bluuebunny/crossref_metadata_2025 huggingface dataset:
Dedifferentiation of Functional Brain Activation Associated With Greater Visual Discrimination Accuracy in Middle-Aged and Older Adults
Authors: Seider Talia R. , Porges Eric C. , Woods Adam J. , Cohen Ronald A.
Published: July 2021

Neural dedifferentiation refers to an age-related phenomenon whereby brain functions that are localized to specific, distinct, and differentiated brain areas in young adults become less so as people reach more advanced age. Older adults tend to exhibit greater spread of cortical activation on fMRI during cognitive processing compared to younger adults, with evidence that this occurs during visuoperceptual processing. Some age-related functional changes are considered compensatory, but whether dedifferentiation is compensatory is not clearly understood. The current study assessed dedifferentiation and visual discrimination performance during simultaneous match-to-sample tasks from the Visual Assessment Battery (VAB) among 40 healthy middle-aged and older adults using fMRI. Task-relevant regions of interest (ROIs) were created in the dorsal stream for discrimination of spatial location, the ventral stream for shape, and an area encompassing V5 for velocity. Dedifferentiation, or less specificity in functional activation, was associated with greater discrimination accuracy and more years of education. Secondary analyses showed that reduced functional activation in task-relevant ROIs was associated with faster discrimination speed. Age was unassociated with functional activation. Results suggest that dedifferentiation is compensatory. Lack of age effects suggest that other factors beyond age, such as cognitive or brain reserve, may better predict performance when considering cognitive skills that are relatively stable as adults age, such as visual discrimination.
The Emerging Role of Circular RNAs in Alzheimer’s Disease and Parkinson’s Disease
Authors: Zhang Meng , Bian Zhigang
Published: July 2021

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two neurodegenerative diseases (NDDs) commonly found in elderly patients that are difficult to diagnose and lack effective treatment. Currently, the available diagnostic methods for these two NDDs do not meet clinical diagnostic expectations. Circular RNAs (circRNAs) are a diverse group of endogenous non-coding RNAs (ncRNAs) found in eukaryotic cells. Emerging studies suggest that altered expression of circRNAs is involved in the pathological processes of NDDs. CircRNAs could also prove to be promising biomarkers for the early diagnosis of NDDs such as AD and PD. Growing evidence has improved our knowledge of the roles of circRNAs in NDDs, which may lead to new therapeutic approaches that target transcription for preventing neurodegeneration. In this review, we describe the formation mechanisms and functions of circRNAs as well as methods of validation. We also discuss the emerging role of circRNAs in the pathophysiology of AD and PD and their potential value as biomarkers and therapeutic targets for AD and PD in the future.
Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease
Authors: Martinez Jose L. , Zammit Matthew D. , West Nicole R. , Christian Bradley T. , Bhattacharyya Anita
Published: July 2021

Down syndrome (DS, trisomy 21) is characterized by intellectual impairment at birth and Alzheimer’s disease (AD) pathology in middle age. As individuals with DS age, their cognitive functions decline as they develop AD pathology. The susceptibility to degeneration of a subset of neurons, known as basal forebrain cholinergic neurons (BFCNs), in DS and AD is a critical link between cognitive impairment and neurodegeneration in both disorders. BFCNs are the primary source of cholinergic innervation to the cerebral cortex and hippocampus, as well as the amygdala. They play a critical role in the processing of information related to cognitive function and are directly engaged in regulating circuits of attention and memory throughout the lifespan. Given the importance of BFCNs in attention and memory, it is not surprising that these neurons contribute to dysfunctional neuronal circuitry in DS and are vulnerable in adults with DS and AD, where their degeneration leads to memory loss and disturbance in language. BFCNs are thus a relevant cell target for therapeutics for both DS and AD but, despite some success, efforts in this area have waned. There are gaps in our knowledge of BFCN vulnerability that preclude our ability to effectively design interventions. Here, we review the role of BFCN function and degeneration in AD and DS and identify under-studied aspects of BFCN biology. The current gaps in BFCN relevant imaging studies, therapeutics, and human models limit our insight into the mechanistic vulnerability of BFCNs in individuals with DS and AD.
A Novel Multi-Feature Fusion Method in Merging Information of Heterogenous-View Data for Oil Painting Image Feature Extraction and Recognition
Authors: Chen Tong , Yang Juan
Published: July 2021

The art of oil painting reflects on society in the form of vision, while technology constantly explores and provides powerful possibilities to transform the society, which also includes the revolution in the way of art creation and even the way of thinking. The progress of science and technology often provides great changes for the creation of art, and also often changes people's way of appreciation and ideas. The oil painting image feature extraction and recognition is an important field in computer vision, which is widely used in video surveillance, human-computer interaction, sign language recognition and medical, health care. In the past few decades, feature extraction and recognition have focused on the multi-feature fusion method. However, the captured oil painting image is sensitive to light changes and background noise, which limits the robustness of feature extraction and recognition. Oil painting feature extraction is the basis of feature classification. Feature classification based on a single feature is easily affected by the inaccurate detection accuracy of the object area, object angle, scale change, noise interference and other factors, resulting in the reduction of classification accuracy. Therefore, we propose a novel multi-feature fusion method in merging information of heterogenous-view data for oil painting image feature extraction and recognition in this paper. It fuses the width-to-height ratio feature, rotation invariant uniform local binary mode feature and SIFT feature. Meanwhile, we adopt a modified faster RCNN to extract the semantic feature of oil painting. Then the feature is classified based on the support vector machine and K-nearest neighbor method. The experiment results show that the feature extraction method based on multi-feature fusion can significantly improve the average classification accuracy of oil painting and have high recognition efficiency.
Prefrontal GABAergic Interneurons Gate Long-Range Afferents to Regulate Prefrontal Cortex-Associated Complex Behaviors
Authors: Yang Sha-Sha , Mack Nancy R. , Shu Yousheng , Gao Wen-Jun
Published: July 2021

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.
Resting-State Functional Connectivity of the Ageing Female Brain—Differences Between Young and Elderly Female Adults on Multislice Short TR rs-fMRI
Authors: Podgórski Przemysław , Waliszewska-Prosół Marta , Zimny Anna , Sąsiadek Marek , Bladowska Joanna
Published: July 2021

Introduction:Age-related brain changes are one of the most important world health problems due to the rising lifespan and size of the elderly populations. The aim of the study was to assess the effect of ageing in women on coordinated brain activity between eight resting-state networks.

Material and Methods:The study group comprised 60 healthy female volunteers who were divided into two age groups: younger women (aged 20–30n= 30) and older women (aged 55–80n= 30). Resting-state data were collected during a 15 min scan in the eyes-closed condition using a 3T MR scanner. Data were preprocessed and analysed using the CONN toolbox version 19.c. The large-scale network analysis includeda prioriselected regions of interest of the default mode, the sensorimotor, the visual, the salience, the dorsal attention, the fronto-parietal, the language, and the cerebellar network.

Results:Within the visual, the default mode, the salience, and the sensorimotor network, the intra-network resting-state functional connectivity (RSFC) was significantly higher with increasing age. There was also a significant increase in the inter-network RSFC in older females compared to young females found in the following networks: sensorimotor lateral and salience, salience and language, salience and fronto-parietal, cerebellar anterior and default mode, cerebellar posterior and default mode, visual and sensorimotor lateral, visual and sensorimotor, visual lateral and default mode, language and cerebellar anterior, language and cerebellar posterior, fronto-parietal and cerebellar anterior, dorsal attention and sensorimotor, dorsal attention and default mode, sensorimotor superior, and salience. Compared to young females, elderly women presented bilaterally significantly lower inter-network RSFC of the salience supramarginal gyrus and cerebellar posterior, sensorimotor lateral, and cerebellar anterior network, and sensorimotor lateral and cerebellar posterior as well as sensorimotor superior and cerebellar posterior network.

Conclusion:Increased RSFC between some brain networks including the visual, the default mode, the salience, the sensorimotor, the language, the fronto-parietal, the dorsal attention, and the cerebellar networks in elderly females may function as a compensation mechanism during the ageing process of the brain. To the best of our knowledge, this study is the first to report the importance of increase of cerebellar networks RSFC during healthy female ageing.
Neural Mechanism of Repeated Transcranial Magnetic Stimulation to Enhance Visual Working Memory in Elderly Individuals With Subjective Cognitive Decline
Authors: Liu Meng , Nie Zhi-Yu , Li Ren-Ren , Zhang Wei , Huang Li-He , Wang Jie-Qun , Xiao Wei-Xin , Zheng Jialin C. , Li Yun-Xia
Published: July 2021

Visual working memory (VWM), the core process inherent to many advanced cognitive processes, deteriorates with age. Elderly individuals usually experience defects in the processing of VWM. The dorsolateral prefrontal cortex is a key structure for the top-down control of working memory processes. Many studies have shown that repeated transcranial magnetic stimulation (rTMS) improves VWM by modulating the excitability of neurons in the target cortical region, though the underlying neural mechanism has not been clarified. Therefore, this study sought to assess the characteristics of brain memory function post-rTMS targeting the left dorsolateral prefrontal cortex. The study stimulated the left dorsolateral prefrontal cortex in elderly individuals by performing a high-frequency rTMS protocol and evaluated behavioral performance using cognitive tasks and a VWM task. Based on the simultaneously recorded electroencephalogram signals, event-related potential and event-related spectral perturbation analysis techniques were used to investigate the variation characteristics of event-related potential components' (N2PC and CDA) amplitudes and neural oscillations in elderly individuals to elucidate the effect of high-frequency rTMS. The results found that rTMS enhanced VWM performance and significantly improved attention and executive function in elderly individuals with subjective cognitive decline. We therefore speculate that rTMS enhances VWM by increasing the N2PC and CDA amplitude, alongside increasing β oscillation activity. This would improve the attention and allocation of resources in elderly individuals such as to improve an individual's VWM.
The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control
Authors: Pilitsis Julie G. , Chakravarthy Krishnan V. , Will Andrew J. , Trutnau Karen C. , Hageman Kristin N. , Dinsmoor David A. , Litvak Leonid M.
Published: July 2021

Objectives

Spinal cord stimulation (SCS) is a drug free treatment for chronic pain. Recent technological advances have enabled sensing of the evoked compound action potential (ECAP), a biopotential that represents neural activity elicited from SCS. The amplitudes of many SCS paradigms – both sub- and supra-threshold – are programmed relative to the patient’s perception of SCS. The objective of this study, then, is to elucidate relationships between the ECAP and perception thresholds across posture and SCS pulse width. These relationships may be used for the automatic control and perceptually referenced programming of SCS systems.

Methods

ECAPs were acquired from 14 subjects across a range of postures and pulse widths with swept amplitude stimulation. Perception (PT) and discomfort (DT) thresholds were recorded. A stimulation artifact reduction scheme was employed, and growth curves were constructed from the sweeps. An estimate of the ECAP threshold (ET), was calculated from the growth curves using a novel approach. Relationships between ET, PT, and DT were assessed.

Results

ETs were estimated from 112 separate growth curves. For the postures and pulse widths assessed, the ET tightly correlated with both PT (r = 0.93; p < 0.0001) and DT (r = 0.93; p < 0.0001). The median accuracy of ET as a predictor for PT across both posture and pulse width was 0.5 dB. Intra-subject, ECAP amplitudes at DT varied up to threefold across posture.

Conclusion

We provide evidence that the ET varies across both different positions and varying pulse widths and suggest that this variance may be the result of postural dependence of the recording electrode-tissue spacing. ET-informed SCS holds promise as a tool for SCS parameter configuration and may offer more accuracy over alternative approaches for neural and perceptual control in closed loop SCS systems.
The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy
Authors: Purnell Benton , Murugan Madhuvika , Jani Raja , Boison Detlev
Published: July 2021

Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in increased adenosine release, thereby constraining excessive excitation. The exceptionally high neuronal activity of a seizure results in a surge in extracellular adenosine to concentrations many-fold higher than would be observed under normal conditions. In this review, we discuss the multifarious effects of adenosine signaling in the context of epilepsy, with emphasis on sudden unexpected death in epilepsy (SUDEP). We describe and categorize the beneficial, detrimental, and potentially deadly aspects of adenosine signaling. The good or beneficial characteristics of adenosine signaling in the context of seizures include: (1) its direct effect on seizure termination and the prevention of status epilepticus; (2) the vasodilatory effect of adenosine, potentially counteracting postictal vasoconstriction; (3) its neuroprotective effects under hypoxic conditions; and (4) its disease modifying antiepileptogenic effect. The bad or detrimental effects of adenosine signaling include: (1) its capacity to suppress breathing and contribute to peri-ictal respiratory dysfunction; (2) its contribution to postictal generalized EEG suppression (PGES); (3) the prolonged increase in extracellular adenosine following spreading depolarization waves may contribute to postictal neuronal dysfunction; (4) the excitatory effects of A2Areceptor activation is thought to exacerbate seizures in some instances; and (5) its potential contributions to sleep alterations in epilepsy. Finally, the adverse effects of adenosine signaling may potentiate a deadly outcome in the form of SUDEP by suppressing breathing and arousal in the postictal period. Evidence from animal models suggests that excessive postictal adenosine signaling contributes to the pathophysiology of SUDEP. The goal of this review is to discuss the beneficial, harmful, and potentially deadly roles that adenosine plays in the context of epilepsy and to identify crucial gaps in knowledge where further investigation is necessary. By better understanding adenosine dynamics, we may gain insights into the treatment of epilepsy and the prevention of SUDEP.
Influence of Body Mass Index on Eating Habits and Food Choice Determinants Among Brazilian Women During the COVID-19 Pandemic
Authors: Mazzolani Bruna Caruso , Smaira Fabiana Infante , Esteves Gabriel Perri , Santo André Heloísa C. , Amarante Milla Cordeiro , Castanho Daniela , Campos Karen , Benatti Fabiana Braga , Pinto Ana Jéssica , Roschel Hamilton , Gualano Bruno , Nicoletti Carolina Ferreira
Published: July 2021

Changes in emotional state due to the COVID-19 pandemic may potentially modify eating habits, which may differ as a function of body mass index (BMI). Using a self-reported, questionnaire-based survey we evaluated Brazilian women during the pandemic for: (i) the influence of BMI on changes in eating habits, food choice determinants, and psychological symptoms; (ii) associations between eating habits, food choice determinants and psychological symptoms. General characteristics, anthropometric data, eating habits before and during the pandemic, food choice determinants and psychological symptoms during the pandemic were collected between June and September, 2020. Participants (n = 1,183) were normal weight (60.4%), overweight (26.2%) and obese (13.4%). A higher frequency of “cooking” (72.3–77.6%, p = 0.004) and “use of delivery service” (29.8–48.8%, p < 0.001) was reported during, in comparison to before the pandemic. Additionally, a higher prevalence of “snacking” (57.1–63.8%, p = 0.005) and “eating at table” (78.5–82.7%, p < 0.001) was reported during the pandemic, while the number of participants reporting “dieting” decreased (28.7–20.4%, p < 0.001). “Health”, “natural concerns” and “need and hunger” were less important determinants for participants with overweight/obesity compared to normal weight. Regression analysis indicated that (i) “health”, “natural concerns” and “affect regulation”; (ii) “health”, “pleasure”, “convenience”, and “natural concerns”; and (iii) “visual appeal” and “pleasure” were the food choice determinants more associated with eating habits among women with normal weight, overweight, and obesity, respectively. In conclusion, eating habits were modified during the pandemic despite BMI, whereas food choice determinants differed between overweight/obesity and normal weight women.
Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Are Associated With Diet, BMI, and Age
Authors: Kellerer Teresa , Kleigrewe Karin , Brandl Beate , Hofmann Thomas , Hauner Hans , Skurk Thomas
Published: July 2021

Background: Fatty acid esters of hydroxy fatty acids (FAHFAs) are a group of fatty acids with potential anti-inflammatory and anti-diabetic effects. The blood levels of FAHFAs and their regulation in humans have hardly been studied.

Objective: We aimed to investigate serum FAHFA levels in well-characterized human cohorts, to evaluate associations with age, sex, BMI, weight loss, diabetic status, and diet.

Methods: We analyzed levels of stearic-acid-9-hydroxy-stearic-acid (9-SAHSA), oleic-acid-9-hydroxy-stearic-acid (9-OAHSA) and palmitic-acid-9-hydroxy-palmitic-acid (9-PAHPA) as well as different palmitic acid-hydroxy-stearic-acids (PAHSAs) by HPLC-MS/MS with the use of an internal standard in various cohorts: A cohort of different age groups (18–25y; 40–65y; 75–85y; Σn = 60); severely obese patients undergoing bariatric surgery and non-obese controls (Σn = 36); obese patients with and without diabetes (Σn = 20); vegetarians/vegans (n = 10) and omnivores (n = 9); and young men before and after acute overfeeding with saturated fatty acids (SFA) (n = 15).

Results: Omnivores had substantially higher FAHFA levels than vegetarians/vegans [median (25th percentile; 75th percentile) tFAHFAs = 12.82 (7.57; 14.86) vs. 5.86 (5.10; 6.71) nmol/L; P < 0.05]. Dietary overfeeding by supplementation of SFAs caused a significant increase within 1 week [median tFAHFAs = 4.31 (3.31; 5.27) vs. 6.96 (6.50; 7.76) nmol/L; P < 0.001]. Moreover, obese patients had lower FAHFA levels than non-obese controls [median tFAHFAs = 3.24 (2.80; 4.30) vs. 5.22 (4.18; 7.46) nmol/L; P < 0.01] and surgery-induced weight loss increased 9-OAHSA level while other FAHFAs were not affected. Furthermore, significant differences in some FAHFA levels were found between adolescents and adults or elderly, while no differences between sexes and between diabetic and non-diabetic individuals were detected.

Conclusions: FAHFA serum levels are strongly affected by high SFA intake and reduced in severe obesity. Age also may influence FAHFA levels, whereas there was no detectable relation with sex and diabetic status. The physiological role of FAHFAs in humans remains to be better elucidated.

Trial Registration: All studies referring to these analyses were registered in the German Clinical Trial Register (https://www.drks.de/drks_web/) with the numbers DRKS00009008, DRKS00010133, DRKS00006211, and DRKS00009797.
Identification of a Three-RNA Binding Proteins (RBPs) Signature Predicting Prognosis for Breast Cancer
Authors: Liu Yang , Sun Hefen , Li Xuan , Liu Qiqi , Zhao Yuanyuan , Li Liangdong , Xu Baojin , Hou Yifeng , Jin Wei
Published: July 2021

Background

To date, breast cancer remains the primary cause of tumor-related death among women, even though some leap-type developments of oncology have been done to slash the mortality. Considering the tumor heterogeneity and individual variation, the more reliable biomarkers are required to be identified for supporting the development of precision medicine in breast cancer.

Methods

Based on the TCGA-BRCA and METABRIC databases, the differently expressed RNA binding proteins (RBPs) between tumor and normal tissues were investigated. In this study, we focused on the communal differently expressed RBPs in four subtypes of breast cancer. Lasso-penalized Cox analysis, Stepwise-multivariate Cox analysis and Kaplan–Meier survival curve were performed to identify the hub RBP-coding genes in predicting prognosis of breast cancer, and a prognostic model was established. The efficiency of this model was further validated in other independent GSE20685, GSE4922 and FUSCC-TNBC cohorts by calculating the risk score and performing survival analysis, ROC and nomogram. Moreover, pathologic functions of the candidate RBPs in breast cancer were explored using some routine experiments in vitro, and the potential compounds targeting these RBPs were predicted by reviewing the Comparative Toxicogenomics Database.

Results

Here, we identified 62 RBPs which were differently expressed between the tumor and normal tissues. Thereinto, three RBPs (MRPL12, MRPL13 and POP1) acted as independent risk factors, and their expression pattern also correlated with poor prognosis of patients. A prognostic model, built with these 3-RBPs, possessed statistical significance to predict the survival probability of patients with breast cancer. Furthermore, experimental validations showed that down-regulating the expression of endogenous MRPL12, MRPL13 or POP1 could dramatically suppress the cellular viability and migration of breast cancer cells in vitro. Besides, some compounds (such as the Acetaminophen, Urethane and Tunicamycin) were predicted for curing breast cancer via targeting MRPL12, MRPL13 and POP1 simultaneously.

Conclusion

This study identified and established a 3-RBPs-based signature and nomogram for predicting the survival probability of patients with breast cancer. MRPL12, MRPL13 and POP1 might act as oncogenes in maintaining cellular viability and accelerating metastasis of breast cancer cells, implying the possibility of which to be designed as biomarkers and/or therapeutic targets for breast cancer.
Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues
Authors: Braun Attila , Anders Hans-Joachim , Gudermann Thomas , Mammadova-Bach Elmina
Published: July 2021

Although platelets are critically involved in thrombosis and hemostasis, experimental and clinical evidence indicate that platelets promote tumor progression and metastasis through a wide range of physical and functional interactions between platelets and cancer cells. Thrombotic and thromboembolic events are frequent complications in patients with solid tumors. Hence, cancer modulates platelet function by directly inducing platelet-tumor aggregates and triggering platelet granule release and altering platelet turnover. Also, platelets enhance tumor cell dissemination by activating endothelial cell function and recruiting immune cells to primary and metastatic tumor sites. In this review, we summarize current knowledge on the complex interactions between platelets and tumor cells and the host microenvironment. We also critically discuss the potential of anti-platelet agents for cancer prevention and treatment.
The Risk of Immune-Related Thyroid Dysfunction Induced by PD-1/PD-L1 Inhibitors in Cancer Patients: An Updated Systematic Review and Meta-Analysis
Authors: Tian Yuan , Li Ran , Liu Yan , Li Meng , Song Yuxiao , Zheng Yan , Gao Aiqin , Wen Qing , Su Guohai , Sun Yuping
Published: July 2021

Background

Thyroid dysfunction is common for cancer patients receiving PD-1/PD-L1 inhibitor therapies. To clarify the incidence risk of thyroid dysfunction would be important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, the updated meta-analysis was conducted to evaluate the incidence risk of thyroid dysfunction caused by PD-1/PD-L1 inhibitors.

Methods

PD-1/PD-L1 inhibitor related clinical trials were collected by a systematic search of the PubMed. Some relevant studies were identified by a manual search. The incidence risk of all grades and grades 3-5 was analyzed and evaluated by random effect model. The Newcastle Ottawa Scale was used for the quality assessment of all clinical trials.

Results

Forty-three clinical trials were collected. Compared with chemotherapy, the risk of hypothyroidism of all grades was significantly higher (OR=7.15, 95%CI:[4.85, 10.55], I2 = 40%, Z=9.91(P <0.00001)) in PD-1/PD-L1 group. Similar results could also be noted, when the control group was placebo or CTLA-4. When PD-1/PD-L1 was combined with other treatments for cancer patients, the risk of hypothyroidism of all grades was also significantly increased. Similar to the analysis results of hypothyroidism, PD-1/PD-L1 inhibitors played the same role in increasing the risk of hyperthyroidism and thyroiditis. Few significant analysis results was noted, when the risk of thyroid dysfunction of grades 3-5 was assessed.

Conclusion

Whether used alone or in combination with other anti-tumor drugs, PD-1/PD-L1 inhibitors increased the risk of thyroid dysfunction, especially for hypothyroidism. Furthermore, PD-1/PD-L1 was better than chemotherapy and CTLA-4 in increasing the risk of thyroid dysfunction.
Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor
Authors: Bauer Sebastian , George Suzanne , von Mehren Margaret , Heinrich Michael C.
Published: July 2021

The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.
Prognostic Value of Perineural Invasion in Oral Tongue Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
Authors: Li Jiajia , Liu Shan , Li Zhangao , Han Xinxin , Que Lin
Published: July 2021

Objectives

A significant number of recently published research has outlined the contribution of perineural invasion (PNI) to clinical outcomes in oral tongue squamous cell carcinoma (OTSCC), but some results remain conflicting. This study aimed to determine whether patients with OTSCC with PNI have a worse prognosis than those without PNI.

Materials and Methods

PubMed, Embase, and the Cochrane Library were queried for potentially eligible articles published up to December 2020. The primary outcomes were the hazard ratio (HR) for locoregional recurrence, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). The random-effect model was used in all analyses.

Results

Seventeen studies (4445 patients) were included. Using adjusted HRs, the presence of PNI was associated with a higher risk of locoregional recurrence (HR=1.73, 95%CI: 1.07-2.79, P=0.025, I2 = 33.1%, Pheterogeneity=0.224), worse OS (HR=1.94, 95%CI: 1.39-2.72, P<0.001, I2 = 0.0%, Pheterogeneity=0.838), worse DFS (HR=2.13, 95%CI: 1.53-2.96, P<0.001, I2 = 48.4%, Pheterogeneity=0.071), and worse CSS (HR=1.93, 95%CI: 1.40-2.65, P<0.001, I2 = 25.5%, Pheterogeneity=0.251). PNI had an impact on locoregional recurrence in early-stage OTSCC but not in all stages, and on OS, DFS, and CSS in all-stage and early-stage OTSCC. The sensitivity analyses showed that the results were robust.

Conclusion

The presence of PNI significantly affects the locoregional recurrence and survival outcomes among patients with OTSCC.
Functional Connectivity Density for Radiation Encephalopathy Prediction in Nasopharyngeal Carcinoma
Authors: Zhao Lin-Mei , Kang Ya-Fei , Gao Jian-Ming , Li Li , Chen Rui-Ting , Zeng Jun-Jie , Zhang You-Ming , Liao Weihua
Published: July 2021

The diagnostic efficiency of radiation encephalopathy (RE) remains heterogeneous, and prediction of RE is difficult at the pre-symptomatic stage. We aimed to analyze the whole-brain resting-state functional connectivity density (FCD) of individuals with pre-symptomatic RE using multivariate pattern analysis (MVPA) and explore its prediction efficiency. Resting data from NPC patients with nasopharyngeal carcinoma (NPC; consisting of 20 pre-symptomatic RE subjects and 26 non-RE controls) were collected in this study. We used MVPA to classify pre-symptomatic RE subjects from non-RE controls based on FCD maps. Classifier performances were evaluated by accuracy, sensitivity, specificity, and area under the characteristic operator curve. Permutation tests and leave-one-out cross-validation were applied for assessing classifier performance. MVPA was able to differentiate pre-symptomatic RE subjects from non-RE controls using global FCD as a feature, with a total accuracy of 89.13%. The temporal lobe as well as regions involved in the visual processing system, the somatosensory system, and the default mode network (DMN) revealed robust discrimination during classification. Our findings suggest a good classification efficiency of global FCD for the individual prediction of RE at a pre-symptomatic stage. Moreover, the discriminating regions may contribute to the underlying mechanisms of sensory and cognitive disturbances in RE.
Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer
Authors: George Mridula A. , Qureshi Sadaf , Omene Coral , Toppmeyer Deborah L. , Ganesan Shridar
Published: July 2021

Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy. The three approved agents currently in the market are palbociclib, ribociclib and abemaciclib. Besides the overall similarities associated with CDK4/6 inhibition, there are differences between the three approved agents that may explain the differences noted in unique clinical scenarios- monotherapy, patients with brain metastases or use in the adjuvant setting. This review article will explore the preclinical and pharmacological differences between the three agents and help understand the benefits seen with these agents in certain subgroups of patients with metastatic HR positive breast cancer.
Single Nucleotide Polymorphisms in HOTAIR Are Related to Breast Cancer Risk and Prognosis in the Northeastern Chinese Population
Authors: Lv Zheng , Kou Changgui , Chen Naifei , Jia Lin , Sun Xu , Gao Yangyang , Bai Rilan , Yang Ming , Cui Jiuwei
Published: July 2021

Background

The long noncoding RNA HOX transcript antisense RNA (HOTAIR) is highly expressed in breast cancer (BC) tissues and is associated with the recurrence and metastasis of BC. Until now, the results of studies on associations between several functional single nucleotide polymorphisms(SNPs) (rs920778, rs1899663, and rs4759314) in HOTAIR with BC susceptibility carried out in different regions of China are still inconsistent. There is no study on correlation between HOTAIR SNPs and prognosis of Chinese population. Therefore, we investigated the relationship between HOTAIR SNPs and susceptibility to and prognosis of BC.

Method

We conducted a population-based case-control study involving 828 BC cases and 905 healthy controls. Peripheral blood DNA was used for genotyping. The association between HOTAIR genotypes and BC risk were estimated by odds ratios (ORs) computed using the binary logistic regression model. The relationships between HOTAIR SNPs and clinicopathological features were tested by Pearson’s chi-square test or Fisher’s exact test. Survival was analyzed using the Kaplan-Meier method.

Results

The functional rs920778 genetic variant increased BC risk in the codominant model. Individuals with the rs920778 GG genotype had an OR of 2.426 (95% confidence interval [CI] = 1.491–3.947, P < 0.001) for developing BC compared to individuals with the AA genotype. Individuals with the AG genotype had an OR of 1.296 (95% CI = 1.040–1.614, P = 0.021) for developing BC compared to individuals with the AA genotype. Individuals with the rs4759314 GA genotype had a lower BC risk than individuals with the rs4759314 AA/GG genotype (OR = 0.566, 95% CI = 0.398–0.803, P = 0.001). The rs1899663 genotype had no correlation with BC susceptibility. Haplotypes composed of rs920778–rs1899663 and rs920778–rs1899663–rs4759314 could increase BC risk (all P < 0.001). There were no statistically significant associations between HOTAIR SNPs and clinicopathological characteristics. The rs920778 GG/AG genotypes were associated with worse disease-free survival (DFS) (p = 0.012), and the rs4759314 GA genotype was associated with worse DFS and overall survival (OS) (p = 0.011).

Conclusion

HOTAIR SNPs(rs920778 and rs4759314) are significantly related to BC susceptibility and prognosis in the northeastern Chinese population, indicating the significance in the occurrence and development of BC.
Long Non-Coding RNAs in Diagnosis, Treatment, Prognosis, and Progression of Glioma: A State-of-the-Art Review
Authors: Momtazmanesh Sara , Rezaei Nima
Published: July 2021

Glioma is the most common malignant central nervous system tumor with significant mortality and morbidity. Despite considerable advances, the exact molecular pathways involved in tumor progression are not fully elucidated, and patients commonly face a poor prognosis. Long non-coding RNAs (lncRNAs) have recently drawn extra attention for their potential roles in different types of cancer as well as non-malignant diseases. More than 200 lncRNAs have been reported to be associated with glioma. We aimed to assess the roles of the most investigated lncRNAs in different stages of tumor progression and the mediating molecular pathways in addition to their clinical applications. lncRNAs are involved in different stages of tumor formation, invasion, and progression, including regulating the cell cycle, apoptosis, autophagy, epithelial-to-mesenchymal transition, tumor stemness, angiogenesis, the integrity of the blood-tumor-brain barrier, tumor metabolism, and immunological responses. The well-known oncogenic lncRNAs, which are upregulated in glioma, are H19, HOTAIR, PVT1, UCA1, XIST, CRNDE, FOXD2-AS1, ANRIL, HOXA11-AS, TP73-AS1, and DANCR. On the other hand, MEG3, GAS5, CCASC2, and TUSC7 are tumor suppressor lncRNAs, which are downregulated. While most studies reported oncogenic effects for MALAT1, TUG1, and NEAT1, there are some controversies regarding these lncRNAs. Expression levels of lncRNAs can be associated with tumor grade, survival, treatment response (chemotherapy drugs or radiotherapy), and overall prognosis. Moreover, circulatory levels of lncRNAs, such as MALAT1, H19, HOTAIR, NEAT1, TUG1, GAS5, LINK-A, and TUSC7, can provide non-invasive diagnostic and prognostic tools. Modulation of expression of lncRNAs using antisense oligonucleotides can lead to novel therapeutics. Notably, a profound understanding of the underlying molecular pathways involved in the function of lncRNAs is required to develop novel therapeutic targets. More investigations with large sample sizes and increased focus on in-vivo models are required to expand our understanding of the potential roles and application of lncRNAs in glioma.
Differential Use of Pediatric Video Visits by a Diverse Population During the COVID-19 Pandemic: A Mixed-Methods Study
Authors: Rosenthal Jennifer L. , O'Neal Christina , Sanders April , Fernandez y Garcia Erik
Published: July 2021

Objective: To describe and explore pediatric ambulatory video visit use by patient characteristics during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: We conducted an explanatory sequential mixed methods study with integration at the design and methods level. Phase 1 was a cross-sectional analysis of general and specialty pediatric ambulatory encounters to profile the use of video visits by patient characteristics. We performed descriptive analyses for each variable of interest and estimated a multivariable logistic regression model to analyze factors associated with the odds of having a video visit. Phase 2 was a qualitative exploration using semi-structured interviews with healthcare team members to understand the contextual factors influencing video visit usage. We used an interview guide to solicit information related to general perceptions about ambulatory video visits, reactions to the quantitative phase data, and strategies for optimizing equitable reach of video visits. Data were analyzed using a combination of deductive and inductive analysis.

Results: Among the 5,464 pediatric ambulatory encounters completed between March 11 and June 30, 2020, 2,127 were video visits. Patient factors associated with lower odds of having a video visit rather than an in-person visit included being Spanish-speaking (aOR 0.27, 95% CI 0.20–0.37) and other non-English-speaking (aOR 0.50, 95% CI 0.34–0.75) in comparison to English-speaking. Patients with public insurance also had a lower odds of having a video visit in comparison to privately insured patients (aOR 0.77, 95% CI 0.67–0.88). Qualitative interviews identified five solution-based themes: (1) Promoting video visits in a way that reaches all patient families; (2) Offering video visits to all patient families; (3) Mitigating digital literacy barriers; (4) Expanding health system resources to support families' specific needs; and (5) Engaging and empowering health system personnel to expand video visit access.

Conclusion: We identified differences in pediatric ambulatory video visit use by patient characteristics, with lower odds of video visit use among non-English-speaking and publicly insured patients. The mixed-methods approach allowed for the perspectives of our interview participants to contextualize the finding and lead to suggestions for improvement. Both our findings and the approach can be used by other health systems to ensure that all patients and families receive equal video visit access.
COVID-19 Disease in Infants Less Than 90 Days: Case Series
Authors: Shaiba Lana A. , Altirkawi Khalid , Hadid Adnan , Alsubaie Sara , Alharbi Omar , Alkhalaf Hamad , Alharbi Musaed , Alruqaie Nourah , Alzomor Omar , Almughaileth Fahad , Alyousef Nasser , Shah Prakesh S.
Published: July 2021

The objective of this study is to describe the clinical presentations, radiological and laboratory findings, and outcomes of COVID-19 disease in infants ≤ 90 days of age at presentation. We conducted a retrospective study of infants in this age group who were found to be SARS-CoV-2 positive. Asymptomatic infants who were identified through routine testing following delivery to COVID-19-positive mothers were excluded. We classified infants according to their presentation: asymptomatic, mildly symptomatic, moderately symptomatic, and severely/critically symptomatic. A total of 36 infants were included. Of them, two were asymptomatic and four had severe/critical presentation. Of the severely symptomatic infants, two were considered as multisystem inflammatory syndrome in children (MIS-C) and there was one death. One infant in the severe symptomatic group presented with cardiac failure, with the possibility of congenital infection. Another infant presented with cardiogenic shock. None of these infants received antiviral medication. The study found that infants ≤ 90 days can present with a severe form of COVID-19 disease. Multisystem inflammatory syndrome in children, although rarely reported in infants, is a possible complication of COVID-19 disease and can be associated with significant morbidity and mortality.
Ginkgo biloba L. Prevents Hypobaric Hypoxia–Induced Spatial Memory Deficit Through Small Conductance Calcium-Activated Potassium Channel Inhibition: The Role of ERK/CaMKII/CREB Signaling
Authors: Kushwah Neetu , Jain Vishal , Kadam Manisha , Kumar Rahul , Dheer Aastha , Prasad Dipti , Kumar Bhuvnesh , Khan Nilofar
Published: July 2021

Hypobaric hypoxia (HH) is a stressful condition, which is more common at high altitudes and can impair cognitive functions.Ginkgo bilobaL. leaf extract (GBE) is widely used as herbal medicine against different disorders. Its ability to improve cognitive functions, reduce oxidative stress, and promote cell survival makes it a putative therapeutic candidate against HH. The present study has been designed to explore the effect of GBE on HH-induced neurodegeneration and memory impairment as well as possible signaling mechanisms involved. 220–250 gm (approximately 6- to 8-week-old) Sprague Dawley rats were randomly divided into different groups. GBE was orally administered to respective groups at a dose of 100 mg/kg/day throughout the HH exposure, i.e., 14 days. Memory testing was performed followed by hippocampus isolation for further processing of different molecular and morphological parameters related to cognition. The results indicated that GBE ameliorates HH-induced memory impairment and oxidative damage and reduces apoptosis. Moreover, GBE modulates the activity of the small conductance calcium-activated potassium channels, which further reduces glutamate excitotoxicity and apoptosis. The exploration of the downstream signaling pathway demonstrated that GBE administration prevents HH-induced small conductance calcium-activated potassium channel activation, and that initiates pro-survival machinery by activating extracellular signal–regulated kinase (ERK)/calmodulin-dependent protein kinase II (CaMKII) and the cAMP response element–binding protein (CREB) signaling pathway. In summary, the current study demonstrates the beneficial effect of GBE on conditions like HH and provides various therapeutic targets involved in the mechanism of action of GBE-mediated neuroprotection.
Vascular Adhesion Protein-1 (VAP-1)/Semicarbazide-Sensitive Amine Oxidase (SSAO): A Potential Therapeutic Target for Atherosclerotic Cardiovascular Diseases
Authors: Li Hui , Du Shiyu , Niu Panpan , Gu Xiaosong , Wang Jun , Zhao Ying
Published: July 2021

Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO), whose enzymatic activity regulates the adhesion/exudation of leukocytes in/from blood vessels. Due to its abundant expressions in vascular systems and prominent roles in inflammations, increasing attentions have been paid to the roles of VAP-1/SSAO in atherosclerosis, a chronic vascular inflammation that eventually drives clinical cardiovascular events. Clinical studies have demonstrated a potential value of soluble VAP-1 (sVAP-1) for the diagnosis and prognosis of cardiovascular diseases. Recent findings revealed that VAP-1 is expressed in atherosclerotic plaques and treatment with VAP-1 inhibitors alleviates the progression of atherosclerosis. This review will focus on the roles of VAP-1/SSAO in the progression of atherosclerotic lesions and therapeutic potentials of VAP-1 inhibitors for cardiovascular diseases.