bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Dissection of a Prevalent Plasmid-Encoded Conjugation System in Lactococcus lactis
Authors: Ortiz Charneco Guillermo , Kelleher Philip , Buivydas Andrius , Streekstra Hugo , van Themaat Emiel Ver Loren , de Waal Paul P. , Mahony Jennifer , van Sinderen Douwe
Published: May 2021

Plasmid pNP40, which was first identified nearly 40 years ago in Lactococcus lactis subsp. lactis biovar diacetylactis DRC3, encodes functions such as heavy metal-, bacteriophage-, and nisin-resistance, as well as plasmid transfer ability by conjugation. Here, we report an optimized conjugation protocol for this plasmid, yielding a transfer frequency that is approximately 4,000-fold higher than those previously reported in literature, while we also observed high-frequency plasmid co-mobilization. Individual mutations in 18 genes that encompass the presumed conjugation cluster of pNP40 were generated using ssDNA recombineering to evaluate the role of each gene in the conjugation process. A possible transcriptional repressor of this conjugation cluster, the product of the traR gene, was identified in this manner. This mutational analysis, paired with bioinformatic predictions as based on sequence and structural similarities, allowed us to generate a preliminary model of the pNP40 conjugation machinery.
Green Approach: ‘‘A Forwarding Step for Curing Leishmaniasis—A Neglected Tropical Disease’’
Authors: Sharma Lakshika , Dhiman Mamta , Singh Abhijeet , Sharma M. M.
Published: May 2021

The present review focuses on a dreaded vector-mediated leishmaniasis, with the existing therapeutic approaches including a variety of drugs along with their limitations, the treatment with natural compounds, and different types of metal/metal oxide nanoparticles (NPs). As evidenced, various metallic NPs, comprising silver, silver oxide, gold, zinc oxide, titanium, lead oxide, etc., played a curative role to treat leishmaniasis, are also presented. Keeping in view the advance success of vaccines against the prevalent dreaded diseases in the past and the present scenario, efforts are also being made to develop vaccines based on these NP formulations.
CRISPReader System Sensing the Ets-1 Transcription Factor Can Effectively Identify Cancer Cells
Authors: Yang Kang , Zhou Yan , Zhong Hongcai
Published: May 2021

By targeting key genes, the CRISPR system can effectively exert its anti-cancer activity. The latest research suggests that the CRISPReader system that regulates gene transcription can effectively target and inhibit bladder cancer cells by sensing transcription factors such as c-Myc and Get-1 in the cell. An interesting question is whether the CRISPReader system can exert its anti-cancer ability against a variety of tumors by sensing the broad-spectrum transcription factor Ets-1. In this work, a CRISPReader system that senses the Ets-1 transcription factor has been constructed. It can effectively identify a variety of cancer cell lines, and specifically induce apoptosis in cancer cells. This study fully confirmed the effectiveness of Ets-1 as a broad-spectrum cancer related signal and provided a new anti-cancer tool based on the CRISPReader system.
Immune Crosstalk Between Lymph Nodes and Breast Carcinomas, With a Focus on B Cells
Authors: Alberts Elena , Wall Isobelle , Calado Dinis Pedro , Grigoriadis Anita
Published: May 2021

Lymph nodes (LNs) are highly organized secondary lymphoid organs, and reflective of immune responses to infection, injuries, or the presence of cancer. Extensive molecular and morphological analyses of immune and stromal features in tumors and LNs of breast cancer patients have revealed novel patterns indicative of disease progression. Within LNs, there are dynamic structures called germinal centers (GCs), that act as the immunological hubs for B cell development and generation of affinity matured memory B and antibody-producing plasma cells. Acting as a bridge between systemic and local immunity, associations are observed between the frequency of GCs within cancer-free LNs, the levels of stromal tumor infiltrating lymphocytes, and cancer progression. Scattered throughout the tumor microenvironment (TME) or aggregated in clusters forming tertiary lymphoid structures (TLS), the occurrence of tumor infiltrating B cells (TIL-Bs) has been linked mostly to superior disease trajectories in solid cancers. Recent TIL-Bs profiling studies have revealed a plethora of different TIL-B populations, their functional roles, and whether they are derived from GC reactions in the LN, and/or locally from GC-like structures within the TME remains to be investigated. However, parallels between the immunogenic nature of LNs as a pre-metastatic niche, TIL-B populations within the TME, and the presence of TLS will help to decipher local and widespread TIL-Bs responses and their influence on cancer progression to the lymphatics. Therapies that enhance TIL-Bs responses in the LN GC and/or in GC-like structures in the TME are thus emerging management strategies for breast and other cancer patients.
Better Identification of Cognitive Decline With Interleukin-2 Than With Amyloid and Tau Protein Biomarkers in Amnestic Mild Cognitive Impairment
Authors: Liang Chih-Sung , Tsai Chia-Lin , Lin Guan-Yu , Lee Jiunn-Tay , Lin Yu-Kai , Chu Che-Sheng , Sung Yueh-Feng , Tsai Chia-Kuang , Yeh Ta-Chuan , Chu Hsuan-Te , Su Ming-Wei , Yang Fu-Chi
Published: May 2021

The rate of cognitive decline among patients with amnestic mild cognitive impairment (aMCI) varies, and it is thus crucial to accurately predict the probability of cognitive deterioration in patients with MCI. We compared the potential of cytokines with amyloid beta (Aβ) and tau biomarkers for predicting cognitive decline in patients with aMCI or Alzheimer’s disease (AD). All participants (controls, aMCI, and AD patients) underwent plasma biomarker examinations for Aβ1–40, Aβ1–42, total tau (t-tau), tau phosphorylated at threonine 181 [p-Tau181]), and 29 cytokines and baseline cognitive tests, including Mini-Mental State Examination (MMSE). The correlation between biomarker levels and annual MMSE change during the follow-up was examined. Receiver operating characteristic (ROC) curve analysis was performed to determine whether the statistically significant plasma biomarkers could identify cognitive decline. Higher baseline levels of IL-2, sCD40L, IL-8, and VEGF were associated with a lower annual cognitive decline in the aMCI group, and higher baseline levels of Aβ1–40, IFNγ, IL-5, IL-17A, IL-25, and FGF were associated with a rapid annual cognitive decline in the AD group. IL-2 had a high discriminatory capacity for identifying cognitive decline, with an area under curve (AUC) of 85.7% in the aMCI group, and the AUC was slightly increased when combining IL-2 with Aβ or tau biomarkers. However, none of the biomarkers had a satisfactory discriminatory capacity in the AD group. IL-2 may have a better discriminatory capacity for identifying cognitive decline than Aβ and tau biomarkers in patients with aMCI.
Amitriptyline Decreases GABAergic Transmission in Basal Forebrain Neurons Using an Optogenetic Model of Aging
Authors: Bang Eunyoung , Tobery Angelika , Montgomery Karienn S. , Fincher Annette S. , Earnest David J. , Murchison David A. , Griffith William H.
Published: May 2021

The antidepressant drug amitriptyline is used in the treatment of clinical depression and a variety of neurological conditions such as anxiety, neuropathic pain disorders and migraine. Antidepressants are associated with both therapeutic and untoward effects, and their use in the elderly has tripled since the mid-1990s. Because of this widespread use, we are interested in testing the acute effects of amitriptyline on synaptic transmission at therapeutic concentrations well below those that block voltage-gated calcium channels. We found that 3 μM amitriptyline reduced the frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and reduced quantal content in mice at ages of 7–10 mo. and 23–25 mo., suggesting a presynaptic mechanism of action that does not diminish with age. We employed a reduced synaptic preparation of the basal forebrain (BF) and a new optogenetic aging model utilizing a bacterial artificial chromosome (BAC) transgenic mouse line with stable expression of the channelrhodopsin-2 (ChR2) variant H134R specific for GABAergic neurons [VGAT-ChR2(H134R)-EYFP]. This model enables optogenetic light stimulation of specific GABAergic synaptic terminals across aging. Age-related impairment of circadian behavior was used to confirm predictable age-related changes associated with this model. Our results suggest that low concentrations of amitriptyline act presynaptically to reduce neurotransmitter release and that this action is maintained during aging.
Similar Genetic Architecture of Alzheimer’s Disease and Differential APOE Effect Between Sexes
Authors: Wang Hao , Lo Min-Tzu , Rosenthal Sara Brin , Makowski Carolina , Andreassen Ole A. , Salem Rany M. , McEvoy Linda K. , Fiecas Mark , Chen Chi-Hua
Published: May 2021

Sex differences have been observed in the clinical manifestations of Alzheimer’s disease (AD) and elucidating their genetic basis is an active research topic. Based on autosomal genotype data of 7,216 men and 10,680 women, including 8,136 AD cases and 9,760 controls, we explored sex-related genetic heterogeneity in AD by investigating SNP heritability, genetic correlation, as well as SNP- and gene-based genome-wide analyses. We found similar SNP heritability (men: 19.5%; women: 21.5%) and high genetic correlation (Rg = 0.96) between the sexes. The heritability of APOE ε4-related risks for AD, after accounting for effects of all SNPs excluding chromosome 19, was nominally, but not significantly, higher in women (10.6%) than men (9.7%). In age-stratified analyses, ε3/ε4 was associated with a higher risk of AD among women than men aged 65–75 years, but not in the full sample. Apart from APOE, no new significant locus was identified in sex-stratified gene-based analyses. Our result of the high genetic correlation indicates overall similar genetic architecture of AD in both sexes at the genome-wide averaged level. Our study suggests that clinically observed sex differences may arise from sex-specific variants with small effects or more complicated mechanisms involving epigenetic alterations, sex chromosomes, or gene-environment interactions.
Autoimmunomic Signatures of Aging and Age-Related Neurodegenerative Diseases Are Associated With Brain Function and Ribosomal Proteins
Authors: Yin Junping , Ibrahim Saleh , Petersen Frank , Yu Xinhua
Published: May 2021

Biological aging is a complex process featured by declined function of cells and tissues, including those of the immune system. As a consequence, aging affects the expression and development of autoantibodies and autoreactive T cells, which can be seen in their sum as the autoimmunome of an individual. In this study we analyzed whether sets of autoimmune features are associated with specific phenotypes which form autoimmunomic signatures related to age and neurodegenerative diseases. The autoantibody profile data of healthy subjects and patients from the GEO database was used to explore autoimmunomic signatures of aging and three neurodegenerative diseases including Parkinson's disease (PD), Alzheimer disease (AD) and Multiple Sclerosis (MS). Our results demonstrate that the autoimmunomic signature of aging is featured by an undulated increase of IgG autoantibodies associated with learning and behavior and a consistent increase of IgG autoantibodies related to ribosome and translation, and the autoimmunomic signature of aging are also associated with age-related neurodegenerative diseases. Intriguingly, Differential Expression-Sliding Window Analysis (DE-SWAN) identified three waves of changes of autoantibodies during aging at an age of 30, 50, and 62 years, respectively. Furthermore, IgG autoantibodies, in particular those against ribosomal proteins, could be used as prediction markers for aging and age-related neurodegenerative diseases. Therefore, this study for the first time uncovers comprehensive autoimmunomic signatures for aging and age-related neurodegenerative diseases.
Advanced Nanoporous Anodic Alumina-Based Optical Sensors for Biomedical Applications
Authors: Feng Silu , Ji Weiwei
Published: May 2021

Close-packed hexagonal array nanopores are widely used both in research and industry. A self-ordered nanoporous structure makes anodic aluminum oxide (AAO) one of the most popular nanomaterials. This paper describes the main formation mechanisms for AAO, the AAO fabrication process, and optical sensor applications. The paper is focused on four types of AAO-based optical biosensor technology: surface-Enhanced Raman Scattering (SERS), surface Plasmon Resonance (SPR), reflectometric Interference Spectroscopy (RIfS), and photoluminescence Spectroscopy (PL). AAO-based optical biosensors feature very good selectivity, specificity, and reusability.
The Perception of the Müller-Lyer Visual Illusion in Schizophrenics and Non-human Primates: A Translational Approach
Authors: Costa Ana Luísa Lamounier , Silva Ronaldo Coelho , Coelho-Cordeiro Pedro H. , da Silveira Fernando Silva , Barros Marilia , Caixeta Fabio Viegas , Maior Rafael S.
Published: May 2021

The Müller-Lyer Illusion (MLI) has been suggested as a potential marker for the perceptual impairments observed in schizophrenia patients. Along with some positive symptoms, these deficits are not easily modeled in rodent experiments, and novel animal models are warranted. Previously, MK-801 was shown to reduce susceptibility to MLI in monkeys, raising the prospects of an effective perception-based model. Here, we evaluate the translational feasibility of the MLI task under NMDA receptor blockage as a primate model for schizophrenia. In Experiment 1, eight capuchin monkeys (Sapajus spp.) were trained on a touchscreen MLI task. Upon reaching the learning criteria, the monkeys were given ketamine (0.3 mg/kg; i.m.) or saline on four consecutive days and then retested on the MLI task. In Experiment 2, eight chronic schizophrenia patients (and eight matching controls) were tested on the Brentano version of the MLI. Under saline treatment, monkeys were susceptible to MLI, similarly to healthy human participants. Repeated ketamine administrations, however, failed to improve their performance as previous results with MK-801 had shown. Schizophrenic patients, on the other hand, showed a higher susceptibility to MLI when compared to healthy controls. In light of the present and previous studies, the MLI task shows consistent results across monkeys and humans. In spite of potentially being an interesting translational model of schizophrenia, the MLI task warrants further refinement in non-human primates and a broader sample of schizophrenia subtypes.
Efficacy and Safety of Endovascular Treatment for Acute Large-Vessel Ischemic Stroke Beyond 6 h After Symptom Onset: A Meta-Analysis
Authors: Zhongxing Ye , Zhiqiang Liu , Jiangjie Wang , Qing Chen , Jinfeng Zhang , Chaoqun Weng , Feng Li
Published: May 2021

Background: There is considerable evidence on the benefits of endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) within 6 h after symptom onset. However, uncertainties remain regarding EVT efficacy beyond 6 h after symptom onset. We undertook a meta-analysis to assess the efficacy and safety of EVT in patients with AIS >6 h after symptom onset.

Methods: We searched PubMed, EMBASE, and Chinese Biomedical through July 2019. We included studies involving early (≤6 h) vs. delayed (>6 h) EVT in selected patients with AIS, based on radiological evaluation criteria. Functional independence, successful recanalization, mortality, and symptomatic intracranial hemorrhage (sICH) rates were assessed.

Results: Eight articles, with 3,265 patients who had undergone early EVT and 1,078 patients who had received delayed EVT, were included in the meta-analysis. Patients treated with early EVT showed a similar proportion of functional independence at 90 days [odds ratio (OR) = 1.14, 95% confidence interval (CI) = 0.926–1.397, P = 0.219; I2 = 36.2%, P = 0.128] as those treated with delayed EVT. Delayed EVT was also associated with no significant difference in mortality (OR = 1.015, 95% CI = 0.852–1.209; P = 0.871; I2 = 0.0%, P = 0.527), successful recanalization (OR = 1.255, 95% CI = 0.923–1.705; P = 0.147; I2 = 60.5%, P = 0.009), and sICH (OR = 0.976, 95% CI = 0.737–1.293; P = 0.871; I2 = 0.0%, P = 0.742) rates compared with early EVT.

Conclusions: Among selected patients with AIS, delayed EVT showed comparable outcomes in functional independence, recanalization, mortality, and sICH rates compared with early EVT.
Fixed-Life or Rechargeable Batteries for Deep Brain Stimulation: Preference and Satisfaction Among Patients With Hyperkinetic Movement Disorders
Authors: Qiu Xian , Wang Yuhan , Lin Zhengyu , Wu Yunhao , Xu Wenying , Wu Yiwen , Sun Bomin , Ashkan Keyoumars , Zhang Chencheng , Li Dianyou
Published: May 2021

Background: Deep brain stimulation (DBS) is an established treatment for hyperkinetic movement disorders. Patients undergoing DBS can choose between the use of a rechargeable or non-rechargeable battery for implanted pulse generators (IPG).

Objectives: In this study, we aimed to evaluate patient preferences and satisfaction with rechargeable and non-rechargeable batteries for IPGs after undergoing DBS.

Methods: Overall, 100 patients with hyperkinetic movement disorders (dystonia: 79, Tourette syndrome: 21) who had undergone DBS took a self-designed questionnaire to assess their satisfaction and experience with the type of battery they had chosen and the factors influencing their choice.

Results: Of the participants, 87% were satisfied with the stimulating effects of the treatment as well as the implanted device; 76% had chosen rechargeable devices (r-IPGs), 71.4% of whom recharged the battery themselves. Economic factors were the main reason for choosing both r-IPG and non-rechargeable IPG (nr-IPG). The questionnaire revealed that 66% of the patients checked their r-IPG battery every week. The mean interval for battery recharge was 4.3 days.

Conclusions: The majority of the patients were satisfied with their in-service-IPG, regardless of whether it was a r-IPG or nr-IPG. Affordability was the main factor influencing the choice of IPG. The majority of the patients were confident in recharging the battery of their r-IPG themselves; only 11% of patients experienced difficulties. Understanding the recharge process remains difficult for some patients and increasing the number of training sessions for the device may be helpful.
Atherosclerotic Components in Thrombi Retrieved by Thrombectomy for Internal Carotid Artery Occlusion Due to Large Artery Atherosclerosis: A Case Report
Authors: Eto Futoshi , Koge Junpei , Tanaka Kanta , Yoshimoto Takeshi , Shiozawa Masayuki , Hatakeyama Kinta , Toyoda Kazunori , Koga Masatoshi
Published: May 2021

Introduction: The correlation between the composition of thrombi retrieved by mechanical thrombectomy (MT) and stroke etiology is inconclusive. We describe a case with atherosclerotic components in thrombi retrieved by MT for acute internal carotid artery (ICA) occlusion.

Case Presentation: A 69-year-old man with acute onset of global aphasia and right hemiplegia was transferred to our institute. His baseline National Institutes of Health Stroke Scale score was 24. Magnetic resonance imaging demonstrated acute ischemic stroke in the left parietal lobe. Magnetic resonance angiography revealed occlusion of the left ICA. MT was attempted for acute left ICA occlusion. The initial angiography showed occlusion of the proximal ICA, while intraprocedural angiography revealed a large thrombus that extended from the cervical ICA to the intracranial ICA. Successful reperfusion was achieved by five passes using stent retrievers and an aspiration catheter. A large volume of red thrombus was retrieved by each pass. The final angiogram showed successful reperfusion with modified Thrombolysis in Cerebral Ischemia grade 2b and severe stenosis in the proximal ICA. Neck magnetic resonance imaging showed severe left ICA stenosis with a vulnerable plaque. Hence, his stroke etiology was determined as large artery atherosclerosis. Histopathological examination of the retrieved thrombi revealed atheromatous components, including cholesterol clefts, foam cells, and a necrotic core.

Conclusions: Atherosclerotic components in retrieved thrombi might provide useful clues for diagnosing stroke pathogenesis. Further studies are warranted to clarify the utility of assessing atheromatous components in retrieved thrombi in diagnosing stroke etiology.
Differential Modulating Effect of Acupuncture in Patients With Migraine Without Aura: A Resting Functional Magnetic Resonance Study
Authors: Liu Shanshan , Luo Shilei , Yan Tianwei , Ma Wen , Wei Xiangyu , Chen Yilei , Zhan Songhua , Wang Bo
Published: May 2021

Introduction: Migraine is a recurrent neurological disorder, the symptoms of which can be significantly relieved by acupuncture. However, the central mechanism via which acupuncture exerts its therapeutic effect in migraine is unclear. The aim of this study was to compare the differences in regional homogeneity (ReHo) between patients with migraine without aura (MwoA) and healthy controls (HCs) and to explore the immediate and cumulative therapeutic effect of acupuncture in patients with MwoA using resting-state functional magnetic resonance imaging (fMRI).

Methods: The study subjects were 40 patients with MwoA and 16 matched HCs. The patients with MwoA received acupuncture on 2 days per week for 6 weeks for a total of 12 sessions followed by 24 weeks of follow-up. The primary clinical efficacy outcomes were the number of days with migraine and the average severity of headache. Secondary outcomes were the Migraine-Specific Quality of Life Questionnaire, Self-Rating Anxiety Scale, and Self-Rating Depression Scale scores. In the migraine group, resting-state blood-oxygen-level-dependent fMRI scans were obtained at baseline and after the first and 12th acupuncture sessions to measure the ReHo value. In the HCs, only a baseline resting-state blood-oxygen-level-dependent fMRI scan was obtained.

Results: Compared with the control group, the migraine group had a significantly lower ReHo value in the cerebellum, which increased after the first acupuncture session. Long-term acupuncture significantly improved migraine symptoms and mood with a therapeutic effect that lasted for at least 6 months. After 12 acupuncture sessions, there were significant increase of cerebellum and angular gyrus in the migraine group.

Conclusion: These findings suggest that migraine is related to cerebellar dysfunction. Acupuncture can relieve the symptoms of migraine, improve dysfunction of cerebellum, and activate brain regions involved in modulation of pain and emotion The cumulative therapeutic effect of acupuncture is more extensive and significant than its immediate effect.
Classification-Biased Apparent Brain Age for the Prediction of Alzheimer's Disease
Authors: Varzandian Ali , Razo Miguel Angel Sanchez , Sanders Michael Richard , Atmakuru Akhila , Di Fatta Giuseppe
Published: May 2021

Machine Learning methods are often adopted to infer useful biomarkers for the early diagnosis of many neurodegenerative diseases and, in general, of neuroanatomical ageing. Some of these methods estimate the subject age from morphological brain data, which is then indicated as “brain age”. The difference between such a predicted brain age and the actual chronological age of a subject can be used as an indication of a pathological deviation from normal brain ageing. An important use of the brain age model as biomarker is the prediction of Alzheimer's disease (AD) from structural Magnetic Resonance Imaging (MRI). Many different machine learning approaches have been applied to this specific predictive task, some of which have achieved high accuracy at the expense of the descriptiveness of the model. This work investigates an appropriate combination of data science techniques and linear models to provide, at the same time, high accuracy and good descriptiveness. The proposed method is based on a data workflow that include typical data science methods, such as outliers detection, feature selection, linear regression, and logistic regression. In particular, a novel inductive bias is introduced in the regression model, which is aimed at improving the accuracy and the specificity of the classification task. The method is compared to other machine learning approaches for AD classification based on morphological brain data with and without the use of the brain age, including Support Vector Machines and Deep Neural Networks. This study adopts brain MRI scans of 1, 901 subjects which have been acquired from three repositories (ADNI, AIBL, and IXI). A predictive model based only on the proposed apparent brain age and the chronological age has an accuracy of 88% and 92%, respectively, for male and female subjects, in a repeated cross-validation analysis, thus achieving a comparable or superior performance than state of the art machine learning methods. The advantage of the proposed method is that it maintains the morphological semantics of the input space throughout the regression and classification tasks. The accurate predictive model is also highly descriptive and can be used to generate potentially useful insights on the predictions.
RETRACTED: Oral Administration of Brain Protein Combined With Probiotics Induces Immune Tolerance Through the Tryptophan Pathway
Authors: Hou Yongxin , Xu Lixia , Song Sirong , Fan Weijia , Wu Qiaoli , Tong Xiaoguang , Yan Hua
Published: May 2021

Excessive inflammation leads to secondary immune damage after traumatic brain injury (TBI). The intestinal mucosa is a key component of immune tolerance due to gut-brain axis regulation, but the curative effect is not optimal. Intestinal dysfunction impairs the establishment of immune tolerance in patients with TBI. Therefore, we orally administered brain protein (BP) combined with probiotics to induce immune tolerance and explored the mechanism by which the homeostasis of the microbiota contributes to the enhancement of curative effects by BPs. Herein, we demonstrated that patients with TBI and surgical brain injury (SBI) models of rats had obvious dysbiosis. Notably, the intestinal barrier, proinflammatory cytokines, and activation of microglia demonstrated that excessive inflammatory damage was better controlled in the combined group (oral administration of BP combined with probiotics) than in the BP group (oral administration of BP). Fundamentally, tandem mass tag (TMT)-based quantitative proteomics analysis revealed that BP and probiotics preferentially affect Try-related pathways. A series of experiments further confirmed that Indoleamine 2,3 dioxygenase (IDO)/Kynurenine (Kyn)/Aryl hydrocarbon receptor (AhR) expression was high in the BP group, while Tryptophan hydroxylase 1(TpH1)/5-hydroxytryptamine (5-HT) only changed in the combined group. This study suggests that probiotics can enhance the efficacy of oral BP-induced immune tolerance through the Try pathway.
Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective
Authors: Shepard Ryan D. , Nugent Fereshteh S.
Published: May 2021

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.
The Role of Unimodal Feedback Pathways in Gender Perception During Activation of Voice and Face Areas
Authors: Abbatecola Clement , Gerardin Peggy , Beneyton Kim , Kennedy Henry , Knoblauch Kenneth
Published: May 2021

Cross-modal effects provide a model framework for investigating hierarchical inter-areal processing, particularly, under conditions where unimodal cortical areas receive contextual feedback from other modalities. Here, using complementary behavioral and brain imaging techniques, we investigated the functional networks participating in face and voice processing during gender perception, a high-level feature of voice and face perception. Within the framework of a signal detection decision model, Maximum likelihood conjoint measurement (MLCM) was used to estimate the contributions of the face and voice to gender comparisons between pairs of audio-visual stimuli in which the face and voice were independently modulated. Top–down contributions were varied by instructing participants to make judgments based on the gender of either the face, the voice or both modalities (N = 12 for each task). Estimated face and voice contributions to the judgments of the stimulus pairs were not independent; both contributed to all tasks, but their respective weights varied over a 40-fold range due to top–down influences. Models that best described the modal contributions required the inclusion of two different top–down interactions: (i) an interaction that depended on gender congruence across modalities (i.e., difference between face and voice modalities for each stimulus); (ii) an interaction that depended on the within modalities’ gender magnitude. The significance of these interactions was task dependent. Specifically, gender congruence interaction was significant for the face and voice tasks while the gender magnitude interaction was significant for the face and stimulus tasks. Subsequently, we used the same stimuli and related tasks in a functional magnetic resonance imaging (fMRI) paradigm (N = 12) to explore the neural correlates of these perceptual processes, analyzed with Dynamic Causal Modeling (DCM) and Bayesian Model Selection. Results revealed changes in effective connectivity between the unimodal Fusiform Face Area (FFA) and Temporal Voice Area (TVA) in a fashion that paralleled the face and voice behavioral interactions observed in the psychophysical data. These findings explore the role in perception of multiple unimodal parallel feedback pathways.
Chinese Breast Milk Fat Composition and Its Associated Dietary Factors: A Pilot Study on Lactating Mothers in Beijing
Authors: Wu Wei , Balter Adi , Vodsky Victoria , Odetallh Yatreb , Ben-Dror Gai , Zhang Yumei , Zhao Ai
Published: May 2021

Regional differences were found in breast milk composition. This study intended to profile the composition of fatty acid (FA) and triacylglycerol (TAG) in Chinese breast milk and to explore its association with maternal diet. Breast milk samples and data of 52 lactating women at 60–90 days postpartum were collected. The FA composition was measured using gas chromatography–flame ionization detection (GC-FID), and the TAG profile was detected by an ultra-performance liquid chromatography system, coupled with accurate-mass quadrupole time-of-flight mass spectrometer. A semi-quantitative food intake frequency questionnaire and a one-time 24-h dietary recall were used to evaluate the previous month's and the short-term dietary intake, including dietary patterns, food groups, and nutrients. Oleic–palmitic–linoleic (OPL) is the most predominant TAG within the Chinese human milk, followed by oleic–palmitic–oleic (OPO), with an average OPL-to-OPO ratio of 1.35. Linoleic acid (LA) and oleic acid (OA) accounted for 23.9 and 32.0% of the total FAs, respectively. Among the food groups consumed during the preceding month, LA content was positively associated with the consumption of soybeans and soybean products (r = 0.311, p = 0.030), whereas a negative correlation was identified with seafood consumption (r = −0.302, p = 0.030). Negative correlations were found between the OA content and the consumption of soybeans and soybean products (r = −0.363, p = 0.009), livestock and poultry meat (r = −0.375, p = 0.006), nuts (r = −0.305, p = 0.028), as well as cooking oil (r = −0.445, p = 0.001). No significant associations were identified between the LA and OA contents and the dietary patterns. This study confirmed a high OPL level in Chinese breast milk and revealed associations of FAs with maternal dietary intake.
Metabolic Hormone Profiles in Breast Milk From Mothers of Moderate-Late Preterm Infants Are Associated With Growth From Birth to 4 Months in a Sex-Specific Manner
Authors: Galante Laura , Reynolds Clare M. , Milan Amber M. , Alexander Tanith , Bloomfield Frank H. , Jiang Yannan , Asadi Sharin , Muelbert Mariana , Cameron-Smith David , Pundir Shikha , Vickers Mark H. ,   the DIAMOND study team
Published: May 2021

Background:Differing environmental conditions experienced by mother-infant dyads may influence composition of the milk received by the infant. As a consequence, diverse milk compositional profiles may contribute to different postnatal outcomes, especially in infants facing adverse perinatal environments. We investigated whether variability in milk concentrations of key metabolic hormones is associated with different growth outcomes in infants born preterm, a perinatal complication known to impact on infant growth.

Methods:Human milk samples were collected from 169 mothers of 191 infants enrolled in the DIAMOND trial, a randomized trial of nutrition for moderate-late preterm infants, at 5 and 10 days postpartum and again at 4 months' corrected age and analyzed for leptin, adiponectin and insulin-like growth factor (IGF)-1. Infant weight and body composition were measured at birth, discharge and 4 months' corrected age. Multiple linear regression models were used to examine correlations between milk hormone concentrations, weight z-scores and body composition at discharge and 4 months' corrected age, and weight gain from birth to 4 months' corrected age. Sex-specific interactions were examined.

Results:Higher milk IGF-1 concentrations on day 5 after birth were associated with greater infant fat-free mass at 4 months' corrected age. Milk IGF-1 concentrations at 4 months were positively associated with fat mass and fat-free mass at 4 months in boys but not girls. Milk leptin concentrations on day 5 after birth were positively associated with fat mass at discharge from hospital, but negatively associated with fat mass at 4 months' corrected age. No significant association was found for milk adiponectin concentrations.

Conclusion:Milk IGF-1 and leptin concentrations in mothers of moderate-late preterm babies are associated with different growth and body composition through to 4 months' corrected age and these associations are often different in boys and girls. The sex-specific effects of nutrient and hormone exposure during early life in preterm infants warrants further investigation to optimize the nutritional care these infants receive, particularly in hospital, where the same nutrition is provided to boys and girls.
Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research
Authors: Varayathu Hrishi , Sarathy Vinu , Thomas Beulah Elsa , Mufti Suhail Sayeed , Naik Radheshyam
Published: May 2021

Immune checkpoint inhibitor therapy has revolutionized the field of cancer immunotherapy. Even though it has shown a durable response in some solid tumors, several patients do not respond to these agents, irrespective of predictive biomarker (PD-L1, MSI, TMB) status. Multiple preclinical, as well as early-phase clinical studies are ongoing for combining immune checkpoint inhibitors with anti-cancer and/or non-anti-cancer drugs for beneficial therapeutic interactions. In this review, we discuss the mechanistic basis behind the combination of immune checkpoint inhibitors with other drugs currently being studied in early phase clinical studies including conventional chemotherapy drugs, metronomic chemotherapy, thalidomide and its derivatives, epigenetic therapy, targeted therapy, inhibitors of DNA damage repair, other small molecule inhibitors, anti-tumor antibodies hormonal therapy, multiple checkpoint Inhibitors, microbiome therapeutics, oncolytic viruses, radiotherapy, drugs targeting myeloid-derived suppressor cells, drugs targeting Tregs, drugs targeting renin-angiotensin system, drugs targeting the autonomic nervous system, metformin, etc. We also highlight how translational research strategies can help better understand the true therapeutic potential of such combinations.
Family History and Risk of Upper Gastrointestinal Cancer in the Linxian General Population
Authors: Yang Huan , Wang Jian-bing , Zhang Jin-yu , Fan Jin-hu , Qiao You-lin , Taylor Philip R.
Published: May 2021

Objective

The objective of this study was to investigate family history (FH) of upper gastrointestinal (UGI) cancer and risk of esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric non-cardia carcinoma (GNCC) in the Linxian General Population Nutrition Intervention Trial (NIT) cohort. Methods: This prospective analysis was conducted using the Linxian NIT cohort data. Subjects with FH of UGI cancer was treated as an exposed group while the remainders were considered as a comparison group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between FH of UGI cancer and risk of UGI cancer incidence and mortality were estimated using Cox proportional hazards models.

Results

There were 5,680 newly diagnosed UGI cancer cases during the follow-up period, with a total of 4,573 UGI cancer deaths occurred, including 2,603 ESCC, 1,410 GCC, and 560 GNCC deaths. A positive FH of UGI cancer was associated with a significantly increased risk of ESCC and GCC (Incidence: HRESCC = 1.45, 95%CI: 1.35–1.56; HRGCC = 1.27, 95%CI: 1.15–1.40; Mortality: HRESCC = 1.40, 95%CI: 1.30–1.52; HRGCC = 1.27, 95%CI: 1.14–1.42) after adjusting for age at baseline, gender, smoking status, alcohol drinking, education level, and frequency of fresh fruit and vegetable consumption. Subjects with FH in both parents had the highest risk of ESCC and GCC incidence (HRESCC = 1.65, 95%CI: 1.40–1.95; HRGCC = 1.42, 95%CI: 1.12–1.81) and deaths (HRESCC = 1.65, 95%CI: 1.38–1.97; HRGCC = 1.42, 95%CI: 1.09–1.85). Spouse diagnosed with UGI cancer did not increase the risk of any UGI cancers of the subjects. In subgroup analysis, FH of UGI cancer was shown to significantly increase the risk of GCC in non-drinkers (Incidence: HR = 1.31, 95%CI: 1.17–1.47; Mortality: HR = 1.33, 95%CI: 1.17–1.50). No associations were observed for risk of GNCC. Sensitivity analysis by excluding subjects who were followed up less than three years did not materially alter our results.

Conclusion

Our data point to the role of the FH of UGI cancer to the risk of ESCC and GCC incidence and mortality. The influence of family history on the risk of UGI cancer varies from different types of family members.
Metastasis Patterns and Prognosis of Elderly Patients With Esophageal Adenocarcinoma in Stage IVB: A Population-Based Study
Authors: Qiu Guanghao , Zhang Hanlu , Wang Fuqiang , Zheng Yu , Wang Zihao , Wang Yun
Published: May 2021

Background

Esophageal adenocarcinoma (EAC) is the most common kind of esophageal cancer. Age at diagnosis of advanced EAC is greater. Studies about practice patterns for elderly EAC patients with distant metastasis (DM) in stage IVB are limited. This retrospective, population-based study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) to evaluate 855 elderly EAC patients with DM in stage IVB from 2010 to 2015.

Methods

855 elderly EAC patients with DM in stage IVB between 2010 and 2015 were included in this study. Univariate and multivariate Cox-regression and Kaplan-Meier analyses were used to assess prognosis. These patients were classified to bone-only, brain-only, lung-only, liver-only, and multiple (patients with two or more organs in metastasis)-site group according to the site of metastasis. Overall survival (OS), cancer-specific survival (CSS), median survival time (MST), and survival rate (SR) were evaluated to analyze the survival outcomes.

Results

The most common metastasis site was the liver among the single-organ metastasis population, followed by lung, bone, and brain. Compared with the bone-only group, the multiple-site group was associated with worst OS (HR: 1.037, 95% CI: 0.811–1.327, p = 0.770) and CSS (HR: 1.052, 95% CI: 0.816–1.357, p = 0.695). The multiple-site group also had the lowest MST in the population (MST: 2 months in OS and 3 months in CSS) and SR (6-month SR: 27.1% in OS, 29.9% in CSS, 1-year SR: 10.7% in OS, 12.0% in CSS, 3-year SR: 2.5% in OS, 2.8% in CSS). Compared to untreated patients (N) in the total population, other patients who were treated with surgery (S), radiotherapy (R), and chemotherapy (C) are beneficial for the prognosis (OS and CSS: p < 0.001).

Conclusion

This population-based study was conducted to ascertain metastasis patterns and survival outcomes of EAC patients with DM in stage IVB. Elderly patients with multiple-site metastasis exhibited the worst OS and CSS among all the populations, and patients with bone-only metastasis had the worst OS and CSS among single-organ metastasis populations. Active treatment is beneficial for elderly EAC patients with DM in stage IVB, especially chemotherapy. This study also shows that more than one third of the patients had not received any therapy.
Pooled Analysis on the Effectiveness and Safety of Lipegfilgrastim in Patients With Urological Malignancies in the Real-World Setting
Authors: Merseburger Axel S. , Geiges Götz , Klier Jörg , Wiesholzer Martin , Pichler Petra
Published: May 2021

Lipegfilgrastim is a long-acting glycopegylated granulocyte-colony stimulating factor (G-CSF) approved for the management of chemotherapy-induced neutropenia. In general, there is little information on the use of any G-CSFs specifically in patients with urological malignancies receiving chemotherapy. This report combines information from two prospective non-interventional studies on the prophylactic use of lipegfilgrastim in urological cancer patients receiving chemotherapy in the real-world setting. Data were derived from two phase IV studies (NADIR and LEOS) with similar protocols conducted in nine European countries. Analysis included 228 patients (142 prostate, 50 testicular, 27 bladder, and 9 other urological cancers). Chemotherapy-induced febrile neutropenia risk was classified as high (43.0%), intermediate (49.1%), or low (7.5%). Lipegfilgrastim was administered as primary (n=180, 78.9%) or secondary (n=29, 12.7%) prophylaxis. The incidence of febrile neutropenia over all chemotherapy cycles (n=998) and first cycles (n=228) for which lipegfilgrastim was administered for prophylaxis was 2.6% and 1.3%, respectively. Corresponding results for Grade 3/4 neutropenia were 2.2% and 0.9%, respectively. Adverse drug reactions occurred in 24 patients (10.5%): those in more than one patient were bone pain (n=6, 2.6%) and pyrexia (n=3, 1.3%). The use of lipegfilgrastim for the prophylaxis of chemotherapy-induced neutropenia was effective and well tolerated in patients with urological malignancies in the real-world setting.
Safety and Efficacy of Personalized Cancer Vaccines in Combination With Immune Checkpoint Inhibitors in Cancer Treatment
Authors: Liao Juan-Yan , Zhang Shuang
Published: May 2021

Cancer immunotherapy can induce sustained responses in patients with cancers in a broad range of tissues, however, these treatments require the optimized combined therapeutic strategies. Despite immune checkpoint inhibitors (ICIs) have lasting clinical benefit, researchers are trying to combine them with other treatment modalities, and among them the combination with personalized cancer vaccines is attractive. Neoantigens, arising from mutations in cancer cells, can elicit strong immune response without central tolerance and out-target effects, which is a truly personalized method. Growing studies show that the combination can elevate the antitumor efficacy with acceptable safety and minimal additional toxicity compared with single agent vaccine or ICI. Herein, we have searched these preclinical and clinical trials and summarized safety and efficacy of personalized cancer vaccines combined with ICIs in several malignancies. Meanwhile, we discuss the rationale of the combination and future challenges.
QTMP, a Novel Thiourea Polymer, Causes DNA Damage to Exert Anticancer Activity and Overcome Multidrug Resistance in Colorectal Cancer Cells
Authors: Bai Zhaoshi , Zhou Qing , Zhu Huayun , Ye Xinyue , Wu Pingping , Ma Lingman
Published: May 2021

Colorectal cancer (CRC) is one of the most common malignancies, and multidrug resistance (MDR) severely restricts the effectiveness of various anticancer drugs. Therefore, the development of novel anticancer drugs for the treatment of CRC patients with MDR is necessary. Quaternized thiourea main-chain polymer (QTMP) is a self-assembled nanoparticle with good water solubility. Notably, QTMP is not a P-glycoprotein (P-gp) substrate, and it exhibits potent cytotoxic activity against CRC cells, including HCT116/DDP and P-gp-mediated multidrug-resistant Caco2 cells. QTMP also exhibits a strong anticancer activity against SW480 cells in vivo. Interestingly, reactive oxygen species (ROS) and reactive nitrogen species (RNS) production were increased in a concentration-dependent manner in QTMP-treated HCT116, SW480 and Caco2 cells. Importantly, QTMP causes DNA damage in these CRC cells via direct insertion into the DNA or regulation of ROS and/or RNS production. QTMP also induces caspase-dependent apoptosis via overproduction of ROS and RNS. Therefore, QTMP is a promising anticancer therapeutic agent for patients with CRC, including those cancer cells with P-gp-mediated MDR. The present study also indicates that the design and synthesis of anticancer drugs based on thiourea polymers is promising and valuable, thereby offering a new strategy to address MDR, and provides reference resources for further investigations of thiourea polymers.