. Contrariwise, co-administration of wortmannin mostly attenuated the protective effects of rupatadine affording more or less similar results to that of isoproterenol-untreated rats. In conclusion, rupatadine could be an effective therapy against the development of isoproterenol-induced heart failure where PI3K/Akt pathway seems to play a crucial role in its protective effect.