bluuebunny/crossref_metadata_2025 huggingface dataset:
Features and Colonization Strategies of Enterococcus faecalis in the Gut of Bombyx mori
Authors: Zhang Xiancui , Feng Huihui , He Jintao , Muhammad Abrar , Zhang Fan , Lu Xingmeng
Published: June 2022

The complex gut microbiome is a malleable microbial community that can undergo remodeling in response to many factors, including the gut environment and microbial properties. Enterococcus has emerged as one of the predominant gut commensal bacterial and plays a fundamental role in the host physiology and health of the major economic agricultural insect, Bombyx mori. Although extensive research on gut structure and microbiome diversity has been carried out, how these microbial consortia are established in multifarious niches within the gut has not been well characterized to date. Here, an Enterococcus species that was stably associated with its host, the model organism B. mori, was identified in the larval gut. GFP–tagged E. faecalis LX10 was constructed as a model bacterium to track the colonization mechanism in the intestine of B. mori. The results revealed that the minimum and optimum colonization results were obtained by feeding at doses of 105 CFU/silkworm and 107 CFU/silkworm, respectively, as confirmed by bioassays and fluorescence-activated cell sorting analyses (FACS). Furthermore, a comprehensive genome-wide exploration of signal sequences provided insight into the relevant colonization properties of E. faecalis LX10. E. faecalis LX10 grew well under alkaline conditions and stably reduced the intestinal pH through lactic acid production. Additionally, the genomic features responsible for lactic acid fermentation were characterized. We further expressed and purified E. faecalis bacteriocin and found that it was particularly effective against other gut bacteria, including Enterococcus casselifavus, Enterococcus mundtii, Serratia marcescens, Bacillus amyloliquefaciens, and Escherichia coli. In addition, the successful colonization of E. faecalis LX10 led to drastically increased expression of all adhesion genes (znuA, lepB, hssA, adhE, EbpA, and Lap), defense genes (cspp, tagF, and esp), regulation gene (BfmRS), secretion gene (prkC) and immune evasion genes (patA and patB), while the expression of iron acquisition genes (ddpD and metN) was largely unchanged or decreased. This work establishes an unprecedented conceptual model for understanding B. mori–gut microbiota interactions in an ecological context. Moreover, these results shed light on the molecular mechanisms of gut microbiota proliferation and colonization in the intestinal tract of this insect.
Erythropoietin Enhances Post-ischemic Migration and Phagocytosis and Alleviates the Activation of Inflammasomes in Human Microglial Cells
Authors: Arik Eren , Heinisch Ole , Bienert Michaela , Gubeljak Lara , Slowik Alexander , Reich Arno , Schulz Jörg B. , Wilhelm Thomas , Huber Michael , Habib Pardes
Published: June 2022

Recombinant human erythropoietin (rhEPO) has been shown to exert anti-apoptotic and anti-inflammatory effects after cerebral ischemia. Inflammatory cytokines interleukin-1β and -18 (IL-1β and IL-18) are crucial mediators of apoptosis and are maturated by multiprotein complexes termed inflammasomes. Microglia are the first responders to post-ischemic brain damage and are a main source of inflammasomes. However, the impact of rhEPO on microglial activation and the subsequent induction of inflammasomes after ischemia remains elusive. To address this, we subjected human microglial clone 3 (HMC-3) cells to various durations of oxygen-glucose-deprivation/reperfusion (OGD/R) to assess the impact of rhEPO on cell viability, metabolic activity, oxidative stress, phagocytosis, migration, as well as on the regulation and activation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Administration of rhEPO mitigated OGD/R-induced oxidative stress and cell death. Additionally, it enhanced metabolic activity, migration and phagocytosis of HMC-3. Moreover, rhEPO attenuated post-ischemic activation and regulation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes as well as their downstream effectors CASPASE1 and IL-1β. Pharmacological inhibition of NLRP3 via MCC950 had no effect on the activation of CASPASE1 and maturation of IL-1β after OGD/R, but increased protein levels of NLRP1, NLRC4, and AIM2, suggesting compensatory activities among inflammasomes. We provide evidence that EPO-conveyed anti-inflammatory actions might be mediated via the regulation of the inflammasomes.
An Open-Source Real-Time Motion Correction Plug-In for Single-Photon Calcium Imaging of Head-Mounted Microscopy
Authors: Li Mingkang , Liu Changhao , Cui Xin , Jung Hayoung , You Heecheon , Feng Linqing , Zhang Shaomin
Published: June 2022

Single-photon-based head-mounted microscopy is widely used to record the brain activities of freely-moving animals. However, during data acquisition, the free movement of animals will cause shaking in the field of view, which deteriorates subsequent neural signal analyses. Existing motion correction methods applied to calcium imaging data either focus on offline analyses or lack sufficient accuracy in real-time processing for single-photon data. In this study, we proposed an open-source real-time motion correction (RTMC) plug-in for single-photon calcium imaging data acquisition. The RTMC plug-in is a real-time subpixel registration algorithm that can run GPUs in UCLA Miniscope data acquisition software. When used with the UCLA Miniscope, the RTMC algorithm satisfies real-time processing requirements in terms of speed, memory, and accuracy. We tested the RTMC algorithm by extending a manual neuron labeling function to extract calcium signals in a real experimental setting. The results demonstrated that the neural calcium dynamics and calcium events can be restored with high accuracy from the calcium data that were collected by the UCLA Miniscope system embedded with our RTMC plug-in. Our method could become an essential component in brain science research, where real-time brain activity is needed for closed-loop experiments.
Neuropsychiatric or Behavioral and Psychological Symptoms of Dementia (BPSD): Focus on Prevalence and Natural History in Alzheimer's Disease and Frontotemporal Dementia
Authors: Laganà Valentina , Bruno Francesco , Altomari Natalia , Bruni Giulia , Smirne Nicoletta , Curcio Sabrina , Mirabelli Maria , Colao Rosanna , Puccio Gianfranco , Frangipane Francesca , Cupidi Chiara , Torchia Giusy , Muraca Gabriella , Malvaso Antonio , Addesi Desirèe , Montesanto Alberto , Di Lorenzo Raffaele , Bruni Amalia Cecilia , Maletta Raffaele
Published: June 2022

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important “red flag” in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.
Leukoaraiosis Distribution and Cerebral Collaterals: A Systematic Review and Meta-Analysis
Authors: Xu Mangmang , Guo Wen , Rascle Lucie , Mechtouff Laura , Nighoghossian Norbert , Eker Omer , Wang Lu , Henninger Nils , Mikati Abdul Ghani , Zhang Shihong , Wu Bo , Liu Ming
Published: June 2022

Background and Objective

Microvascular failure might result in the collapse of cerebral collaterals. However, controversy remains regarding the role of leukoaraiosis (LA) in collateral recruitment. We, therefore, performed a systematic review and meta-analysis of the association between LA and cerebral collaterals.

Methods

Ovid Medline, PubMed, Embase, Web of Science, and three Chinese databases were searched from inception to August 2021. Two types of cerebral collaterals, including Circle of Willis (CoW) and leptomeningeal collaterals (LC), were investigated separately. Random effect models were used to calculate the pooled odds ratio (OR). Meta-regression and subgroup analyses were performed to explore the potential sources of heterogeneity.

Results

From 14 studies (n = 2,451) that fulfilled our inclusion criteria, data from 13 could be pooled for analysis. Overall, there was a significant association between severe LA and incomplete CoW (pooled OR 1.66, 95% CI 1.18–2.32, p = 0.003), with low heterogeneity (I2 = 5.9%). This association remained significant in deep LA (pooled OR 1.48, 95% CI 1.04–2.11, p = 0.029, I2 = 0), but not periventricular LA. Similarly, there was a significant association between LA and LC (pooled OR 1.73, 95% CI 1.03–2.90, p = 0.037), but with high heterogeneity (I2 = 67.2%). Meta-regression indicated a negative association of sample size with the effect sizes (p = 0.029). In addition, most of the studies (7/9) included into the analysis of the relationship of severe LA with poor LC enrolled subjects with large vessel occlusion stroke, and this relationship remained significant when pooling the seven studies, but with high heterogeneity.

Conclusion

Severe LA is associated with a higher prevalence of poor collaterals. This association is robust for CoW but weak for LC. Further studies are required to explore the underlying mechanisms.
Diagnostic Accuracy of the Diffusion-Weighted Imaging Method Used in Association With the Apparent Diffusion Coefficient for Differentiating Between Primary Central Nervous System Lymphoma and High-Grade Glioma: Systematic Review and Meta-Analysis
Authors: Du Xiaoli , He Yue , Lin Wei
Published: June 2022

Background

It is difficult to differentiate between a few primary central nervous system lymphoma (PCNSL) and high-grade glioma (HGG) using conventional magnetic resonance imaging techniques. The purpose of this study is to explore whether diffusion-weighted imaging (DWI) can be effectively used to differentiate between these two types of tumors by analyzing the apparent diffusion coefficient (ADC).

Research Design and Methods

Data presented in Pubmed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and China Science and Technology Journal Database (CQVIP) were analyzed. High-quality literature was included, and the quality was evaluated using the quality assessment of diagnostic accuracy studies-2 (QUADAS-2) tool, and the studies were based on the inclusion and exclusion rules. The pooled sensitivity, pooled specificity, pooled positive likelihood ratio (PLR), pooled negative likelihood ratio (NLR), pooled diagnostic odds ratio (DOR), area under the curve (AUC) of the summary operating characteristic curve (SROC), and corresponding 95% confidence interval (CI) were calculated using the bivariate mixed effect model. Meta-regression analysis and subgroup analysis were used to explore the sources of heterogeneity. The publication bias was evaluated by conducting Deek's test.

Results

In total, eighteen high-quality studies were included. The pooled sensitivity was 0.82 (95% CI: 0.75–0.88), the pooled specificity was 0.87 (95% CI: 0.84–0.90), the pooled positive likelihood ratio was 6.49 (95% CI: 5.06–8.32), the pooled NLR was 0.21 (95% CI: 0.14–0.30), the pooled DOR was 31.31 (95% CI: 18.55–52.86), and the pooled AUC was 0.90 (95% CI: 0.87–0.92). Sample size, language and country of publication, magnetic field strength, region of interest (ROI), and cut-off values of different types of ADC can potentially be the sources of heterogeneity. There was no publication bias in this meta-analysis.

Conclusions

The results obtained from the meta-analysis suggest that DWI is characterized by high diagnostic accuracy and thus can be effectively used for differentiating between PCNSL and HGG.
Pre-Operative Predictors for Post-Operative Pneumonia in Aneurysmal Subarachnoid Hemorrhage After Surgical Clipping and Endovascular Coiling: A Single-Center Retrospective Study
Authors: Yuan Kexin , Li Runting , Zhao Yahui , Wang Ke , Lin Fa , Lu Junlin , Chen Yu , Ma Li , Han Heze , Yan Debin , Li Ruinan , Yang Jun , He Shihao , Li Zhipeng , Zhang Haibin , Ye Xun , Wang Hao , Li Hongliang , Zhang Linlin , Shi Guangzhi , Zhou Jianxin , Zhao Yang , Zhang Yukun , Li Youxiang , Wang Shuo , Chen Xiaolin , Zhao Yuanli , Hao Qiang
Published: June 2022

Objective

Postoperative pneumonia (POP) is one of the major complications after aneurysmal subarachnoid hemorrhage (aSAH) associated with postoperative mortality, prolonged hospitalization, and increased medical cost. Early recognition of pneumonia and more aggressive management may improve patient outcomes.

Methods

We retrospectively reviewed all patients with aSAH who were admitted to our institution between January 2015 and December 2020. Baseline clinical characteristics, imaging data, and inflammatory biomarkers were reviewed. The risk factors derived from multivariate logistic regression of surgical clipping (SC) and endovascular coiling (EC) were analyzed. The area under the receiver operating characteristic (ROC) curve (AUC) was used to calculate each independent predictor's prediction ability.

Results

A total of 843 patients were enrolled. Compared with patients in the EC group, the incidence of POP was higher in the SC group [143/414 (34.54%) vs. 114/429 (26.57%), p = 0.015]. In the EC group, multivariate analysis revealed that age [p = 0.001; odds ratio (OR) = 1.04, 95% CI = 1.02–1.07], posterior circulation aneurysms (p = 0.021; OR = 2.07, 95% CI = 1.14–3.83), higher neutrophil (NEUT; p < 0.001; OR = 1.13, 95% CI = 1.06–1.21), World Federation of Neurosurgical Societies (WFNS) grade 4 or 5 (p < 0.001; OR = 4.84, 95% CI = 2.67–8.79), modified Fisher Scale (mFS) grade 3 or 4 (p = 0.022; OR = 2.60, 95% CI = 1.15–5.89), and acute hydrocephalus (p = 0.048; OR = 1.74, 95% CI = 1.01–3.00) were independent risk factors for POP. In the SC group, multivariate analysis revealed that age (p = 0.015; OR = 1.03, 95% CI = 1.01–1.05), WFNS grade 4 or 5 (p = 0.037; OR = 1.76, 95% CI = 1.03–3.00), heart disease (p < 0.001; OR = 5.02, 95% CI = 2.03–12.45), higher white blood cell (WBC; p < 0.001; OR = 1.13, 95% CI = 1.07–1.20), and mFS grade 3 or 4 (p = 0.019; OR = 2.34, 95% CI = 1.15–4.77) were independent risk factors for POP.

Conclusion

Patients treated with SC are more likely to develop POP. Comprehensive preoperative evaluation of patients may help physicians to better predict POP and implement preventive measures to improve outcomes.
Downregulation of Neurofilament Light Chain Expression in Human Neuronal-Glial Cell Co-Cultures by a Microbiome-Derived Lipopolysaccharide-Induced miRNA-30b-5p
Authors: Pogue Aileen I. , Jaber Vivian R. , Sharfman Nathan M. , Zhao Yuhai , Lukiw Walter J.
Published: June 2022

Microbiome-derived Gram-negative bacterial lipopolysaccharide (LPS) has been shown by multiple laboratories to reside within Alzheimer's disease (AD)-affected neocortical and hippocampal neurons. LPS and other pro-inflammatory stressors strongly induce a defined set of NF-kB (p50/p65)-sensitive human microRNAs, including a brain-enriched Homo sapien microRNA-30b-5p (hsa-miRNA-30b-5p; miRNA-30b). Here we provide evidence that this neuropathology-associated miRNA, known to be upregulated in AD brain and LPS-stressed human neuronal-glial (HNG) cells in primary culture targets the neurofilament light (NF-L) chain mRNA 3'-untranslated region (3'-UTR), which is conducive to the post-transcriptional downregulation of NF-L expression observed within both AD and LPS-treated HNG cells. A deficiency of NF-L is associated with consequent atrophy of the neuronal cytoskeleton and the disruption of synaptic organization. Interestingly, miRNA-30b has previously been shown to be highly expressed in amyloid-beta (Aβ) peptide-treated animal and cell models, and Aβ peptides promote LPS entry into neurons. Increased miRNA-30b expression induces neuronal injury, neuron loss, neuronal inflammation, impairment of synaptic transmission, and synaptic failure in neurodegenerative disease and transgenic murine models. This gut microbiota-derived LPS-NF-kB-miRNA-30b-NF-L pathological signaling network: (i) underscores a positive pathological link between the LPS of gastrointestinal (GI)-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic signaling of the AD brain and stressed brain cells; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-30b-mediated actions on the expression of NF-L, an abundant neuron-specific filament protein known to be important in the maintenance of neuronal cell shape, axonal caliber, and synaptic homeostasis.
Neuromuscular Complications of SARS-CoV-2 and Other Viral Infections
Authors: Jacob Sarah , Kapadia Ronak , Soule Tyler , Luo Honglin , Schellenberg Kerri L. , Douville Renée N. , Pfeffer Gerald
Published: June 2022

In this article we review complications to the peripheral nervous system that occur as a consequence of viral infections, with a special focus on complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We discuss neuromuscular complications in three broad categories; the direct consequences of viral infection, autoimmune neuromuscular disorders provoked by viral infections, and chronic neurodegenerative conditions which have been associated with viral infections. We also include discussion of neuromuscular disorders that are treated by immunomodulatory therapies, and how this affects patient susceptibility in the current context of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is associated with direct consequences to the peripheral nervous system via presumed direct viral injury (dysgeusia/anosmia, myalgias/rhabdomyolysis, and potentially mononeuritis multiplex) and autoimmunity (Guillain Barré syndrome and variants). It has important implications for people receiving immunomodulatory therapies who may be at greater risk of severe outcomes from COVID-19. Thus far, chronic post-COVID syndromes (a.k.a: long COVID) also include possible involvement of the neuromuscular system. Whether we may observe neuromuscular degenerative conditions in the longer term will be an important question to monitor in future studies.
Behavioral and Brain Reactivity Associated With Drug-Related and Non-Drug-Related Emotional Stimuli in Methamphetamine Addicts
Authors: Li Xiawen , Zhou Yu , Zhang Guanghui , Lu Yingzhi , Zhou Chenglin , Wang Hongbiao
Published: June 2022

Background

Methamphetamine addicts can experience severe emotional processing disorders, with abnormal responses to emotional and drug-related stimuli. These aberrant behaviors are one of the key factors leading to relapse. Nevertheless, the characteristics of addicts’ responses to drug-related stimuli and their responses to emotional stimuli remain controversial.

Methods

52 methamphetamine addicts from China passively viewed three different categories of images: Drug-related; positive emotional; and negative emotional. In the first task, participants completed a 9-point Self-Assessment Manikin (SAM) scale, rating the valence of each image. In the second, they performed a cued-action task while electroencephalography (EEG) data were recorded.

Result

Drug-related images were rated negatively, with an average rating of 3.57. However, reaction times to drug-related stimuli were significantly faster than for negative stimuli (p = 0.030), and were indistinguishable from positive stimuli (p > 0.99). Similarly, EPN amplitudes evoked by drug-related images were significantly larger than those evoked by negative stimuli (p < 0.001), but no different than positive stimuli (p > 0.99). LPP amplitudes evoked by drug-related stimuli were significantly smaller than those evoked by negative (p < 0.001) and positive stimuli (p = 0.004).

Conclusion

Despite negative self-assessments of drug-related imagery, MA-addicts reaction times were no slower than positive reactions. Similarly, drug-related and positive imagery EPN amplitudes were indistinguishable. Together, these results suggest increased attentional resources were allocated to the processing of drug-related stimuli and the pathways responsible partially overlap with the those recruited in processing positive emotional imagery in addicts. Moreover, in the late stage of visual processing, MA-addicts showed reduced brain activity in response to drug-related stimuli, suggesting reverse inhibition in response preparation and emotional appraisal. These findings may provide a reference for clinicians treating drug-taking behavior and for the development of new models of rehabilitation therapy.
Pre-gelled Electrode Grid for Self-Applied EEG Sleep Monitoring at Home
Authors: da Silva Souto Carlos F. , Pätzold Wiebke , Paul Marina , Debener Stefan , Wolf Karen Insa
Published: June 2022

The need for diagnostic capabilities for sleep disorders such as sleep apnea and insomnia far exceeds the capacity of inpatient sleep laboratories. Some home monitoring systems omit electroencephalography (EEG) because trained personnel may be needed to apply EEG sensors. Since EEG is essential for the detailed evaluation of sleep, better systems supporting the convenient and robust recording of sleep EEG at home are desirable. Recent advances in EEG acquisition with flex-printed sensors promise easier application of EEG sensor arrays for chronic recordings, yet these sensor arrays were not designed for sleep EEG. Here we explored the self-applicability of a new sleep EEG sensor array (trEEGrid) without prior training. We developed a prototype with pre-gelled neonatal ECG electrodes placed on a self-adhesive grid shape that guided the fast and correct positioning of a total of nine electrodes on the face and around the ear. Positioning of the sensors was based on the results of a previous ear-EEG sleep study (da Silva Souto et al., 2021), and included electrodes around the ear, one eye, and the chin. For comparison, EEG and electrooculogram channels placed according to the American Academy of Sleep Medicine criteria, as well as respiratory inductance plethysmography on thorax and abdomen, oxygen saturation, pulse and body position were included with a mobile polysomnography (PSG) system. Two studies with 32 individuals were conducted to compare the signal quality of the proposed flex-printed grid with PSG signals and to explore self-application of the new grid at home. Results indicate that the new array is self-applicable by healthy participants without on-site hands-on support. A comparison of the hypnogram annotations obtained from the data of both systems revealed an overall substantial agreement on a group level (Cohen’s κ = 0.70 ± 0.01). These results suggest that flex-printed pre-gelled sensor arrays designed for sleep EEG acquisition can facilitate self-recording at home.
Osmotic Stress Uncovers Correlations and Dissociations Between Larval Zebrafish Anxiety Endophenotypes
Authors: Cheng Ruey-Kuang , Tan Jazlynn Xiu Min , Chua Kai Xin , Tan Cheryl Jia Xin , Wee Caroline Lei
Published: June 2022

Larval zebrafish are often used to model anxiety disorders. However, since it is impossible to recapitulate the full complexity and heterogeneity of anxiety in this model, examining component endophenotypes is key to dissecting the mechanisms underlying anxiety. While individual anxiety endophenotypes have been examined in zebrafish, an understanding of the relationships between them is still lacking. Here, we investigate the effects of osmotic stress on a range of anxiety endophenotypes such as thigmotaxis, dark avoidance, light-dark transitions, sleep, night startle, and locomotion. We also report a novel assay for stress-induced anorexia that extends and improves on previously reported food intake quantification methods. We show that acute <30 min osmotic stress decreases feeding but has no effect on dark avoidance. Further, acute osmotic stress dose-dependently increases thigmotaxis and freezing in a light/dark choice condition, but not uniform light environmental context. Prolonged >2 h osmotic stress has similar suppressive effects on feeding while also significantly increasing dark avoidance and sleep, with weaker effects on thigmotaxis and freezing. Notably, the correlations between anxiety endophenotypes were dependent on both salt and dark exposure, with increased dissociations at higher stressor intensities. Our results demonstrate context-dependent effects of osmotic stress on diverse anxiety endophenotypes, and highlight the importance of examining multiple endophenotypes in order to gain a more complete understanding of anxiety mechanisms.
Genomic Strategies for Understanding the Pathophysiology of Autism Spectrum Disorder
Authors: Doi Miyuki , Li Mengwei , Usui Noriyoshi , Shimada Shoichi
Published: June 2022

Recent breakthroughs in sequencing technology and technological developments have made it easier to analyze the entire human genome than ever before. In addition to disease-specific genetic mutations and chromosomal aberrations, epigenetic alterations in individuals can also be analyzed using genomics. Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) caused by genetic and/or environmental factors. More than a thousand genes associated with ASD have been identified which are known to be involved in brain development. However, it is difficult to decode the roles of ASD-associated genes without in vitro and in vivo validations, particularly in the process of brain development. In this review, we discuss genomic strategies for understanding the pathological mechanisms underlying ASD. For this purpose, we discuss ASD-associated genes and their functions, as well as analytical strategies and their strengths and weaknesses in cellular and animal models from a basic research perspective.
Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis
Authors: Liao Guixiang , Fu Yuxiang , Arooj Sumbal , Khan Muhammad , Li Xianming , Yan Maosheng , Li Zihuang , Yang Hongli , Zheng Tao , Xu Ruilian
Published: June 2022

Background

Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial activity in both treatment-naïve and previously treated BM patients. We aimed to investigate if there was any difference in response of BRAF inhibitors in these two cohorts.

Materials and Methods

Electronic database search included PubMed, Medline, and Cochrane library until March 2021 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included intracranial response rate as the primary outcome and survival and safety outcomes as the secondary outcomes. Review Manager version 5.4 was used for data analysis.

Results

Three studies comprising 410 BRAF-mutated melanoma patients with BMs were included according to eligibility criteria. The comparative cohort included patients with treatment-naïve BMs (TN cohort; n = 255) and those who had progressive disease after receiving local brain treatment for BMs (PT cohort; n = 155). Meta-analysis revealed that BRAF inhibitors (vemurafenib and dabrafenib) and BRAF/MEK inhibitor combination (dabrafenib and trametinib) induced significantly higher intracranial disease control (OR 0.58 [95% CI: 0.34, 0.97], p = 0.04) and a trend toward improved progression-free survival (PFS) (HR 1.22 [95% CI: 0.98, 1.52], p = 0.08) in the PT cohort as compared to the TN cohort. Overall survival was not significantly different between the cohorts (HR 1.16 [95% CI: 0.89, 1.51], p = 0.28). Subgroup analysis revealed that PFS was significantly improved (HR 1.67 [95% CI: 1.06, 2.62], p = 0.03), and a trend toward improved OS (HR 1.62 [95% CI: 0.95, 2.75], p = 0.08) was achieved in patients receiving BRAF/MEK inhibitor combination and patients with BRAFv600K mutation receiving dabrafenib alone. No increase in overall adverse events (AEs), grade 3/4 AEs, and severe adverse events (SAEs) was observed between the cohorts.

Conclusions

BRAF inhibitors (plus MEK inhibitor) may achieve better intracranial disease stability in BRAF-mutant melanoma patients who have received previous local treatment for BMs.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/), identifier CRD42020185984.
Postoperative Complications of Free Flap Reconstruction in Moderate-Advanced Head and Neck Squamous Cell Carcinoma: A Prospective Cohort Study Based on Real-World Data
Authors: Li Delong , Wang Chong , Wei Wei , Li Bo , Liu Huan , Cheng Aoming , Niu Qifang , Han Zhengxue , Feng Zhien
Published: June 2022

Background

Postoperative complications (POCs) of moderate-advanced head and neck squamous cell carcinoma (HNSCC) after free flap reconstruction have received little attention. We investigated the risk factors that lead to POCs and their impact on management and prognosis.

Patients and Methods

A single-center, prospective cohort study was conducted at Beijing Stomatological Hospital on primary HNSCC patients treated between 2015 and 2020.

Results

In total, 399 consecutive HNSCC patients who underwent radical resection of the primary tumor and free flap reconstruction were enrolled in this study, 155(38.8%) experienced POCs. The occurrence of POCs directly led to worse short-term outcomes and poorer long-term overall survival (P=0.0056). Weight loss before the operation (P=0.097), Tumor site (P=0.002), stage T4b (P=0.016), an ACE-27 index of 2-3 (P=0.040), operation time≥8h (P=0.001) and Clindamycin as antibiotic prophylaxis (P=0.001) were significantly associated with POCs.

Conclusions

The occurrence of POCs significantly leads to worse short-term outcomes and increases the patients’ burden.
Prognostic Value and Biological Function of Galectins in Malignant Glioma
Authors: Zhu Hongtao , Liu Dan , Cheng Lidong , Liu Jingdian , Wang Guanghui , Li Huan , Zhang Yang , Mi Hailong , Zhang Suojun , Shu Kai , Yu Xingjiang
Published: June 2022

Malignant glioma is the most common solid tumor of the adult brain, with high lethality and poor prognosis. Hence, identifying novel and reliable biomarkers can be advantageous for diagnosing and treating glioma. Several galectins encoded by LGALS genes have recently been reported to participate in the development and progression of various tumors; however, their detailed role in glioma progression remains unclear. Herein, we analyzed the expression and survival curves of all LGALS across 2,217 patients with glioma using The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Rembrandt databases. By performing multivariate Cox analysis, we built a survival model containing LGALS1, LGALS3, LGALS3BP, LGALS8, and LGALS9 using TCGA database. The prognostic power of this panel was assessed using CGGA and Rembrandt datasets. ESTIMATE and CIBERSORT algorithms confirmed that patients in high-risk groups exhibited significant stromal and immune cell infiltration, immunosuppression, mesenchymal subtype, and isocitrate dehydrogenase 1 (IDH1) wild type. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), CancerSEA, and Gene Set Enrichment Analysis (GSEA) showed that pathways related to hypoxia, epithelial-to-mesenchymal transition (EMT), stemness, and inflammation were enriched in the high-risk group. To further elucidate the function of LGALS in glioma, we performed immunohistochemical staining of tissue microarrays (TMAs), Western blotting, and cell viability, sphere formation, and limiting dilution assays following lentiviral short hairpin RNA (shRNA)-mediated LGALS knockdown. We observed that LGALS expression was upregulated in gliomas at both protein and mRNA levels. LGALS could promote the stemness maintenance of glioma stem cells (GSCs) and positively correlate with M2-tumor-associated macrophages (TAMs) infiltration. In conclusion, we established a reliable survival model for patients with glioma based on LGALS expression and revealed the essential roles of LGALS genes in tumor growth, immunosuppression, stemness maintenance, pro-neural to mesenchymal transition, and hypoxia in glioma.
Primary Tumor Fluorine‐18 Fluorodeoxydglucose (18F‐FDG) Is Associated With Cancer-Associated Weight Loss in Non-Small Cell Lung Cancer (NSCLC) and Portends Worse Survival
Authors: Olaechea Santiago , Gannavarapu Bhavani S. , Alvarez Christian , Gilmore Anne , Sarver Brandon , Xie Donglu , Infante Rodney , Iyengar Puneeth
Published: June 2022

Aim

To investigate the diagnostic potential of and associations between tumor 18F‐FDG uptake on PET imaging and cancer-associated weight loss.

Methods

774 non-small cell lung cancer (NSCLC) patients with pre-treatment PET evaluated between 2006 and 2014 were identified. Using the international validated definition of cachexia, the presence of clinically significant pretreatment cancer-associated weight loss (WL) was retrospectively determined. Maximum Standardized Uptake Value (SUVMax) of 18F‐FDG was recorded and dichotomized based on 3 experimental cutpoints for survival analyses. Each SUVMax cutpoint prioritized either survival differences, total cohort comparison sample sizes, or sample size by stage. Patient outcomes and associations between SUVMax and cancer-associated weight loss were assessed by multivariate, categorical, and survival analyses.

Results

Patients were found to have an increased likelihood of having WL at diagnosis associated with increasing primary tumor SUVMax after controlling for potentially confounding patient and tumor characteristics on multivariate logistic regression (OR 1.038; 95% CI: 1.012, 1.064; P=0.0037). After stratifying the cohort by WL and dichotomized SUVMax, both factors were found to be relevant in predicting survival outcomes when the alternative variable was constant. Of note, the most striking survival differences contributed by WL status occurred in high SUVMax groups, where the presence of WL predicted a median survival time detriment of up to 10 months, significant regardless of cutpoint determination method applied to categorize high SUVMax patients. SUVMax classification was found to be most consistently relevant in both WL and no WL groups.

Conclusions

The significant positive association between significant pretreatment cancer-associated weight loss and primary tumor SUVMax underscores increased glucose uptake as a component of catabolic tumor phenotypes. This substantiates 18F‐FDG PET analysis as a prospective tool for assessment of cancer-associated weight loss and corresponding survival outcomes. Furthermore, the survival differences observed between WL groups across multiple SUVMax classifications supports the importance of weight loss monitoring in oncologic workups. Weight loss in the setting of NSCLCs with higher metabolic activity as determined by 18F‐FDG PET signal should encourage more aggressive and earlier palliative care interventions.
“Surviving Discrimination by Pulling Together”: LGBTQI Cancer Patient and Carer Experiences of Minority Stress and Social Support
Authors: Power Rosalie , Ussher Jane M. , Perz Janette , Allison Kimberley , Hawkey Alexandra J.
Published: June 2022

Background

Lesbian, gay, bisexual, transgender, queer and/or intersex (LGBTQI) people with cancer and their carers report poorer psychological outcomes than the general non-LGBTQI cancer population. There is growing acknowledgement that these health inequities can be explained by minority stress, which can be buffered by social support.

Study Aim

To examine subjective experiences of minority stress and social support for LGBTQI people with cancer and their carers, drawing on qualitative findings from the Out with Cancer study.

Method

An online survey including open ended items was completed by 430 LGBTQI cancer patients and 132 partners and other carers, representing a range of tumor types, sexual and gender identities, age and intersex status. A sub-sample of 104 patients and 31 carers completed an interview, with a follow-up photovoice activity and second interview completed by 45 patients and 10 carers. Data was thematically analysed using an intersectional theoretical framework.

Results

Historical and present-day experiences of discrimination, violence, family rejection and exclusion created a legacy of distress and fear. This impacted on trust of healthcare professionals and contributed to distress and unmet needs in cancer survivorship and care. Social support, often provided by partners and other chosen family, including intimate partners and other LGBTQI people, buffered the negative impacts of minority stress, helping LGBTQI patients deal with cancer. However, some participants lacked support due to not having a partner, rejection from family of origin and lack of support within LGBTQI communities, increasing vulnerability to poor psychological wellbeing. Despite the chronic, cumulative impacts of minority stress, LGBTQI patients and carers were not passive recipients of discriminatory and exclusion in cancer care, demonstrating agency and resistance through collective action and advocacy.

Conclusion

LGBTQI people have unique socio-political histories and present-day psycho-social experiences that contribute to distress during cancer. Social support serves to buffer and ameliorate this distress. There is a need for cancer healthcare professionals and support services to be aware of and responsive to these potential vulnerabilities, including the intersectional differences in experiences of minority stress and social support. There is also a need for recognition and facilitation of social support among LGBTQI people with cancer and their carers.
Bioinformatics-Driven Identification of p62 as A Crucial Oncogene in Liver Cancer
Authors: Wang Ling , Hensley Culton R. , Howell Mary E. , Ning Shunbin
Published: June 2022

Liver hepatocellular carcinoma (LIHC) is the major form of liver cancer that is the fourth most common cause of cancer death worldwide. It has been reported that the multifunctional protein p62 (also known as SQSTM1) plays a cancer-promoting role in LIHC, but the detailed mechanisms underlying p62 interaction with LIHC remains unclear. To gain a comprehensive understanding of p62 interaction with LIHC in clinical settings, we performed bioinformatic analyses using various online algorithms derived from high throughput profiling. Our results indicate that p62 expression is significantly upregulated, partially due to its promoter demethylation, rather than p62 gene mutation, in LIHC. Mutation of TP53, CTNNB1, or ALB significantly correlates with, and mutation of AXIN1 reversely correlates with, the p62 expression level. Its upregulation occurs as early as liver cirrhosis, and go through all stages of the carcinogenesis. HCV infection makes a significant contribution to p62 upregulation in LIHC. We further identified p62-associated molecular signatures in LIHC, including many genes that are involved in antioxidant stress and metabolism, such as SRX1 and TXNRD1. Regarding to the clinical outcome, p62 expression level reversely correlates with the survival of LIHC patients (p<0.01). Importantly, we experimentally validated that p62 depletion in liver cancer cell lines downregulates the expression of SRX1 and TXNRD1 at both transcriptional and translational levels, and reduces cell proliferation. As the potential mechanisms underlying the tumor-promoting role of p62, we show that p62 upregulation is remarkably associated with reprogramming of pathways mediated by p53, Wnt/β-catenin, and Keap1-NRF2, which are crucial for oncogenesis in many contexts. Our findings provide a comprehensive insight into the interaction between p62 and LIHC, offering valuable information for understanding of LIHC pathogenesis.
A Necroptosis-Related lncRNA to Develop a Signature to Predict the Outcome, Immune Landscape, and Chemotherapeutic Responses in Bladder Urothelial Carcinoma
Authors: Hou Jian , Lu Zhenquan , Dong Runan , Wu Guoqing , Nie Haibo , Yang Guang , Tang Cheng , Qu Genyi , Xu Yong
Published: June 2022

Objective

Many studies have drawn their attention to the immunotherapy of bladder urothelial carcinoma in terms of immunologic mechanisms of human body. These include immunogenicity of the tumor cells and involvement of long non-coding RNA (lncRNA). We constructed a necroptosis-related long noncoding RNA (nrlncRNA) risk factor model to predict BLCA outcomes and calculate correlations with chemosensitivity and immune infiltration.

Methods

Transcriptomic data from BLCA specimens were accessed from The Cancer Genome Atlas, and nrlncRNAs were identified by performing co-expression analysis. Univariate analysis was performed to identify differentially expressed nrlncRNA pairs. We constructed least absolute contraction and selector operation regression models and drew receiver operating characteristic curves for 1-, 3-, and 5-year survival rates. Akaike information criterion (AIC) values for survival over 1 year were determined as cutoff values in high- and low-risk subgroups. We reassessed the differences between subgroups in terms of survival, clinicopathological characteristics, chemotherapy efficacy, tumor-infiltrating immune cells, and markers of immunosuppression.

Results

We identified a total of 260 necroptosis-related lncRNA pairs, of which we incorporated 13 into the prognostic model. Areas under the curve of 1-, 3-, and 5- year survival time were 0.763, 0.836, and 0.842, respectively. We confirmed the excellent predictive performance of the risk model. Based on AIC values, we confirmed that the high-risk group was susceptible to unfavorable outcomes. The risk scores correlated with survival were age, clinical stage, grade, and tumor node metastases. The risk model was an independent predictor and demonstrated higher predictive power. The risk model can also be utilized to determine immune cell infiltration status, expression levels of immune checkpoint genes, and the sensitivity to cisplatin, doxorubicin, and methotrexate.

Conclusion

We constructed a novel necroptosis-related signature that predicts BLCA outcomes and performs satisfactorily in the immune landscape and chemotherapeutic responses.
Older Age, Polypharmacy, and Low Systolic Blood Pressure Are Associated With More Hypotension-Related Adverse Events in Patients With Type 2 Diabetes Treated With Antihypertensives
Authors: Ambrož Martina , de Vries Sieta T. , Hoogenberg Klaas , Denig Petra
Published: June 2022

Background and Aims: Low systolic blood pressure (SBP) levels while being treated with antihypertensives may cause hypotension-related adverse events (hrAEs), especially in the elderly, women, and frail patients. We aimed to assess the association between the occurrence of hrAEs and low SBP levels, age, sex, and polypharmacy among patients with type 2 diabetes (T2D) treated with antihypertensives.

Methods: In this cohort study, we used the Groningen Initiative to ANalyse Type 2 diabetes Treatment (GIANTT) database which includes patients managed for T2D in primary care from the north of the Netherlands. Patients treated with ≥1 antihypertensive drug and ≥1 SBP measurement between 2012 and 2014 were included. The outcome was the presence of an hrAE, i.e. postural hypotension, dizziness, weakness/tiredness, and syncope in 90 days before or after the lowest recorded SBP level. Age (≥70 vs. <70 years), sex (women vs. men), polypharmacy (5–9 drugs or ≥10 drugs vs. <5 drugs), and SBP level (<130 or ≥130 mmHg) were included as determinants. Logistic regression analyses were conducted for age, sex and polypharmacy, including the SBP level and their interaction, adjusted for confounders. Odds ratios (OR) with 95% confidence intervals (CI) are presented.

Results: We included 21,119 patients, 49% of which were ≥70 years old, 52% were women, 57% had polypharmacy, 61% had an SBP level <130 mmHg and 5.4% experienced an hrAE. Patients with an SBP level <130 mmHg had a significantly higher occurrence of hrAEs than patients with a higher SBP level (6.2 vs. 4.0%; ORs 1.41, 95%CI 1.14–1.75, 1.43, 95%CI 1.17–1.76 and 1.33, 95%CI 1.06–1.67 by age, sex, and polypharmacy, respectively). Older patients (OR 1.29, 95%CI 1.02–1.64) and patients with polypharmacy (OR 5–9 drugs 1.27, 95%CI 1.00–1.62; OR ≥10 drugs 2.37, 95% CI 1.67–3.37) were more likely to experience an hrAE. The association with sex and the interactions between the determinants and SBP level were not significant.

Conclusion: Low SBP levels in patients with T2D treated with antihypertensives is associated with an increase in hrAEs. Older patients and those with polypharmacy are particularly at risk of hrAEs. Age, sex, and polypharmacy did not modify the risk of hrAEs associated with a low SBP level.
Experimental Study of Almonertinib Crossing the Blood-Brain Barrier in EGFR-Mutant NSCLC Brain Metastasis and Spinal Cord Metastasis Models
Authors: Zhang Yuhan , Zhang Yaoshuai , Niu Wenwen , Ge Xianming , Huang Fuhao , Pang Jinlong , Li Xian , Wang Yu , Gao Wei , Fan Fangtian , Li Shanshan , Liu Hao
Published: June 2022

Roughly one third of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitive mutated (EGFRm) tumors experience disease progression through central nervous system (CNS) metastases during treatment. Although EGFR-TKIs have been reported to be favored in some patients with EGFRm NSCLC CNS metastases, novel EGFR-TKIs with proven efficacy in CNS pathologies are clinically needed.To investigate whether almonertinib, a novel third-generation EGFR-TKI for NSCLC, can cross the blood-brain barrier (BBB) and deliver treatment for EGFR-mutant NSCLC brain metastases and spinal cord metastases, we constructed NSCLC brain metastasis and spinal cord metastasis models in vivo to observe the anti-tumor effects of almonertinib. Using ABCB1-MDCK and BCRP-MDCK monolayer cells as the in vitro study model, the effects of transport time and drug concentration on the apparent permeability coefficient of almonertinib and its active metabolite, HAS-719, were investigated. The results of this study show that almonertinib can significantly inhibit PC9 brain and spinal cord metastases. Pharmacokinetic studies in mice revealed that almonertinib has good BBB penetration ability, whereas the metabolite HAS-719 does not easily penetrate the BBB. Early clinical evidence of almonertinib activity in patients with EGFRm-advanced NSCLC and brain metastases has also been reported. In conclusion, almonertinib easily penetrates the BBB and inhibits advanced NSCLC brain and spinal cord metastases.