bluuebunny/crossref_metadata_2025 huggingface dataset:
Pregnancy Complications and Neonatal Mortality in a Serotonin Transporter Null Mouse Model: Insight Into the Use of Selective Serotonin Reuptake Inhibitor During Pregnancy
Authors: Domingues Rafael R. , Wiltbank Milo C. , Hernandez Laura L.
Published: March 2022

Selective serotonin reuptake inhibitors (SSRI) are widely prescribed to pregnant woman. Although some SSRI compounds are known to cause pregnancy loss and fetal malformations, other SSRI continue to be used by pregnant women. However, several studies have associated the use of SSRI with adverse pregnancy outcomes: intrauterine growth restriction, preterm birth, and neonatal morbidity. Nonetheless, interpretation of studies in humans are typically complicated by the adverse pregnancy outcomes caused by depression itself. Therefore, we used a mutant mouse model with genetic ablation of the serotonin transporter, the target site for SSRI, to unravel the role of the serotonin transporter on pregnancy outcomes. The serotonin transporter null mice had increased pregnancy loss (17.5 vs. 0%), decreased number of pups born (6.6 ± 0.2 vs. 7.5 ± 0.2), and increased neonatal mortality (2.3-fold). Furthermore, preterm birth, dystocia, and fetal malformations were only observed in serotonin transporter null mice. This genetically ablated serotonin transporter mouse recapitulates several adverse pregnancy outcomes similar to those in women undergoing SSRI treatment during gestation. Additionally, neonatal loss in the present study reproduced a sudden infant death phenotype as in humans and mice with altered serotonergic signaling. In conclusion, findings from this study demonstrate a role for serotonin transporter in pregnancy maintenance and neonatal health. Additionally, it suggests that the adverse pregnancy outcomes in women taking SSRI during gestation might be due to altered serotonin transporter function caused by SSRI independent of underlying depression. This is a critical finding, given the number of women prescribed SSRI during pregnancy, and provides the framework for critical research in this area.
Heat Shock Response of the Active Microbiome From Perennial Cave Ice
Authors: Mondini Antonio , Anwar Muhammad Zohaib , Ellegaard-Jensen Lea , Lavin Paris , Jacobsen Carsten Suhr , Purcarea Cristina
Published: March 2022

Ice caves constitute the newly investigated frozen and secluded model habitats for evaluating the resilience of ice-entrapped microbiomes in response to climate changes. This survey identified the total and active prokaryotic and eukaryotic communities from millennium-old ice accumulated in Scarisoara cave (Romania) using Illumina shotgun sequencing of the ribosomal RNA (rRNA) and messenger RNA (mRNA)-based functional analysis of the metatranscriptome. Also, the response of active microbiome to heat shock treatment mimicking the environmental shift during ice melting was evaluated at both the taxonomic and metabolic levels. The putatively active microbial community was dominated by bacterial taxa belonging to Proteobacteria and Bacteroidetes, which are highly resilient to thermal variations, while the scarcely present archaea belonging to Methanomicrobia was majorly affected by heat shock. Among eukaryotes, the fungal rRNA community was shared between the resilient Chytridiomycota and Blastocladiomycota, and the more sensitive Ascomycota and Basidiomycota taxa. A complex microeukaryotic community highly represented by Tardigrada and Rotifera (Metazoa), Ciliophora and Cercozoa (Protozoa), and Chlorophyta (Plantae) was evidenced for the first time in this habitat. This community showed a quick reaction to heat shock, followed by a partial recovery after prolonged incubation at 4°C due to possible predation processes on the prokaryotic cluster. Analysis of mRNA differential gene expression revealed the presence of an active microbiome in the perennial ice from the Scarisoara cave and associated molecular mechanisms for coping with temperature variations by the upregulation of genes involved in enzyme recovery, energy storage, carbon and nitrogen regulation, and cell motility. This first report on the active microbiome embedded in perennial ice from caves and its response to temperature stress provided a glimpse into the impact of glaciers melting and the resilience mechanisms in this habitat, contributing to the knowledge on the functional role of active microbes in frozen environments and their response to climatic changes.
Inactivated Vaccines Against SARS-CoV-2: Neutralizing Antibody Titers in Vaccine Recipients
Authors: Zhang Haiying , Jia Yuyuan , Ji Ying , Cong Xu , Liu Yan , Yang Ruifeng , Kong Xiangsha , Shi Yijun , Zhu Ling , Wang Zhenyu , Wang Wei , Fei Ran , Liu Feng , Lu Fengmin , Chen Hongsong , Rao Huiying
Published: March 2022

Background

Although effective vaccines have been developed against coronavirus disease 2019 (COVID-19), the level of neutralizing antibodies (NAbs) induced after vaccination in the real world is still unknown. The aim of this work was to evaluate the level and persistence of NAbs induced by two inactivated COVID-19 vaccines in China.

Methods

Serum samples were collected from 1,335 people aged 18 years and over who were vaccinated with an inactivated COVID-19 vaccine at Peking University People’s Hospital from January 19 to June 23, 2021, for the detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies.

Results

The positive rate for NAbs against SARS-CoV-2 was 79–91% from the first month to the second month after the second vaccine dose. The gradual decline in positivity rate for NAb response was observed from 78% at 3 months post-vaccination to 0% at 12 months post-vaccination. When there was a 21-day interval between the two doses of vaccine, the NAb positivity rate was 0% 6 months after the second dose. NAb levels were significantly higher when the interval between two doses were 3–8 weeks than when it was 0–3 weeks (χ2 = 14.04, p < 0.001). There was a linear correlation between NAbs and IgG antibodies in 1,335 vaccinated patients. NAb levels decreased in 31 patients (81.6%) and increased in 7 patients (18.4%) over time in the series of 38 patients after the second vaccination. The NAb positivity rate was significantly higher in 18- to 40-year-old subjects than in 41- to 60-year-old subjects (t = −1.959, p < 0.01; t = 0.839, p < 0.01).

Conclusion

The NAb positivity rate was the highest at the first and second month after the second dose of vaccine, and gradually decreased over time. With a 21-day interval between two doses of vaccine, neutralizing antibody levels persisted for only 6 months after the second dose of vaccine. Therefore, a third vaccine dose is recommended. Our results suggest that in cases in which NAbs cannot be detected, IgM/IgG antibodies can be detected instead. The level of NAbs produced after vaccination was affected by age but not by sex. Our results suggest that an interval of 21 to 56 days between shots is suitable for vaccination.
Prudent Antimicrobial Use Is Essential to Prevent the Emergence of Antimicrobial Resistance in Yersinia enterocolitica 4/O:3 Strains in Pigs
Authors: Koskinen Juho , Ortiz-Martínez Pilar , Keto-Timonen Riikka , Joutsen Suvi , Fredriksson-Ahomaa Maria , Korkeala Hannu
Published: March 2022

Yersinia enterocolitica is a psychrotrophic zoonotic foodborne pathogen. Pigs are considered the main reservoir of Y. enterocolitica 4/O:3, which is the most commonly isolated bioserotype in many European countries. Consuming pork contaminated with Y. enterocolitica can be a health threat, and antimicrobial-resistant strains may complicate the treatment of the most severe forms of yersiniosis. We analyzed the antimicrobial resistance of 1,016 pathogenic porcine Y. enterocolitica 4/O:3 strains originating from Belgium, Estonia, Finland, Germany, Italy, Latvia, Russia, Spain, and the United Kingdom. Based on available reports, we also compared antimicrobial sales for food production animals in these countries, excluding Russia. Antimicrobial resistance profiles were determined using a broth microdilution method with VetMIC plates for 13 antimicrobial agents: ampicillin, cefotaxime, ceftiofur (CTF), chloramphenicol (CHL), ciprofloxacin, florfenicol, gentamicin, kanamycin, nalidixic acid (NAL), streptomycin (STR), sulfamethoxazole (SME), tetracycline (TET), and trimethoprim (TMP). The antimicrobial resistance of Y. enterocolitica 4/O:3 strains varied widely between the countries. Strains resistant to antimicrobial agents other than ampicillin were rare in Estonia, Finland, Latvia, and Russia, with prevalence of 0.7, 0.4, 0, and 8.3%, respectively. The highest prevalence of antimicrobial resistance was found in Spanish and Italian strains, with 98 and 61% of the strains being resistant to at least two antimicrobial agents, respectively. Resistance to at least four antimicrobial agents was found in 34% of Spanish, 19% of Italian, and 7.1% of English strains. Antimicrobial resistance was more common in countries where the total sales of antimicrobials for food production animals are high and orally administered medications are common. Our results indicate that antimicrobials should be used responsibly to treat infections, and parenteral medications should be preferred to orally administered mass medications.
An Overview of the Mechanisms Against “Candidatus Liberibacter asiaticus”: Virulence Targets, Citrus Defenses, and Microbiome
Authors: Yang Chuanyu , Ancona Veronica
Published: March 2022

Citrus Huanglongbing (HLB) or citrus greening, is the most destructive disease for citrus worldwide. It is caused by the psyllid-transmitted, phloem-limited bacteria “CandidatusLiberibacter asiaticus” (CLas). To date, there are still no effective practical strategies for curing citrus HLB. Understanding the mechanisms againstCLas can contribute to the development of effective approaches for combatting HLB. However, the unculturable nature ofCLas has hindered elucidating mechanisms againstCLas. In this review, we summarize the main aspects that contribute to the understanding about the mechanisms againstCLas, including (1)CLas virulence targets, focusing on inhibition of virulence genes; (2) activation of citrus host defense genes and metabolites of HLB-tolerant citrus triggered byCLas, and by agents; and (3) we also review the role of citrus microbiome in combattingCLas. Finally, we discuss novel strategies to continue studying mechanisms againstCLas and the relationship of above aspects.
A Novel Elastomeric UNet for Medical Image Segmentation
Authors: Cai Sijing , Wu Yi , Chen Guannan
Published: March 2022

Medical image segmentation is of important support for clinical medical applications. As most of the current medical image segmentation models are limited in the U-shaped structure, to some extent the deep convolutional neural network (CNN) structure design is hard to be accomplished. The design in this study mimics the way the wave is elastomeric propagating, extending the structure from both the horizontal and spatial dimensions for realizing the Elastomeric UNet (EUNet) structure. The EUNet can be divided into two types: horizontal EUNet and spatial EUNet, based on the propagation direction. The advantages of this design are threefold. First, the training structure can be deepened effectively. Second, the independence brought by each branch (a U-shaped design) makes the flexible design redundancy available. Finally, a horizontal and vertical series-parallel structure helps on feature accumulation and recursion. Researchers can adjust the design according to the requirements to achieve better segmentation performance for the independent structural design. The proposed networks were evaluated on two datasets: a self-built dataset (multi-photon microscopy, MPM) and publicly benchmark retinal datasets (DRIVE). The results of experiments demonstrated that the performance of EUNet outperformed the UNet and its variants.
Microvascular Changes in Parkinson’s Disease- Focus on the Neurovascular Unit
Authors: Paul Gesine , Elabi Osama F.
Published: March 2022

Vascular alterations emerge as a common denominator for several neurodegenerative diseases. In Parkinson’s disease (PD), a number of observations have been made suggesting that the occurrence of vascular pathology is an important pathophysiological aspect of the disease. Specifically, pathological activation of pericytes, blood-brain barrier (BBB) disruption, pathological angiogenesis and vascular regression have been reported. This review summarizes the current evidence for the different vascular alterations in patients with PD and in animal models of PD. We suggest a possible sequence of vascular pathology in PD ranging from early pericyte activation and BBB leakage to an attempt for compensatory angiogenesis and finally vascular rarefication. We highlight different pathogenetic mechanisms that play a role in these vascular alterations including perivascular inflammation and concomitant metabolic disease. Awareness of the contribution of vascular events to the pathogenesis of PD may allow the identification of targets to modulate those mechanisms. In particular the BBB has for decades only been viewed as an obstacle for drug delivery, however, preservation of its integrity and/or modulation of the signaling at this interface between the blood and the brain may prove to be a new avenue to take in order to develop disease-modifying strategies for neurodegenerative disorders.
IoT-Enabled Integrated Smart Wound Sensor for Multiplexed Monitoring of Inflammatory Biomarkers at the Wound Site
Authors: Noushin Tanzila , Hossain Nafize Ishtiaque , Tabassum Shawana
Published: March 2022

Chronic wounds that stall at the inflammatory phase of healing may create several life-threatening complications such as tissue damage, septicemia, and organ failures. In order to prevent these adverse clinical outcomes and accelerate the wound healing process, it is crucial to monitor the wound status in real-time so that immediate therapeutic interventions can be implemented. In addition, continuous monitoring of the wound status can prevent drug overdose at the wound site, leading to on-demand and personalized drug delivery. Inflammatory mediators, such as Interleukin-6 (IL-6) and Interleukin-10 (IL-10) are promising indicators for the progression of wound healing and predictors of disease severity. Toward this end, this work reports a flexible wound patch for multiplexed monitoring of IL-6 and IL-10 at the wound site in order to provide real-time feedback on the inflammation phase of the wound. An optimized composition of gold nanoparticles integrated multiwalled carbon nanotube was demonstrated to improve sensor performance substantially. The sensor also exhibited excellent repeatable, reversible, and drift characteristics. A miniaturized Internet-of-things (IoT)-enabled potentiostat was also developed and integrated with the flexible sensor to realize a wearable system. This IoT-enabled wearable device provides a smart and cost-effective solution to improving the existing wound care through continuous, real-time, and in-situ monitoring of multiple wound biomarkers.
Neuroinflammation in a Rat Model of Tourette Syndrome
Authors: Zhongling Ke , Yanhui Chen , Guofeng Chen , Yanyan Liu
Published: March 2022

Objective

Tourette syndrome (TS) is a group of childhood-onset chronic neuropsychiatric disorders characterized by tics, i.e., repetitive, sudden, and involuntary movements or vocalizations, which is often associated with various psychopathological and/or behavioral comorbidities, including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, depression, and sleep disorders and have a worse prognosis. The mechanism of TS is still not clear. The relationship between immune activation, neuroinflammation, and neuropsychiatric disorders has attracted much attention in the past two decades. To explore the underlying mechanism in TS, the relationship between neuroinflammation and behavioral alterations in TS rats was investigated in this study.

Methods

A total of 36 Sprague-Dawley male rats were divided into three groups randomly as follows: the TS, control (CON), and drug intervention groups. The TS rat group was treated with haloperidol (Hal) (the TS + Hal group). The TS rat model was established using 3,3-iminodipropionitrile (IDPN), which is a well-known animal model of TS. The behavioral syndromes, brain tissue cytokines, like interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), and microglial activation of the three groups were assessed.

Results

The behavioral scores of rats in the TS group and the TS + Hal group were higher than those in the CON group (P < 0.05), but the scores of behavioral tests in the TS + Hal group were lower than those in the TS group (P < 0.05). The levels of IL-6 and TNF-α in the rat brain tissue were significantly higher in the TS group than in the CON group (P < 0.05), while no significant differences were found between the CON group and the TS + Hal group (P > 0.05). The microglia was significantly activated in the TS group and slightly activated in the TS + Hal group, which was considerably less than that in the TS group.

Conclusion

The IDPN-induced TS rats had significant neuroinflammation in the brain, and the interaction between dopamine (DA) dysregulation and immune dysfunction may play a vital role in the pathogenic mechanisms of TS.
Late-Onset MS: Disease Course and Safety-Efficacy of DMTS
Authors: Buscarinu Maria Chiara , Reniè Roberta , Morena Emanuele , Romano Carmela , Bellucci Gianmarco , Marrone Antonio , Bigi Rachele , Salvetti Marco , Ristori Giovanni
Published: March 2022

Multiple sclerosis (MS), an inflammatory demyelinating and neurodegenerative disease of the central nervous system, usually begins between the ages of 20 and 49 years, though in rare cases it is diagnosed in childhood and adolescence before the age of 18 years, or at the age of 50 years and later. When the onset of the disease occurs at 50 years or older it is conventionally defined as late onset MS (LOMS). Compared to classical MS, the LOMS is characterized by progressive course, a greater delay in diagnosis and a higher prevalence of motor disability. The older the patients, the greater is the risk of comorbidities that can negatively influence the course of the disease and can limit therapeutic strategies. To date, there is no study focused on the efficacy of Disease Modifying Therapies (DMT) in older patients with MS. The only data available are retrievable from subgroup analysis from phase-3 trials of DMT efficacy. In this work, we discuss how the aging process influences the onset, the clinical course and the therapeutic approach in LOMS.
The Role of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in the Context of Aneurysmal Subarachnoid Hemorrhage (aSAH)—A Prospective Observational Study
Authors: Schmidt Tobias P. , Albanna Walid , Weiss Miriam , Veldeman Michael , Conzen Catharina , Nikoubashman Omid , Blume Christian , Kluger Daniel S. , Clusmann Hans , Loosen Sven H. , Schubert Gerrit A.
Published: March 2022

Objective

Outcome after aneurysmal subarachnoid hemorrhage (aSAH) is highly variable and largely determined by early brain injury and delayed cerebral ischemia (DCI). Soluble urokinase plasminogen activator receptor (suPAR) represents a promising inflammatory marker which has previously been associated with outcome in traumatic brain injury and stroke patients. However, its relevance in the context of inflammatory changes after aSAH is unclear. Here, we aimed to characterize the role of circulating suPAR in both serum and cerebrospinal fluid (CSF) as a novel biomarker for aSAH patients.

Methods

A total of 36 aSAH patients, 10 control patients with unruptured abdominal aneurysm and 32 healthy volunteers were included for analysis. suPAR was analyzed on the day of admission in all patients. In aSAH patients, suPAR was also determined on the day of DCI and the respective time frame in asymptomatic patients. One- and two-sample t-tests were used for simple difference comparisons within and between groups. Regression analysis was used to assess the influence of suPAR levels on outcome in terms of modified Rankin score.

Results

Significantly elevated suPAR serum levels (suPAR-SL) on admission were found for aSAH patients compared to healthy controls, but not compared to vascular control patients. Disease severity as documented according to Hunt and Hess grade and modified Fisher grade was associated with higher suPAR CSF levels (suPAR-CSFL). In aSAH patients, suPAR-SL increased daily by 4%, while suPAR-CSFL showed a significantly faster daily increase by an average of 22.5% per day. Each increase of the suPAR-SL by 1 ng/ml more than tripled the odds of developing DCI (OR = 3.06). While admission suPAR-CSFL was not predictive of DCI, we observed a significant correlation with modified Rankin's degree of disability at discharge.

Conclusion

Elevated suPAR serum level on admission as a biomarker for early inflammation after aSAH is associated with an increased risk of DCI. Elevated suPAR-CSFL levels correlate with a higher degree of disability at discharge. These distinct relations and the observation of a continuous increase over time affirm the role of inflammation in aSAH and require further study.
Is There Evidence for the Specificity of Closed-Loop Brain Training in the Treatment of Internalizing Disorders? A Systematic Review
Authors: Perez Tyson Michael , Mathew Jerin , Glue Paul , Adhia Divya B. , De Ridder Dirk
Published: March 2022

Introduction

Internalizing disorders (IDs), e.g., major depressive disorder (MDD), posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) are the most prevalent psychopathologies experienced worldwide. Current first-line therapies (i.e., pharmacotherapy and/or psychotherapy) offer high failure rates, limited accessibility, and substantial side-effects. Electroencephalography (EEG) guided closed-loop brain training, also known as EEG-neurofeedback (EEG-NFB), is believed to be a safe and effective alternative, however, there is much debate in the field regarding the existence of specificity [i.e., clinical effects specific to the modulation of the targeted EEG variable(s)]. This review was undertaken to determine if there is evidence for EEG-NFB specificity in the treatment of IDs.

Methods

We considered only randomized, double-blind, sham-controlled trials. Outcomes of interest included self/parent/teacher reports and clinician ratings of ID-related symptomatology.

Results

Of the four reports (total participant number = 152) meeting our eligibility criteria, three had point estimates suggesting small to moderate effect sizes favoring genuine therapy over sham, however, due to small sample sizes, all 95% confidence intervals (CIs) were wide and spanned the null. The fourth trial had yet to post results as of the submission date of this review. The limited overall number of eligible reports (and participants), large degree of inter-trial heterogeneity, and restricted span of ID populations with published/posted outcome data (i.e., PTSD and OCD) precluded a quantitative synthesis.

Discussion

The current literature suggests that EEG-NFB may induce specific effects in the treatment of some forms of IDs, however, the evidence is very limited. Ultimately, more randomized, double-blind, sham-controlled trials encompassing a wider array of ID populations are needed to determine the existence and, if present, degree of EEG-NFB specificity in the treatment of IDs.

Systematic Review Registration

[https://www.crd.york.ac.uk/prospero], identifier [CRD42020159702].
Prognostic Role of the Neutrophil-to-Lymphocyte Ratio in Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis
Authors: Shi Min , Li Xiao-feng , Zhang Ting-bao , Tang Qing-wen , Peng Mian , Zhao Wen-yuan
Published: March 2022

The neutrophil-to-lymphocyte ratio (NLR) plays an important role in the progression of intracerebral hemorrhage (ICH). An increasing number of studies have reported that a high NLR is correlated with poor clinical outcomes among patients with ICH. Here, we conducted a systematic review and meta-analysis to evaluate the prognostic value of NLR in the setting of ICH. We performed a comprehensive search of electronic literature databases to identify all relevant studies evaluating the prognostic role of NLR in patients with ICH. Two researchers independently screened the studies and extracted relevant data. We extracted, pooled, and weighted odds ratio (OR) and 95% confidence interval (CI) values using a generic inverse-variance method, and then evaluated the heterogeneity among studies using Q test and I2 statistic. Finally, we selected a total of 26 studies including 7,317 patients for the current study. Overall, our results indicated that a high NLR was significantly associated with a poor outcome (OR, 1.32; 95% CI, 1.19–1.46; P < 0.00001), mortality (OR, 1.05; 95% CI, 1.01–1.09; P = 0.02), and neurological deterioration (OR, 1.65; 95% CI, 1.08–2.52; P = 0.02). We did not observe a significant association between NLR and hematoma expansion (OR, 1.04; 95% CI, 0.99–1.08; P = 0.09). Our study indicated that a high NLR is significantly associated with poor clinical outcomes in patients with ICH. As NLR is a simple and easily available biomarker, future studies should focus on exploring its application in the prognostic evaluation of patients with ICH.
How Tilting the Head Interferes With Eye-Hand Coordination: The Role of Gravity in Visuo-Proprioceptive, Cross-Modal Sensory Transformations
Authors: Bernard-Espina Jules , Dal Canto Daniele , Beraneck Mathieu , McIntyre Joseph , Tagliabue Michele
Published: March 2022

To correctly position the hand with respect to the spatial location and orientation of an object to be reached/grasped, visual information about the target and proprioceptive information from the hand must be compared. Since visual and proprioceptive sensory modalities are inherently encoded in a retinal and musculo-skeletal reference frame, respectively, this comparison requires cross-modal sensory transformations. Previous studies have shown that lateral tilts of the head interfere with the visuo-proprioceptive transformations. It is unclear, however, whether this phenomenon is related to the neck flexion or to the head-gravity misalignment. To answer to this question, we performed three virtual reality experiments in which we compared a grasping-like movement with lateral neck flexions executed in an upright seated position and while lying supine. In the main experiment, the task requires cross-modal transformations, because the target information is visually acquired, and the hand is sensed through proprioception only. In the other two control experiments, the task is unimodal, because both target and hand are sensed through one, and the same, sensory channel (vision and proprioception, respectively), and, hence, cross-modal processing is unnecessary. The results show that lateral neck flexions have considerably different effects in the seated and supine posture, but only for the cross-modal task. More precisely, the subjects’ response variability and the importance associated to the visual encoding of the information significantly increased when supine. We show that these findings are consistent with the idea that head-gravity misalignment interferes with the visuo-proprioceptive cross-modal processing. Indeed, the principle of statistical optimality in multisensory integration predicts the observed results if the noise associated to the visuo-proprioceptive transformations is assumed to be affected by gravitational signals, and not by neck proprioceptive signalsper se. This finding is also consistent with the observation of otolithic projections in the posterior parietal cortex, which is involved in the visuo-proprioceptive processing. Altogether these findings represent a clear evidence of the theorized central role of gravity in spatial perception. More precisely, otolithic signals would contribute to reciprocally align the reference frames in which the available sensory information can be encoded.
Systemic Lactate Acts as a Metabolic Buffer in Humans and Prevents Nutrient Overflow in the Postprandial Phase
Authors: Schlicker Lisa , Zhao Gang , Dudek Christian-Alexander , Boers Hanny M. , Meyer-Hermann Michael , Jacobs Doris M. , Hiller Karsten
Published: March 2022

On an organismal level, metabolism needs to react in a well-orchestrated manner to metabolic challenges such as nutrient uptake. Key metabolic hubs in human blood are pyruvate and lactate, both of which are constantly interconverted by very fast exchange fluxes. The quantitative contribution of different food sources to these metabolite pools remains unclear. Here, we applied in vivo stable isotope labeling to determine postprandial metabolic fluxes in response to two carbohydrate sources of different complexity. Depending on the ingested carbohydrate source, glucose or wheat flour, the net direction of the lactate dehydrogenase, and the alanine amino transferase fluxes were adjusted in a way to ensure sufficient availability, while, at the same time, preventing an overflow in the respective metabolite pools. The systemic lactate pool acts as a metabolic buffer which is fueled in the early- and depleted in the late-postprandial phase and thus plays a key role for systemic metabolic homeostasis.
The Influence of Pasture and Non-pasture-Based Feeding Systems on the Aroma of Raw Bovine Milk
Authors: Clarke Holly J. , Fitzpatrick Ellen , Hennessy Deirdre , O'Sullivan Maurice G. , Kerry Joseph P. , Kilcawley Kieran N.
Published: March 2022

Aroma-active compounds in raw bovine milk produced from cows fed perennial ryegrass (GRS) or total mixed ration (TMR) consisting of grass silage, maize silage, and concentrates were identified by direct immersion sorptive extraction (DI Hi-Sorb), coupled with gas-chromatography-mass spectrometry and olfactometry using odour intensity (OI) and aroma extraction dilution analysis (AEDA). Ninety-nine volatile organic compounds (VOC) were identified in these raw GRS and TMR milk samples; 33 of which were also present in the feed and rumen samples from these diets. Only the abundance of 13 VOC varied significantly based on diet. However, the odours of both raw milks were quite distinct as aroma perception is not influenced by abundance alone but also by the odour activity of each VOC. Approximately, 30% of the VOC influenced the aroma perception of these raw milks. This study clearly highlighted the significant impact of VOC transferring from the diet that influenced the aroma perception of both raw GRS and TMR milk. The aroma of the raw TMR milk was more complex than that of the raw GRS milk, and many of the key dietary-derived-odour-active VOC likely arose during the production of the TMR feed as most were either derived from Maillard reactions or impacted by heat. Seventeen of the 44 odour activities detected differed between both sample types. This study has clearly demonstrated the impact of diet on the aroma perception of raw bovine milk.
Deleterious AHNAK2 Mutation as a Novel Biomarker for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer
Authors: Cui Yanan , Liu Xinyin , Wu Yuemin , Liang Xiao , Dai Jiali , Zhang Zhihong , Guo Renhua
Published: March 2022

Immune checkpoint inhibitors (ICIs) have exhibited promising efficacy in non-small cell lung cancer (NSCLC), but the response occurs in only a minority of patients. In clinic, biomarkers such as TMB (tumor mutation burden) and PD-L1 (programmed cell death 1 ligand 1) still have their limitations in predicting the prognosis of ICI treatment. Hence, reliable predictive markers for ICIs are urgently needed. A public immunotherapy dataset with clinical information and mutational data of 75 NSCLC patients was obtained from cBioPortal as the discovery cohort, and another immunotherapy dataset of 249 patients across multiple cancer types was collected as the validation. Integrated bioinformatics analysis was performed to explore the potential mechanism, and immunohistochemistry studies were used to verify it. AHNAK nucleoprotein 2 (AHNAK2) was reported to have pro-tumor growth effects across multiple cancers, while its role in tumor immunity was unclear. We found that approximately 11% of the NSCLC patients harbored AHNAK2 mutations, which were associated with promising outcomes to ICI treatments (ORR, p = 0.013). We further found that AHNAK2 deleterious mutation (del-AHNAK2mut) possessed better predictive function in NSCLC than non-deleterious AHNAK2 mutation (PFS, OS, log-rank p < 0.05), potentially associated with stronger tumor immunogenicity and an activated immune microenvironment. This work identified del-AHNAK2mut as a novel biomarker to predict favorable ICI response in NSCLC.
Case Report: Hepatic Sarcoid-Like Reaction Associated With Checkpoint Inhibition in a NSCLC Patient and a Literature Review
Authors: Lin Yuxin , Zhu Wei , Wu Bingchen , Lan Huiyin
Published: March 2022

Immune checkpoint inhibitor (ICI) treatment has dramatically revolutionized the landscape of therapeutic approaches in multiple cancers, particularly, non-small-cell lung cancer (NSCLC). With the increasing use of programmed death-1 (PD-1) inhibitors in the clinic, the emerging toxicity profile presents a novel learning curve for clinicians. Here we report the first case of an NSCLC patient displaying sarcoid/granulomatous-like reaction (SLR, also known as GLR) in the liver during an anti-PD-1 therapy which showed efficacious response of complete regression. Also, this is the first report describing the SLR induced by toripalimab, a novel PD-1 inhibitor. Given this kind of hepatic findings can be easily mistaken as metastasis, even resulting in premature use of second-line treatments. In particular, we briefly review the clinical features of all those cases reporting sarcoidosis and SLRs manifested on different organs during anti-PD-(L)1 therapy. We anticipate that these clinical cases would help to alert the attention of clinicians that SLRs, as a rare immune-related adverse event (irAE), is manageable and that histopathological analysis is necessary before interpreting it as disease progression.
Fibroblast Activation Protein Specific Optical Imaging in Non-Small Cell Lung Cancer
Authors: Mathieson Layla , O’Connor Richard A. , Stewart Hazel , Shaw Paige , Dhaliwal Kevin , Williams Gareth O. S. , Megia-Fernandez Alicia , Akram Ahsan R.
Published: March 2022

Fibroblast activation protein (FAP) is a cell surface propyl-specific serine protease involved in the regulation of extracellular matrix. Whilst expressed at low levels in healthy tissue, upregulation of FAP on fibroblasts can be found in several solid organ malignancies, including non-small cell lung cancer, and chronic inflammatory conditions such as pulmonary fibrosis and rheumatoid arthritis. Their full role remains unclear, but FAP expressing cancer associated fibroblasts (CAFs) have been found to relate to a poor prognosis with worse survival rates in breast, colorectal, pancreatic, and non-small cell lung cancer (NSCLC). Optical imaging using a FAP specific chemical probe, when combined with clinically compatible imaging systems, can provide a readout of FAP activity which could allow disease monitoring, prognostication and potentially stratify therapy. However, to derive a specific signal for FAP any sequence must retain specificity over closely related endopeptidases, such as prolyl endopeptidase (PREP), and be resistant to degradation in areas of active inflammation. We describe the iterative development of a FAP optical reporter sequence which retains FAP specificity, confers resistance to degradation in the presence of activated neutrophil proteases and demonstrates clinical tractability ex vivo in NSCLC samples with an imaging platform.
Inhibition of Anti-Inflammatory Macrophage Phenotype Reduces Tumour Growth in Mouse Models of Brain Metastasis
Authors: Economopoulos Vasiliki , Pannell Maria , Johanssen Vanessa A. , Scott Helen , Andreou Kleopatra E. , Larkin James R. , Sibson Nicola R.
Published: March 2022

Breast cancer brain metastasis is a significant clinical problem and carries a poor prognosis. Although it is well-established that macrophages are a primary component of the brain metastasis microenvironment, the role of blood-derived macrophages (BDM) and brain-resident microglia in the progression of brain metastases remains uncertain. The aim of this study, therefore, was to determine the role, specifically, of pro- and anti-inflammatory BDM and microglial phenotypes on metastasis progression. Initial in vitro studies demonstrated decreased migration of EO771 metastatic breast cancer cells in the presence of pro-inflammatory, but not anti-inflammatory, stimulated RAW 264.7 macrophages. In vivo, suppression of the anti-inflammatory BDM phenotype, specifically, via myeloid knock out of Krüppel-like Factor 4 (KLF4) significantly reduced EO771 tumour growth in the brains of C57BL/6 mice. Further, pharmacological inhibition of the anti-inflammatory BDM and/or microglial phenotypes, via either Colony Stimulating Factor 1 Receptor (CSF-1R) or STAT6 pathways, significantly decreased tumour burden in two different syngeneic mouse models of breast cancer brain metastasis. These findings suggest that switching BDM and microglia towards a more pro-inflammatory phenotype may be an effective therapeutic strategy in brain metastasis.
Chemical Biology Screening Identifies a Vulnerability to Checkpoint Kinase Inhibitors in TSC2-Deficient Renal Angiomyolipomas
Authors: Vaughan Robert M. , Kordich Jennifer J. , Chan Chun-Yuan , Sasi Nanda K. , Celano Stephanie L. , Sisson Kellie A. , Van Baren Megan , Kortus Matthew G. , Aguiar Dean J. , Martin Katie R. , MacKeigan Jeffrey P.
Published: March 2022

The tuberous sclerosis complex (TSC) is a rare genetic syndrome and multisystem disease resulting in tumor formation in major organs. A molecular hallmark of TSC is a dysregulation of the mammalian target of rapamycin (mTOR) through loss-of-function mutations in either tumor suppressor TSC1 or TSC2. Here, we sought to identify drug vulnerabilities conferred by TSC2 tumor-suppressor loss through cell-based chemical biology screening. Our small-molecule chemical screens reveal a sensitivity to inhibitors of checkpoint kinase 1/2 (CHK1/2), regulators of cell cycle, and DNA damage response, in both in vitro and in vivo models of TSC2-deficient renal angiomyolipoma (RA) tumors. Further, we performed transcriptional profiling on TSC2-deficient RA cell models and discovered that these recapitulate some of the features from TSC patient kidney tumors compared to normal kidneys. Taken together, our study provides a connection between mTOR-dependent tumor growth and CHK1/2, highlighting the importance of CHK1/2 inhibition as a potential antitumor strategy in TSC2-deficient tumors.
Imaging Sub-Cellular Methionine and Insulin Interplay in Triple Negative Breast Cancer Lipid Droplet Metabolism
Authors: Fung Anthony A. , Hoang Khang , Zha Honghao , Chen Derek , Zhang Wenxu , Shi Lingyan
Published: March 2022

Triple negative breast cancer (TNBC) is a particularly aggressive cancer subtype that is difficult to diagnose due to its discriminating epidemiology and obscure metabolome. For the first time, 3D spatial and chemometric analyses uncover the unique lipid metabolome of TNBC under the tandem modulation of two key metabolites – insulin and methionine - using non-invasive optical techniques. By conjugating heavy water (D2O) probed Raman scattering with label-free two-photon fluorescence (TPF) microscopy, we observed altered de novo lipogenesis, 3D lipid droplet morphology, and lipid peroxidation under various methionine and insulin concentrations. Quantitative interrogation of both spatial and chemometric lipid metabolism under tandem metabolite modulation confirms significant interaction of insulin and methionine, which may prove to be critical therapeutic targets, and proposes a powerful optical imaging platform with subcellular resolution for metabolic and cancer research.
Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases
Authors: Alam Manzar , Ahmed Sarfraz , Elasbali Abdelbaset Mohamed , Adnan Mohd , Alam Shoaib , Hassan Md. Imtaiyaz , Pasupuleti Visweswara Rao
Published: March 2022

Caffeic acid (CA) is found abundantly in fruits, vegetables, tea, coffee, oils, and more. CA and its derivatives have been used for many centuries due to their natural healing and medicinal properties. CA possesses various biological and pharmacological activities, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The potential therapeutic effects of CA are mediated via repression and inhibition of transcription and growth factors. CA possesses potential anticancer and neuroprotective effects in human cell cultures and animal models. However, the biomolecular interactions and pathways of CA have been described highlighting the target binding proteins and signaling molecules. The current review focuses on CA’s chemical, physical, and pharmacological properties, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. We further described CA’s characteristics and therapeutic potential and its future directions.
Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective
Authors: Huang Jian , Lin Biyun , Li Benyi
Published: March 2022

Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.
Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene
Authors: Liu Shu , Wang Zhiqing , Zheng Xianhua , Zhang Ye , Wei Sisi , OuYang Haimei , Liang Jinqun , Chen Nuan , Zeng Weihong , Jiang Jianhui
Published: March 2022

Background

Severe hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.

Methods

The 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.

Results

The infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.

Conclusions

Our study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.
Predictors of Survival Among Preterm Neonates Admitted to Felege Hiwot Comprehensive Specialized Hospital, Northwest Ethiopia
Authors: Belay Demeke Mesfin , Worku Workie Zemene , Wondim Amare , Hailemeskel Habtamu Shimels , Bayih Wubet Alebachew
Published: March 2022

Background

Pre-maturity is the primary cause of neonatal mortality in the world. Although prematurity was the leading cause of neonatal mortality, the survival rate and its predictors may be varied from setting to setting and time to time due to different reasons. Therefore, this study aimed to assess the survival probability and predictors of mortality among preterm neonates at Felege Hiwot comprehensive specialized hospital.

Methods

This is a retrospective follow-up study that included 542 randomly selected preterm neonates admitted at Felege Hiwot comprehensive specialized hospital from the period of 2016-2020. Semi-parametric and parametric survival models were fitted to identify the survival probability of preterm neonates and its association with different predictors. The best fit model was selected using Akaike's information criteria, Bayesian information criteria and likelihood ratio criteria.

Results

The cumulative incidence and incidence rate of mortality among preterm neonates were 31 per 100 live births and 3.5 per 100 neonate days, respectively. From the adjusted cox-proportional-hazard model, predictors with higher preterm mortality risk include the presence of neonatal respiratory distress syndrome [AHR = 2.55, 95% CI: 1.23; 3.74], perinatal asphyxia [AHR = 4.26, 95% CI: 1.35; 6.79] and jaundice [AHR = 3.25, 95% CI: 2.14, 7.24]. However, admission weight of 1,500–2,499 g (AHR = 0.23, 95% CI: 0.11, 0.56) and ≥2,500 g (AHR = 0.12, 95% CI: 0.02; 0.32), early breastfeeding [AHR = 0.44, 95% CI: 0.36; 0.48] and kangaroo mother care [AHR = 0.11, 95% CI: 0.03; 0.15] were protective factors of preterm mortality.

Conclusion

The cumulative incidence of mortality among preterm neonates was consistent with the national incidence of preterm mortality. Factors such as respiratory distress syndrome, perinatal asphyxia, breastfeeding, kangaroo mother care, admission weight, and jaundice are significant predictors of survival. Therefore, considerable attention such as intensive phototherapy, optimal calorie feeding, oxygenation, and good thermal care should be given for admitted preterm neonates.