bluuebunny/crossref_metadata_2025 huggingface dataset:
Kodamaea ohmeri as an Emerging Human Pathogen: A Review and Update
Authors: Zhou Menglan , Li Yanbing , Kudinha Timothy , Xu Yingchun , Liu Zhengyin
Published: September 2021

Background:Kodamaea ohmeri, previously known as Pichia ohmeri or Yamadazyma ohmeri, has been regarded as an emerging human pathogen in recent decades, and has caused various types of infections with high mortality. This study systematically reviewed all the published cases of K. ohmeri infection, aiming to have a better understanding of the clinical and epidemiological characteristics of the organism.

Methods: All the published literature (as of March 31, 2021) on K. ohmeri, in four databases: PubMed, Embase, Web of Science, and CNKI, were systematically reviewed to select appropriate studies for summarizing the demographic information, clinical and microbiological characteristics of relevant infections.

Results: A total of 51 studies involving 67 patients were included for final analysis, including 49 sporadic cases and two clusters of outbreaks. Neonates and the elderly constituted the majority of patients, and fungemia was the dominant infection type. Comorbidities (like malignancy, diabetes, and rheumatism), invasive operations, previous antibiotic use and prematurity, were commonly described in patients. Gene sequencing and broth microdilution method, were the most reliable way for the identification and antifungal susceptibility testing of K. ohmeri, respectively. Amphotericin B and fluconazole were the commonest antifungal therapies administered. The calculated mortality rates for K. ohmeri infection was higher than that of common candidemia.

Conclusion: In this study, we systematically reviewed the epidemiology, clinical characteristics, microbiological features, treatment, and outcomes, of all the published cases on K. ohmeri. Early recognition and increased awareness of K. ohmeri as an emerging human pathogen by clinicians and microbiologists is important for effective management of this organism.
Sanguinarine Inhibits the 2-Ketogluconate Pathway of Glucose Utilization in Pseudomonas aeruginosa
Authors: Falchi Federica A. , Borlotti Giorgia , Ferretti Francesco , Pellegrino Gianvito , Raneri Matteo , Schiavoni Marco , Caselli Alessandro , Briani Federica
Published: September 2021

Interfering with the ability of pathogenic bacteria to import glucose may represent a new promising antibacterial strategy, especially for the treatment of infections occurring in diabetic and other hyperglycemic patients. Such patients are particularly susceptible to infections caused by a variety of bacteria, among which opportunistic pathogens like Pseudomonas aeruginosa. In P. aeruginosa, glucose can be directly imported into the cytoplasm or after its periplasmic oxidation into gluconate and 2-ketogluconate (2-KG). We recently demonstrated that a P. aeruginosa mutant lacking the 2-KG transporter KguT is less virulent than its kguT+ parental strain in an insect infection model, pointing to 2-KG branch of glucose utilization as a possible target for anti-Pseudomonas drugs. In this work, we devised an experimental protocol to find specific inhibitors of the 2-KG pathway of P. aeruginosa glucose utilization and applied it to the screening of the Prestwick Chemical Library. By exploiting mutants lacking genes involved in the transport of glucose derivatives in the primary screening and in the secondary assays, we could identify sanguinarine as an inhibitor of 2-KG utilization. We also demonstrated that sanguinarine does not prevent 2-KG formation by gluconate oxidation or its transport, suggesting that either KguD or KguK is the target of sanguinarine in P. Aeruginosa.
Emotional, Psychological, and Cognitive Changes Throughout the COVID-19 Pandemic in Italy: Is There an Advantage of Being an Older Adult?
Authors: Carbone Elena , Palumbo Rocco , Sella Enrico , Lenti Graziana , Di Domenico Alberto , Borella Erika
Published: September 2021

Introduction: The study examined age-related differences between young and older adults’ emotional and psychological experience as well as cognitive functioning throughout different phases of the COVID-19 pandemic in Italy.

Materials and Methods: Participants were interviewed by phone when confined at home during the national lockdown (T1-May 2020; N = 138 young adults; N = 119 older adults) and after the first wave of contagions, when restrictions were discarded (T2-September 2020; N = 52 young adults; N = 59 older adults). A sub-sample also participated in a third assessment (T3-December 2020). Participants completed questionnaires assessing their emotional and psychological functioning (i.e., positive and negative affect, perceived social and emotional loneliness, resilience) along with memory tasks (Backward Digit Span task and words list recall).

Results: Although individuals reported less positive and more negative emotions during the lockdown than at T2, results showed that older adults displayed overall fewer negative emotions and greater resilience than young adults. The latter were those who reported feeling more emotionally lonely when compared to their older counterpart during the lockdown than afterward. Older adults’ advantage in emotional and psychological functioning was also confirmed 7 months after the national lockdown. Only age-related differences in favor of young adults for the memory tasks were found. The measures of interest were also susceptible to mood and/or concerns of COVID-19 effects.

Discussion: These findings further highlight the age-related advantage of older adults managing the emotional and psychological experience even when facing an unexpected, prolonged, and unpredictable, stressful life event such as the COVID-19 pandemic.
Altered Cortical Cholinergic Network in Parkinson’s Disease at Different Stage: A Resting-State fMRI Study
Authors: Sheng Wenshuang , Guo Tao , Zhou Cheng , Wu Jingjing , Gao Ting , Pu Jiali , Zhang Baorong , Zhang Minming , Yang Yunjun , Guan Xiaojun , Xu Xiaojun
Published: September 2021

The cholinergic system is critical in Parkinson’s disease (PD) pathology, which accounts for various clinical symptoms in PD patients. The substantia innominata (SI) provides the main source of cortical cholinergic innervation. Previous studies revealed cholinergic-related dysfunction in PD pathology at early stage. Since PD is a progressive disorder, alterations of cholinergic system function along with the PD progression have yet to be elucidated. Seventy-nine PD patients, including thirty-five early-stage PD patients (PD-E) and forty-four middle-to-late stage PD patients (PD-M), and sixty-four healthy controls (HC) underwent brain magnetic resonance imaging and clinical assessments. We employed seed-based resting-state functional connectivity analysis to explore the cholinergic-related functional alterations. Correlation analysis was used to investigate the relationship between altered functional connectivity and the severity of motor symptoms in PD patients. Results showed that both PD-E and PD-M groups exhibited decreased functional connectivity between left SI and left frontal inferior opercularis areas and increased functional connectivity between left SI and left cingulum middle area as well as right primary motor and sensory areas when comparing with HC. At advanced stages of PD, functional connectivity in the right primary motor and sensory areas was further increased. These altered functional connectivity were also significantly correlated with the Unified Parkinson’s Disease Rating Scale motor scores. In conclusion, this study illustrated that altered cholinergic function plays an important role in the motor disruptions in PD patients both in early stage as well as during the progression of the disease.
Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors
Authors: Lecordier Sarah , Manrique-Castano Daniel , El Moghrabi Yara , ElAli Ayman
Published: September 2021

Vascular dementia (VaD) constitutes the second most prevalent cause of dementia in the world after Alzheimer’s disease (AD). VaD regroups heterogeneous neurological conditions in which the decline of cognitive functions, including executive functions, is associated with structural and functional alterations in the cerebral vasculature. Among these cerebrovascular disorders, major stroke, and cerebral small vessel disease (cSVD) constitute the major risk factors for VaD. These conditions alter neurovascular functions leading to blood-brain barrier (BBB) deregulation, neurovascular coupling dysfunction, and inflammation. Accumulation of neurovascular impairments over time underlies the cognitive function decline associated with VaD. Furthermore, several vascular risk factors, such as hypertension, obesity, and diabetes have been shown to exacerbate neurovascular impairments and thus increase VaD prevalence. Importantly, air pollution constitutes an underestimated risk factor that triggers vascular dysfunction via inflammation and oxidative stress. The review summarizes the current knowledge related to the pathological mechanisms linking neurovascular impairments associated with stroke, cSVD, and vascular risk factors with a particular emphasis on air pollution, to VaD etiology and progression. Furthermore, the review discusses the major challenges to fully elucidate the pathobiology of VaD, as well as research directions to outline new therapeutic interventions.
Using Machine Learning for Predicting the Best Outcomes With Electrical Muscle Stimulation for Tremors in Parkinson’s Disease
Authors: Phokaewvarangkul Onanong , Vateekul Peerapon , Wichakam Itsara , Anan Chanawat , Bhidayasiri Roongroj
Published: September 2021

Recent studies have identified that peripheral stimulation in Parkinson’s disease (PD) is effective in tremor reduction, indicating that a peripheral feedback loop plays an important role in the tremor reset mechanism. This was an open-label, quasi-experimental, pre- and post-test design, single-blind, single-group study involving 20 tremor-dominant PD patients. The objective of this study is to explore the effect of electrical muscle stimulation (EMS) as an adjunctive treatment for resting tremor during “on” period and to identify the best machine learning model to predict the suitable stimulation level that will yield the longest period of tremor reduction or tremor reset time. In this study, we used a Parkinson’s glove to evaluate, stimulate, and quantify the tremors of PD patients. This adjustable glove incorporates a 3-axis gyroscope to measure tremor signals and an EMS to provide an on-demand muscle stimulation to suppress tremors. Machine learning models were applied to identify the suitable pulse amplitude (stimulation level) in five classes that led to the longest tremor reset time. The study was registered at the www.clinicaltrials.gov under the name “The Study of Rest Tremor Suppression by Using Electrical Muscle Stimulation” (NCT02370108). Twenty tremor-dominant PD patients were recruited. After applying an average pulse amplitude of 6.25 (SD 2.84) mA and stimulation period of 440.7 (SD 560.82) seconds, the total time of tremor reduction, or tremor reset time, was 329.90 (SD 340.91) seconds. A significant reduction in tremor parameters during stimulation was demonstrated by a reduction of Unified Parkinson’s Disease Rating Scale (UPDRS) scores, and objectively, with a reduction of gyroscopic data (p < 0.05, each). None of the subjects reported any serious adverse events. We also compared gyroscopic data with five machine learning techniques: Logistic Regression, Random Forest, Support Vector Machine (SVM), Neural Network (NN), and Long-Short-Term-Memory (LSTM). The machine learning model that gave the highest accuracy was LSTM, which obtained: accuracy = 0.865 and macro-F1 = 0.736. This study confirms the efficacy of EMS in the reduction of resting tremors in PD. LSTM was identified as the most effective model for predicting pulse amplitude that would elicit the longest tremor reset time. Our study provides further insight on the tremor reset mechanism in PD.
Efferent and Afferent Connections of Neuropeptide Y Neurons in the Nucleus Accumbens of Mice
Authors: Yamada Shunji , van Kooten Nienke , Mori Takuma , Taguchi Katsutoshi , Tsujimura Atsushi , Tanaka Masaki
Published: September 2021

Neuropeptide Y (NPY) is a neural peptide distributed widely in the brain and has various functions in each region. We previously reported that NPY neurons in the nucleus accumbens (NAc) are involved in the regulation of anxiety behavior. Anterograde and retrograde tracing studies suggest that neurons in the NAc project to several areas, such as the lateral hypothalamus (LH) and ventral pallidum (VP), and receive afferent projections from the cortex, thalamus, and amygdala. However, the neural connections between accumbal NPY neurons and other brain areas in mice remain unclear. In this study, we sought to clarify these anatomical connections of NPY neurons in the NAc by investigating their neural outputs and inputs. To selectively map NPY neuronal efferents from the NAc, we injected Cre-dependent adeno-associated viruses (AAVs) into the NAc of NPY-Cre mice. This revealed that NAc NPY neurons exclusively projected to the LH. We confirmed this by injecting cholera toxin b subunit (CTb), a retrograde tracer, into the LH and found that approximately 7–10% of NPY neurons in the NAc were double-labeled for mCherry and CTb. Moreover, retrograde tracing using recombinant rabies virus (rRABV) also identified NAc NPY projections to the LH. Finally, we investigated monosynaptic input to the NPY neurons in the NAc using rRABV. We found that NPY neurons in the NAc received direct synaptic connections from the midline thalamic nuclei and posterior basomedial amygdala. These findings provide new insight into the neural networks of accumbal NPY neurons and should assist in elucidating their functional roles.
Mechanisms Underlying Motivational Dysfunction in Schizophrenia
Authors: Saleh Youssuf , Jarratt-Barnham Isaac , Fernandez-Egea Emilio , Husain Masud
Published: September 2021

Negative symptoms are a debilitating feature of schizophrenia which are often resistant to pharmacological intervention. The mechanisms underlying them remain poorly understood, and diagnostic methods rely on phenotyping through validated questionnaires. Deeper endo-phenotyping is likely to be necessary in order to improve current understanding. In the last decade, valuable behavioural insights have been gained through the use of effort-based decision making (EBDM) tasks. These have highlighted impairments in reward-related processing in schizophrenia, particularly associated with negative symptom severity. Neuroimaging investigations have related these changes to dysfunction within specific brain networks including the ventral striatum (VS) and frontal brain regions. Here, we review the behavioural and neural evidence associated with negative symptoms, shedding light on potential underlying mechanisms and future therapeutic possibilities. Findings in the literature suggest that schizophrenia is characterised by impaired reward based learning and action selection, despite preserved hedonic responses. Associations between amotivation and reward-processing deficits have not always been clear, and may be mediated by factors including cognitive dysfunction or dysfunctional or self-defeatist beliefs. Successful endo-phenotyping of negative symptoms as a function of objective behavioural and neural measurements is crucial in advancing our understanding of this complex syndrome. Additionally, transdiagnostic research–leveraging findings from other brain disorders, including neurological ones–can shed valuable light on the possible common origins of motivation disorders across diseases and has important implications for future treatment development.
Systematic Review of Sex and Gender Effects in Traumatic Brain Injury: Equity in Clinical and Functional Outcomes
Authors: Mollayeva Tatyana , Mollayeva Shirin , Pacheco Nicole , Colantonio Angela
Published: September 2021

Background: Although traumatic brain injury (TBI) is a leading cause of death and disability in male and female patients worldwide, little is known about the effect of sex and gender on TBI outcomes.

Objectives: This systematic review summarizes the evidence on the effect of sex and gender on core TBI outcomes.

Methods: All English-language studies from six literature databases that addressed core outcomes in adults with TBI and included sex or gender, TBI severity, and age in their analyses were considered eligible. Two reviewers extracted data, and two reviewers assessed study quality using tools recommended by the National Institutes of Health. The results were sorted according to time post-injury, injury severity, gender equity ranking of the study's country of origin, and outcomes studied. The results from the included studies were grouped based on the approach taken in reporting their respective findings.

Results and Limitations: Of 172 articles assessed, 58 studies were selected, comprising 1, 265, 955 participants with TBI (67% male across all studies) of all injury severities. All studies were conducted in countries with a very high or high human development index, while the Gender Inequality Index (GII) varied. While the heterogeneity across studies limited any meaningful conclusions with respect to the role of sex and gender, we did observe that as gender equality ranking improved, differences between male and female participants in outcomes would diminish. Inclusion of social equity parameters in the studies was limited.

Conclusions and Implications: The non-uniform findings observed bring forth the need to develop and use a comprehensive and consistent methodology in the study of sex and gender post-TBI, incorporating social equity parameters to uncover the potential social underpinnings of gender effects on health and functional outcomes.

Systematic Review Registration: CRD42018098697.
The Association Between Kidney Disease and Mortality Among Adults With Cerebral Palsy—A Cohort Study: It Is Time to Start Talking About Kidney Health
Authors: Whitney Daniel G. , Oliverio Andrea L.
Published: September 2021

Objective: Recent evidence shows that adults with cerebral palsy (CP) have an increased risk for kidney disease, but nothing is known about how kidney disease integrates with their overall health. To begin understanding the importance of kidney health, the objective was to determine if kidney disease is associated with mortality among adults with CP after accounting for comorbidities common to CP and kidney disease.

Methods: Data from 2016 to 2018 from adults ≥18 years with CP were used from a random 20% sample fee-for-service Medicare database. Kidney disease in 2016 was ascertained as chronic kidney disease (CKD) stages 1–4, end stage kidney disease (ESKD), nephritic and nephrotic syndrome, and renal osteodystrophy. A modified version of the Whitney Comorbidity Index (modWCI) was used, which includes 24 comorbidities relevant to CP and kidney disease. Mortality rate ratio (MRR) through the year 2018 was estimated for each kidney disease and Cox regression estimated the hazard ratio (HR) of mortality after adjusting for demographics, co-occurring neurological conditions, and the modWCI.

Results: Prevalence of kidney disease was 7.3% among 16,728 adults with CP. MRR was elevated for any kidney disease (MRR = 3.14; 95%CI = 2.76–3.58) and most subtypes (MRR = 2.21–3.56; all p < 0.05). The adjusted HR of mortality remained elevated for any kidney disease (HR = 1.25; 95%CI = 1.09–1.45) and ESKD (HR = 1.38; 95%CI = 1.10–1.74).

Discussion: Kidney disease, especially ESKD, is associated with mortality among adults with CP independent of comorbidities that are relevant to CP and kidney disease. Findings suggest that nephrology care should be considered as part of routine clinical care for this population.
A Longitudinal Randomized Controlled Trial Protocol to Evaluate the Effects of Wuqinxi on Dynamic Functional Connectivity in Parkinson’s Disease Patients
Authors: Li Yuting , Zhang Lanlan , Wu Yin , Zhang Jian , Liu Ke
Published: September 2021

Background: Parkinson’s disease (PD) is a neurodegenerative movement disease that includes non-motor symptoms such as cognitive impairment. Long-term mind-body exercise has been shown to improve cognitive ability in PD patients, but the methods of assessment and intervention were inconsistent across studies. Wuqinxi is a mind-body exercise that is easy to learn, has few physical and cognitive demands, and is recommended for PD patients. Dynamic functional connectivity (DFC) has been associated with cognitive alterations in PD patients, but no studies have yet explored the effects of Wuqinxi on this association. The current protocol is designed to measure the effects of long-term Wuqinxi intervention on cognition in PD patients, and explore the underlying neural mechanisms through DFC.

Methods: A long-term single-blind, randomized trial will be conducted. PD patients and age- and gender-matched HC will be recruited; PD patients will be randomly assigned to either Wuqinxi or balance groups, and HC will all receive health education. The Wuqinxi group will receive a 90-min session of Wuqinxi intervention three times a week for 24 weeks, while the balance group will receive balance exercise instruction on the same schedule. Primary outcomes will include assessment of cognitive domains and dynamic temporal characteristics of functional connectivity. Secondary outcomes will include severity of motor symptoms, mobility, balance, and emotional state. Assessments will be conducted at baseline, at the end of 24 weeks of intervention, and 12 weeks after interventions have ended.

Discussion: This study will provide evidence to the effects of Wuqinxi exercise on cognitive improvements in PD patients from the perspective of DFC, and will contribute to the understanding of neural mechanisms underlying cognitive enhancement through Wuqinxi practice.

Clinical Trial Registration:www.chictr.org.cn, identifier ChiCTR2000038517.
Impact of Antiepileptic Drugs on Cognition and Neuromagnetic Activity in Childhood Epilepsy With Centrotemporal Spikes: A Magnetoencephalography Study
Authors: Niu Kai , Li Yihan , Zhang Tingting , Sun Jintao , Sun Yulei , Shu Mingzhu , Wang Pengfei , Zhang Ke , Chen Qiqi , Wang Xiaoshan
Published: September 2021

Objective:Childhood epilepsy with centrotemporal spikes (CECTS), the most common childhood epilepsy, still lacks longitudinal imaging studies involving antiepileptic drugs (AEDs). In order to examine the effect of AEDs on cognition and brain activity. We investigated the neuromagnetic activities and cognitive profile in children with CECTS before and after 1 year of treatment.

Methods:Fifteen children with CECTS aged 6–12 years underwent high-sampling magnetoencephalography (MEG) recordings before treatment and at 1 year after treatment, and 12 completed the cognitive assessment (The Wechsler Intelligence Scale for Children). Next, magnetic source location and functional connectivity (FC) were investigated in order to characterize interictal neuromagnetic activity in the seven frequency sub-bands, including: delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), gamma (30–80 Hz), ripple (80–250 Hz), and fast ripple (250–500 Hz).

Results:After 1 year of treatment, children with CECTS had increased scores on full-scale intelligence quotient, verbal comprehension index (VCI) and perceptual reasoning index (PRI). Alterations of neural activity occurred in specific frequency bands. Source location, in the 30–80 Hz frequency band, was significantly increased in the posterior cingulate cortex (PCC) after treatment. Moreover, FC analysis demonstrated that after treatment, the connectivity between the PCC and the medial frontal cortex (MFC) was enhanced in the 8–12 Hz frequency band. Additionally, the whole-brain network distribution was more dispersed in the 80–250 Hz frequency band.

Conclusion:Intrinsic neural activity has frequency-dependent characteristic. AEDs have impact on regional activity and FC of the default mode network (DMN). Normalization of aberrant DMN in children with CECTS after treatment is likely the reason for improvement of cognitive function.
Technology Enhanced Health and Social Care for Vulnerable People During the COVID-19 Outbreak
Authors: Romanopoulou Evangelia D. , Zilidou Vasiliki I. , Gilou Sotiria , Dratsiou Ioanna , Varella Annita , Petronikolou Vasileia , Katsouli Aikaterini-Marina , Karagianni Maria , Bamidis Panagiotis D.
Published: September 2021

The COVID-19 pandemic has spread rapidly worldwide with critical consequences in health, as well as in social, economic, and particularly in psychological conditions of vulnerable people, especially older adults. Therefore, it is necessary the direct attention to their health care needs and related interventions. Information and Communication Technology (ICT) have direct impact on older adults’ health and quality of life leading to decreased depression and loneliness, along with empowerment of independent life. Many studies involve cognitive training programs/software based on new technological systems that provide to vulnerable people access to gamified, attractive, cognitive exercises for overall functionality everywhere and at any time. Twenty-four participants (mean age 69.3 years) were assigned to this study. The cognitive training component of LLM Care was used as an interactive software to enhance participants’ cognitive functions. The intervention lasted 12 weeks with the frequency of 2–4 times per week in sessions of at least 30 min. Participants used their personal devices (tablets/laptops) in their own residence, while technical and consulting guidance was provided by LLM Care certified trainers. They were informed about the purpose of the study, while consent forms along with psychological assessments were distributed every 2 weeks to periodically evaluate their psychosocial and mental health conditions. The assessments included the World Health Organization-Five Well-Being Index (WHO-5), the Short Anxiety Screening Test (SAST), the System Usability Scale (SUS) and the Impact Factor Event Scale (IES-R). According to the results, the participants with improved well-being tended to report decreased subjective distress caused by COVID-19, and their engagement with new technologies can potentially minimize the negative outcomes occurred by the current stressful situation, mitigating the effect of hyperarousal symptoms, while increasing their overall well-being. Well-being seems to remain relatively stable among older adults and decreases only when adversities occur, while the usability of the software was perceived as marginally acceptable by participants. The exploitation of the LLM Care contributes to the improvement of older adults’ well-being and alleviates the negative experience caused by stressful situations like COVID-19.
The Curious Anti-Pathology of the Wlds Mutation: Paradoxical Postsynaptic Spine Growth Accompanies Delayed Presynaptic Wallerian Degeneration
Authors: Steward Oswald , Yonan Jennifer M. , Falk Paula M.
Published: September 2021

The Wlds mutation, which arose spontaneously in C57Bl/6 mice, remarkably delays the onset of Wallerian degeneration of axons. This remarkable phenotype has transformed our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies. Although there are numerous studies of how the Wlds mutation affects axon degeneration, especially in the peripheral nervous system, less is known about how the mutation affects degeneration of CNS synapses. Here, using electron microscopy, we explore how the Wlds mutation affects synaptic terminal degeneration and withering and re-growth of dendritic spines on dentate granule cells following lesions of perforant path inputs from the entorhinal cortex. Our results reveal that substantial delays in the timing of synapse degeneration in Wlds mice are accompanied by paradoxical hypertrophy of spine heads with enlargement of post-synaptic membrane specializations (PSDs) and development of spinules. These increases in the complexity of spine morphology are similar to what is seen following induction of long-term potentiation (LTP). Robust and paradoxical spine growth suggests yet to be characterized signaling processes between amputated but non-degenerating axons and their postsynaptic targets.
Mental Visualization in the Cerebellum: Rapid Non-motor Learning at Sub-Lobular and Causal Network Levels
Authors: Likova Lora T. , Mineff Kristyo N. , Nicholas Spero C.
Published: September 2021

It is generally understood that the main role of the cerebellum is in movement planning and coordination, but neuroimaging has led to striking findings of its involvement in many aspects of cognitive processing. Mental visualization is such a cognitive process, extensively involved in learning and memory, artistic and inventive creativity, etc. Here, our aim was to conduct a multidimensional study of cerebellar involvement in the non-motor cognitive tasks. First, we used fMRI to investigate whether the cognitive task of visualization from an immediate memory of complex spatial structures (line drawings) engages the cerebellum, and identified a cerebellar network of both strongly activated and suppressed regions. Second, the task-specificity of these regions was examined by comparative analysis with the task of perceptual exploration and memorization of the drawings to be later visualized from memory. BOLD response patterns over the iterations of each task differed significantly; unexpectedly, the suppression grew markedly stronger in visualization. Third, to gain insights in the organization of these regions into cerebellar networks, we determined the directed inter-regional causal influences using Granger Causal Connectivity analysis. Additionally, the causal interactions of the cerebellar networks with a large-scale cortical network, the Default Mode Network (DMN), were studied. Fourth, we investigated rapid cognitive learning in the cerebellum at the level of short-term BOLD response evolution within each region of interest, and at the higher level of network reorganization. Our paradigm of interleaved sequences of iteration between two tasks combined with some innovative analyses were instrumental in addressing these questions. In particular, rapid forms of non-motor learning that strongly drive cerebellar plasticity through mental visualization were uncovered and characterized at both sub-lobular and network levels. Collectively, these findings provide novel and expansive insights into high-order cognitive functions in the cerebellum, and its macroscale functional neuroanatomy. They represent a basis for a framework of rapid cerebellar reorganization driven by non-motor learning, with implications for the enhancement of cognitive abilities such as learning and memory.
Three-Tier Prognostic Index in Young Adults With Advanced Gastric Cancer
Authors: Chen Guang-Liang , Huang Yan , Zhang Wen , Pan Xu , Feng Wan-Jing , Zhao Xiao-Ying , Zhu Xiao-Dong , Li Wen-Hua , Huang Mingzhu , Chen Zhi-Yu , Guo Wei-Jian
Published: September 2021

Purpose

To characterize clinical features and identify baseline prognostic factors for survival in young adults with advanced gastric cancer (YAAGC).

Materials and Methods

A total of 220 young inpatients (age less than or equal to 40 years) with an initial diagnosis of advanced gastric cancer were retrospectively enrolled in this study.

Results

Of a consecutive cohort of 220 patients with YAAGC, the median overall survival (OS) time was 16.3 months. One-year survival rate was 43.6% (95% CI: 36.5 to 50.7). In this cohort, a female (71.4%, n = 157) predominance and a number of patients with poorly differentiated tumors (95.9%, n = 211) were observed. In the univariate analysis, OS was significantly associated with neutrophil–lymphocyte ratio (NLR) (≥3.12), hypoproteinemia (<40 g/L), presence of peritoneal or bone metastases, and previous gastrectomy of primary tumor or radical gastrectomy. In multivariate Cox regression analysis, hypoproteinemia [hazard ratio (HR) 1.522, 95% CI 1.085 to 2.137, p = 0.015] and high NLR level (HR 1.446, 95% CI 1.022 to 2.047, p = 0.021) were two independent poor prognostic factors, while previous radical gastrectomy was associated with a favorable OS (HR 0.345, 95% CI 0.205 to 0.583, p = 0.000). A three-tier prognostic index was constructed dividing patients into good-, intermediate-, or poor-risk groups. Median OS for good-, intermediate-, and poor-risk groups was 36.43, 17.87, and 11.27 months, respectively.

Conclusions

Three prognostic factors were identified, and a three-tier prognostic index was devised. The reported prognostic index may aid clinical decision-making, patient risk stratification, and planning of future clinical studies on YAAGC.
Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
Authors: Niu Kai , Chen Xie-Wan , Qin Yu , Zhang Lu-Ping , Liao Rong-Xia , Sun Jian-Guo
Published: September 2021

The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via an off-target effect to radiosensitize NSCLC remains unclear. This study aimed to elucidate the mechanism underlying the radiosensitizing effect of CXB on NSCLC, i.e., whether CXB can inhibit VM formation via binding to newly identified targets other than COX-2. CXB radiosensitivity assay was performed in BALB/c mice bearing H460 xenografts and C57 mice bearing Lewis lung cancer (LLC) xenografts, which were divided into the control, CXB, irradiation (IR) treatment, and IR plus CXB groups. VM formation was observed using 3D Matrigel, periodic acid solution (PAS) staining, and immunofluorescence staining. The potential off-targets of CXB were screened using Protein Data Bank (PDB) database, MGLTools 1.5.6, and AutoDock Vina 1.1.2 and confirmed by Western blotting, enzyme activity assay, and RNA interference in vitro experiments and by immunohistochemistry in vivo experiments. CXB treatment almost eliminated the enhancement of VM formation by IR in vitro and in vivo, partially due to COX-2 inhibition. Four potential off-targets were predicted by molecular docking. Among them, aminopeptidase N (APN) and integrin alpha-V (ITAV) were remarkably inhibited in protein expression and enzyme activity in vitro or in vivo, consistent with the remarkable reduction of VM formation in H460 xenografts in BALB/c mice. In conclusion, CXB dramatically blocked VM through inhibiting newly identified off-targets APN and ITAV, other than COX-2, then radiosensitizing NSCLC.
The Role of Akt in Acquired Cetuximab Resistant Head and Neck Squamous Cell Carcinoma: An In Vitro Study on a Novel Combination Strategy
Authors: Zaryouh Hannah , De Pauw Ines , Baysal Hasan , Pauwels Patrick , Peeters Marc , Vermorken Jan Baptist , Lardon Filip , Wouters An
Published: September 2021

The epidermal growth factor receptor (EGFR) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). Resistance to EGFR-targeted therapies, such as cetuximab, poses a challenging problem. This study aims to characterize acquired cetuximab resistance mechanisms in HNSCC cell lines by protein phosphorylation profiling. Through this, promising combination treatments can be identified to possibly overcome acquired cetuximab resistance in HNSCC. Protein phosphorylation profiling showed increased phosphorylation of Akt1/2/3 after cetuximab treatment in acquired cetuximab resistant cells compared to cetuximab sensitive cells, which was confirmed by western blotting. Based on this protein phosphorylation profile, a novel combination treatment with cetuximab and the Akt1/2/3 inhibitor MK2206 was designed. Synergy between cetuximab and MK2206 was observed in two cetuximab sensitive HNSCC cell lines and one acquired cetuximab resistant variant in simultaneous treatment schedules. In conclusion, this study demonstrates that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Our results also show an additive to synergistic interaction between cetuximab and MK2206 in simultaneous treatment schedules. These data support the hypothesis that the combination of cetuximab with PI3K/Akt pathway inhibition might be a promising novel therapeutic strategy to overcome acquired cetuximab resistance in HNSCC patients.
Evaluation and Validation of the Prognostic Value of Serum Albumin to Globulin Ratio in Patients With Cancer Cachexia: Results From a Large Multicenter Collaboration
Authors: Xie Hai-Lun , Zhang Qi , Ruan Guo-Tian , Ge Yi-Zhong , Hu Chun-Lei , Song Meng-Meng , Song Chun-Hua , Zhang Xi , Zhang Xiao-Wei , Li Xiang-Rui , Zhang Kang-Ping , Liu Tong , Yang Ming , Tang Meng , Xu Hong-Xia , Shi Han-Ping
Published: September 2021

Background

Recently, albumin–globulin ratio (AGR), a serological indicator that reflects nutritional status and systemic inflammatory, has been reported to be associated with the prognosis of various cancers. However, there is currently no research report on its relationship with cancer cachexia.

Objectives

This study aimed to explore the prognostic value of AGR in patients with cancer cachexia through a multicenter retrospective analysis.

Methods

We recruited 2,364 patients with cancer cachexia and randomly divided the patients into training and validation cohorts at a ratio of 7:3. The optimal stratification method was used to determine the optimal cutoff value of AGR. The survival curve was evaluated by the Kaplan–Meier method. Cox regression proportional-hazards model was used to determine independent prognostic factors in patients with cancer cachexia. The time-dependent receiver operating characteristic curve was used to compare the prognostic performance of different malnutrition evaluation tools.

Results

The optimal cutoff value of AGR is 1.24 in patients with cancer cachexia. Increasing AGR was associated with survival in a dose–response manner with a forward L-shape. Compared with the high AGR group, the low AGR group had a shorter overall survival; and there was consistency in training and validation cohorts. In the stratified analysis of TNM stage, AGR has good prognostic distinguishing ability for advanced patients. Multivariate survival analysis determined that low AGR was an independent risk factor affecting all-cause mortality in patients with cancer cachexia. In addition, compared with other malnutrition evaluation tools, AGR could effectively stratify the prognosis of patients with cancer cachexia.

Conclusion

AGR was an independent prognostic factor affecting patients with cancer cachexia, especially in advanced patients. Compared with other malnutrition evaluation tools, AGR can effectively stratify the prognosis of patients with cancer cachexia.
Successful Neoadjuvant Chemotherapy for Small-Cell Neuroendocrine Carcinoma of the Pancreas: A Case Report
Authors: Li Keyu , Yuan Jialong , Li Yichen , Zhang Hao , Liu Xubao , Ke Nengwen
Published: September 2021

Neoadjuvant therapy for pancreatic neuroendocrine tumors may potentially aid downstaging, increase the possibility of radical surgery. We herein report a case of a 63-year-old man who had been diagnosed with locally advanced small-cell neuroendocrine carcinomas of the pancreas according to the diagnostic biopsy. The patient received 6 courses of etoposide and cisplatin as neoadjuvant therapy in an attempt to stop tumor progression, which promoted obvious tumor shrinkage without adverse effects and allowed subsequent Appleby procedure, the distal pancreatectomy with celiac artery resection. The patient showed no recurrence in the follow-up of a contrast-enhanced computed tomographic scan, which is 8 months after surgery. To the best of our knowledge, this is a rare case to report etoposide and cisplatin administration before surgery for unresectable pancreatic neuroendocrine carcinoma promoted a pathological partial response and finally achieved a radical surgery, providing a novel therapeutic option for patients with locally advanced pancreatic neuroendocrine carcinoma.
Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer
Authors: Wei Zhuang , Yang Mengxuan , Feng Mei , Wu Zhongen , Rosin-Arbesfeld Rina , Dong Jibin , Zhu Di
Published: September 2021

Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of β-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients’ prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.
Recovery From Eccentric Squat Exercise in Resistance-Trained Young and Master Athletes With Similar Maximum Strength: Combining Cold Water Immersion and Compression
Authors: Schmidt Julian , Ferrauti Alexander , Kellmann Michael , Beaudouin Florian , Pfeiffer Mark , Volk Nicola Reiner , Wambach Jan Martin , Bruder Oliver , Wiewelhove Thimo
Published: September 2021

The aim of this study was to investigate whether recovery from eccentric squat exercise varies depending on age and to assess whether the use of a mixed-method recovery (MMR) consisting of cold water immersion and compression tights benefits recovery. Sixteen healthy and resistance-trained young (age, 22.1±2.1years; N=8) and master male athletes (age, 52.4±3.5years; N=8), who had a similar half squat 1-repetition maximum relative to body weight, completed two identical squat exercise training sessions, separated by a 2-week washout period. Training sessions were followed by either MMR or passive recovery (PR). Internal training loads [heart rate and blood lactate concentration (BLa)] were recorded during and after squat sessions. Furthermore, maximal voluntary isometric contraction (MVIC) force, countermovement jump (CMJ) height, resting twitch force of the knee extensors, serum concentration of creatine kinase (CK), muscle soreness (MS), and perceived physical performance capability (PPC) were determined before and after training as well as after 24, 48, and 72h of recovery. A three-way mixed ANOVA revealed a significant time effect of the squat protocol on markers of fatigue and recovery (p<0.05; decreased MVIC, CMJ, twitch force, and PPC; increased CK and MS). Age-related differences were found for BLa, MS, and PPC (higher post-exercise fatigue in younger athletes). A significant two-way interaction between recovery strategy and time of measurement was found for MS and PPC (p<0.05; faster recovery after MMR). In three participants (two young and one master athlete), the individual results revealed a consistently positive response to MMR. In conclusion, master athletes neither reach higher fatigue levels nor recover more slowly than the younger athletes. Furthermore, the results indicate that MMR after resistance exercise does not contribute to a faster recovery of physical performance, neuromuscular function, or muscle damage, but promotes recovery of perceptual measures regardless of age.
Identification of Candidate Carboxylesterases Associated With Odorant Degradation in Holotrichia parallela Antennae Based on Transcriptome Analysis
Authors: Yi Jiankun , Wang Shang , Wang Zhun , Wang Xiao , Li Gongfeng , Zhang Xinxin , Pan Yu , Zhao Shiwen , Zhang Juhong , Zhou Jing-Jiang , Wang Jun , Xi Jinghui
Published: September 2021

Insects rely on their olfactory systems in antennae to recognize sex pheromones and plant volatiles in surrounding environments. Some carboxylesterases (CXEs) are odorant-degrading enzymes (ODEs), degrading odorant signals to protect the olfactory neurons against continuous excitation. However, there is no report about CXEs in Holotrichia parallela, one of the most major agricultural underground pests in China. In the present study, 20 candidate CXEs were identified based on transcriptome analysis of female and male antennae. Sequence alignments and phylogenetic analysis were performed to investigate the characterization of these candidate CXEs. The expression profiles of CXEs were compared by RT-qPCR analysis between olfactory and non-olfactory tissues of both genders. HparCXE4, 11, 16, 17, 18, 19, and 20 were antenna-biased expressed genes, suggesting their possible roles as ODEs. HparCXE6, 10, 11, 13, and 16 showed significantly higher expression profiles in male antennae, whereas HparCXE18 was expressed more in female antennae. This study highlighted candidate CXE genes linked to odorant degradation in antennae, and provided a useful resource for further work on the H. parallela olfactory mechanism and selection of target genes for integrative control of H. parallela.