bluuebunny/crossref_metadata_2025 huggingface dataset:
Infants’ Hemodynamic Modulation in the Temporal Region
Authors: Tsuji Yuki , Kanazawa So , Yamaguchi Masami K.
Published: March 2022

This study examined whether 8-month-old infants’ hemodynamic responses in the temporal region were modulated by repeated presentation of “Peekaboo” by using functional near-infrared spectroscopy (fNIRS). Previous studies have shown that infants’ temporal region responds to faces (e.g., Otsuka et al., 2007). A recent electroencephalography study showed that the neural activity of infants was modulated by repeated presentation of “Peekaboo.” Some fNIRS studies also revealed that the movie of “Peekaboo” activated the hemodynamic response of the temporal region in infancy. However, no studies have shown the hemodynamic modulation of the temporal region according to the repeated presentation of “Peekaboo” in infants. In order to examine whether the hemodynamic responses of the temporal region were modulated by repeated presentation of “Peekaboo,” we compared the activity of the temporal region between the early and late trials. We set long and short delays before face-presentation. The results showed that the concentration of oxy-hemoglobin in the right occipitotemporal region (Ch 21) in both conditions increased after the presentation of “Peekaboo” relative to the baseline. Moreover, in the long delay condition, the hemodynamic modulation of the right occipitotemporal region was induced according to the repeated presentation of “Peekaboo” in infants.
The Influence of the Modulation Index on Frequency-Modulated Steady-State Visual Evoked Potentials
Authors: Dreyer Alexander M. , Heikkinen Benjamin L. A. , Herrmann Christoph S.
Published: March 2022

Based on increased user experience during stimulation, frequency-modulated steady-state visual evoked potentials (FM-SSVEPs) have been suggested as an improved stimulation method for brain-computer interfaces. Adapting such a novel stimulation paradigm requires in-depth analyses of all different stimulation parameters and their influence on brain responses as well as the user experience during the stimulation. In the current manuscript, we assess the influence of different values for the modulation index, which determine the spectral distribution in the stimulation signal on FM-SSVEPs. We visually stimulated 14 participants at different target frequencies with four different values for the modulation index. Our results reveal that changing the modulation index in a way that elevates the stimulation power in the targeted sideband leads to increased FM-SSVEP responses. There is, however, a tradeoff with user experience as increased modulation indices also lead to increased perceived flicker intensity as well as decreased stimulation comfort in our participants. Our results can guide the choice of parameters in future FM-SSVEP implementations.
Automated Skull Stripping in Mouse Functional Magnetic Resonance Imaging Analysis Using 3D U-Net
Authors: Ruan Guohui , Liu Jiaming , An Ziqi , Wu Kaiibin , Tong Chuanjun , Liu Qiang , Liang Ping , Liang Zhifeng , Chen Wufan , Zhang Xinyuan , Feng Yanqiu
Published: March 2022

Skull stripping is an initial and critical step in the pipeline of mouse fMRI analysis. Manual labeling of the brain usually suffers from intra- and inter-rater variability and is highly time-consuming. Hence, an automatic and efficient skull-stripping method is in high demand for mouse fMRI studies. In this study, we investigated a 3D U-Net based method for automatic brain extraction in mouse fMRI studies. Two U-Net models were separately trained on T2-weighted anatomical images and T2*-weighted functional images. The trained models were tested on both interior and exterior datasets. The 3D U-Net models yielded a higher accuracy in brain extraction from both T2-weighted images (Dice > 0.984, Jaccard index > 0.968 and Hausdorff distance < 7.7) and T2*-weighted images (Dice > 0.964, Jaccard index > 0.931 and Hausdorff distance < 3.3), compared with the two widely used mouse skull-stripping methods (RATS and SHERM). The resting-state fMRI results using automatic segmentation with the 3D U-Net models are highly consistent with those obtained by manual segmentation for both the seed-based and group independent component analysis. These results demonstrate that the 3D U-Net based method can replace manual brain extraction in mouse fMRI analysis.
Sonification of Complex Spectral Structures
Authors: Sköld Mattias , Bresin Roberto
Published: March 2022

In this article, we present our work on the sonification of notated complex spectral structures. It is part of a larger research project about the design of a new notation system for representing sound-based musical structures. Complex spectral structures are notated with special symbols in the scores, which can be digitally rendered so that the user can hear key aspects of what has been notated. This hearing of the notated data is significantly different from reading the same data, and reveals the complexity hidden in its simplified notation. The digitally played score is not the music itself but can provide essential information about the music in ways that can only be obtained in sounding form. The playback needs to be designed so that the user can make relevant sonic readings of the sonified data. The sound notation system used here is an adaptation of Thoresen and Hedman's spectromorphological analysis notation. Symbols originally developed by Lasse Thoresen from Pierre Schaeffer's typo-morphology have in this system been adapted to display measurable spectral features of timbrel structure for the composition and transcription of sound-based musical structures. Spectrum category symbols are placed over a spectral grand-staff that combines indications of pitch and frequency values for the combined display of music related to pitch-based and spectral values. Spectral features of a musical structure such as spectral width and density are represented as graphical symbols and sonically rendered. In perceptual experiments we have verified that users can identify spectral notation parameters based on their sonification. This confirms the main principle of sonification that is that the data/dimensions relations in one domain, in our case notated representation of spectral features, are transformed in perceived relations in the audio domain, and back.
The Effect of Chronic Alcohol on Cognitive Decline: Do Variations in Methodology Impact Study Outcome? An Overview of Research From the Past 5 Years
Authors: Charlton Annai J. , Perry Christina J.
Published: March 2022

Excessive alcohol use is often associated with accelerated cognitive decline, and extensive research using animal models of human alcohol consumption has been conducted into potential mechanisms for this relationship. Within this literature there is considerable variability in the types of models used. For example, alcohol administration style (voluntary/forced), length and schedule of exposure and abstinence period are often substantially different between studies. In this review, we evaluate recent research into alcohol-induced cognitive decline according to methodology of alcohol access, as well as cognitive behavioral task employed. Our aim was to query whether the nature and severity of deficits observed may be impacted by the schedule and type of alcohol administration. We furthermore examined whether there is any apparent relationship between the amount of alcohol consumed and the severity of the deficit, as well as the potential impact of abstinence length, and other factors such as age of administration, and sex of subject. Over the past five years, researchers have overwhelmingly used non-voluntary methods of intake, however deficits are still found where intake is voluntary. Magnitude of intake and type of task seem most closely related to the likelihood of producing a deficit, however even this did not follow a consistent pattern. We highlight the importance of using systematic and clear reporting styles to facilitate consistency across the literature in this regard. We hope that this analysis will provide important insights into how experimental protocols might influence findings, and how different patterns of consumption are more or less likely to produce an addiction-vulnerable cognitive phenotype in animal models.
Modeling Epilepsy Using Human Induced Pluripotent Stem Cells-Derived Neuronal Cultures Carrying Mutations in Ion Channels and the Mechanistic Target of Rapamycin Pathway
Authors: Weng Octavia Yifang , Li Yun , Wang Lu-Yang
Published: March 2022

Epilepsy is a neurological disorder that affects over 65 million people globally. It is characterized by periods of seizure activity of the brain as a result of excitation and inhibition (E/I) imbalance, which is regarded as the core underpinning of epileptic activity. Both gain- and loss-of-function (GOF and LOF) mutations of ion channels, synaptic proteins and signaling molecules along the mechanistic target of rapamycin (mTOR) pathway have been linked to this imbalance. The pathogenesis of epilepsy often has its roots in the early stage of brain development. It remains a major challenge to extrapolate the findings from many animal models carrying these GOF or LOF mutations to the understanding of disease mechanisms in the developing human brain. Recent advent of the human pluripotent stem cells (hPSCs) technology opens up a new avenue to recapitulate patient conditions and to identify druggable molecular targets. In the following review, we discuss the progress, challenges and prospects of employing hPSCs-derived neural cultures to study epilepsy. We propose a tentative working model to conceptualize the possible impact of these GOF and LOF mutations in ion channels and mTOR signaling molecules on the morphological and functional remodeling of intrinsic excitability, synaptic transmission and circuits, ultimately E/I imbalance and behavioral phenotypes in epilepsy.
Research Progress on the Inflammatory Effects of Long Non-coding RNA in Traumatic Brain Injury
Authors: Wang Jian-peng , Li Chong , Ding Wen-cong , Peng Gang , Xiao Ge-lei , Chen Rui , Cheng Quan
Published: March 2022

Globally, traumatic brain injury (TBI) is an acute clinical event and an important cause of death and long-term disability. However, the underlying mechanism of the pathophysiological has not been fully elucidated and the lack of effective treatment a huge burden to individuals, families, and society. Several studies have shown that long non-coding RNAs (lncRNAs) might play a crucial role in TBI; they are abundant in the central nervous system (CNS) and participate in a variety of pathophysiological processes, including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis, and neurogenesis. Some lncRNAs modulate multiple therapeutic targets after TBI, including inflammation, thus, these lncRNAs have tremendous therapeutic potential for TBI, as they are promising biomarkers for TBI diagnosis, treatment, and prognosis prediction. This review discusses the differential expression of different lncRNAs in brain tissue during TBI, which is likely related to the physiological and pathological processes involved in TBI. These findings may provide new targets for further scientific research on the molecular mechanisms of TBI and potential therapeutic interventions.
Hyperphosphorylated Human Tau Accumulates at the Synapse, Localizing on Synaptic Mitochondrial Outer Membranes and Disrupting Respiration in a Mouse Model of Tauopathy
Authors: Trease Andrew J. , George Joseph W. , Roland Nashanthea J. , Lichter Eliezer Z. , Emanuel Katy , Totusek Steven , Fox Howard S. , Stauch Kelly L.
Published: March 2022

Neurogenerative disorders, such as Alzheimer’s disease (AD), represent a growing public health challenge in aging societies. Tauopathies, a subset of neurodegenerative disorders that includes AD, are characterized by accumulation of fibrillar and hyperphosphorylated forms of microtubule-associated protein tau with coincident mitochondrial abnormalities and neuronal dysfunction. Although, in vitro, tau impairs axonal transport altering mitochondrial distribution, clear in vivo mechanisms associating tau and mitochondrial dysfunction remain obscure. Herein, we investigated the effects of human tau on brain mitochondria in vivo using transgenic htau mice at ages preceding and coinciding with onset of tauopathy. Subcellular proteomics combined with bioenergetic assessment revealed pathologic forms of tau preferentially associate with synaptic over non-synaptic mitochondria coinciding with changes in bioenergetics, reminiscent of an aged synaptic mitochondrial phenotype in wild-type mice. While mitochondrial content was unaltered, mitochondrial maximal respiration was impaired in synaptosomes from htau mice. Further, mitochondria-associated tau was determined to be outer membrane-associated using the trypsin protection assay and carbonate extraction. These findings reveal non-mutant human tau accumulation at the synapse has deleterious effects on mitochondria, which likely contributes to synaptic dysfunction observed in the context of tauopathy.
Body Roundness Index and Waist–Hip Ratio Result in Better Cardiovascular Disease Risk Stratification: Results From a Large Chinese Cross-Sectional Study
Authors: Li Ying , He Yongmei , Yang Lin , Liu Qingqi , Li Chao , Wang Yaqin , Yang Pingting , Wang Jiangang , Chen Zhiheng , Huang Xin
Published: March 2022

Background

The appropriate optimal anthropometric indices and their thresholds within each BMI category for predicting those at a high risk of cardiovascular disease risk factors (CVDRFs) among the Chinese are still under dispute.

Objectives

We aimed to identify the best indicators of CVDRFs and the optimal threshold within each BMI category among the Chinese.

Methods

Between 2012 and 2020, a total of 500,090 participants were surveyed in Hunan, China. Six anthropometric indices including waist circumference (WC), a body shape index (ABSI), body roundness index (BRI), waist–hip ratio (WHR), hip circumference (HC), and waist–height ratio (WHtR) were evaluated in the present study. Considered CVDRFs included dyslipidaemia, hypertension, diabetes mellitus (DM), and chronic kidney disease (CKD). The associations of anthropometrics with CVDRFs within each BMI category were evaluated through logistic regression models. The area under the receiver operating characteristic curve (AUROC) was used to assess the predictive abilities.

Results

For the presence of at least one CVDRFs, the WHR had the highest AUROC in overweight [0.641 (95%CI:0.638, 0.644)] and obese [0.616 (95%CI:0.609, 0.623)] men. BRI had the highest AUROC in underweight [0.649 (95%CI:0.629, 0.670)] and normal weight [0.686 (95%CI:0.683, 0.690)] men. However, the BRI had the highest discrimination ability among women in all the BMI categories, with AUROC ranging from 0.641 to 0.727. In most cases, the discriminatory ability of WHtR was similar to BRI and was easier to calculate; therefore, thresholds of BRI, WHR, and WHtR for CVDRFs identification were all calculated. In men, BRI thresholds of 1.8, 3.0, 3.9, and 5.0, WHtR thresholds of 0.41, 0.48, 0.53, and 0.58, and WHR thresholds of 0.81, 0.88, 0.92, and 0.95 were identified as optimal thresholds across underweight, normal weight, overweight, and obese populations, respectively. The corresponding BRI values in women were 1.9, 2.9, 4.0, and 5.2, respectively, and WHtR were 0.41, 0.48, 0.54, and 0.59, while the WHR values were 0.77, 0.83, 0.88, and 0.90. The recommended BRI, WHtR, or WHR cut-offs could not statistically differentiate high-risk CKD or hypercholesterolemia populations.

Conclusions

We found that BRI and WHR were superior to other indices for predicting CVD risk factors, except CKD or hypercholesterolemia, among the Chinese.
Serum Vitamin D Levels in Relation to Hypertension and Pre-hypertension in Adults: A Systematic Review and Dose–Response Meta-Analysis of Epidemiologic Studies
Authors: Mokhtari Elahe , Hajhashemy Zahra , Saneei Parvane
Published: March 2022

Background

Findings of observational studies that evaluated the association of serum vitamin D status and high blood pressure were contradictory. This meta-analysis of epidemiologic studies assessed the relation of serum vitamin D levels to hypertension (HTN) and pre-hypertension in adults.

Methods

We conducted a systematic search of all published articles up to March 2021, in four electronic databases (MEDLINE (PubMed), Web of Science (ISI), Embase and Scopus), and Google scholar. Seventy epidemiologic studies (10 prospective cohort, one nested case–control, and 59 cross-sectional investigations) that reported relative risks (RRs), odds ratios (ORs), hazard ratios, or prevalence ratios with 95% CIs for HTN or pre-hypertension in relation to serum vitamin D concentrations in adults were included in the analysis.

Results

In prospective studies, a 16% decrease in risk of hypertension was observed in participants with high levels of serum vitamin D compared to low levels (RR: 0.84; 95%CI: 0.73, 0.96; 12 effect sizes). Dose–response analysis in prospective studies revealed that each 25 nmol/L increase in serum vitamin D concentrations resulted in 5% reduced risk of HTN (RR: 0.95; 95% CI: 0.90, 1.00). Also, a significant nonlinear relationship between serum vitamin D levels and HTN was found (Pnonlinearity< 0.001). In cross-sectional investigations, highest vs. lowest level of serum vitamin D was related to reduced odds of HTN (OR: 0.84; 95%CI: 0.79, 0.90; 66 effect sizes) and pre-hypertension (OR: 0.75; 0.95%CI: 0.68, 0.83; 9 effect sizes). Dose–response analysis in these studies showed that each 25 nmol/L increase in serum vitamin D levels was related to a significant 6% reduction in odds of hypertension in all populations (RR: 0.94; 95%CI: 0.90, 0.99) and 3% in studies with representative populations (RR: 0.97; 95%CI: 0.95, 0.99).

Conclusion

This meta-analysis of epidemiologic studies disclosed that serum vitamin D concentrations were inversely related to the risk of HTN in adults, in a dose–response manner in both prospective cohort and cross-sectional studies.

Systematic Review Registration:http://www.crd.york.ac.uk/Prospero, identifier: CRD42021251513.
Detection of Adulteration and Pesticide Residues in Chinese Patent Medicine Qipi Pill Using KASP Technology and GC-MS/MS
Authors: Wang Gang , Bai Xuanjiao , Chen Xiaochen , Ren Ying , Pang Xiaohui , Han Jianping
Published: March 2022

Chinese patent medicines (CPMs) are of great value for the prevention and treatment of diseases. However, adulterants and pesticide residues in CPMs have become the “bottleneck” impeding the globalization of traditional Chinese medicine. In this study, 12 batches of commercially available Qipi pill (a famous CPM recorded in Chinese Pharmacopeia) from different manufacturers were investigated to evaluate their authenticity and quality safety. Considering the severely degraded DNA in CPMs, kompetitive allele specific PCR (KASP) technology combined with DNA mini-barcodes was proposed for the quality regulation of a large number of products in CPM market. The residues of four kinds of pesticides including pentachloronitrobenzene (PCNB), hexachlorocyclohexane (HCH), aldrin, and dichlorodiphenyltrichloroethane (DDT) were quantified using gas chromatography and tandem mass spectrometry (GC-MS/MS). The results indicated that in two of the 12 batches of Qipi pill, the main herbal ingredient Panax ginseng was completely substituted by P. quinquefolius, and one sample was partially adulterated with P. quinquefolius. The PCNB residue was detected in 11 batches of Qipi pill, ranging from 0.11 to 0.46 mg/kg, and the prohibited pesticide HCH was present in four samples. Both adulteration and banned pesticides were found in two CPMs. This study suggests that KASP technology combined with DNA mini-barcodes can be used for the quality supervision of large sample size CPMs with higher efficiency but lower cost. Our findings also provide the insight that pesticide residues in CPMs should be paid more attention in the future.
Cerebral Ischemic Complications After Surgical Revascularization for Moyamoya Disease: Risk Factors and Development of a Predictive Model Based on Preoperative Nutritional Blood Parameters
Authors: Li Fangbao , Li Chuanfeng , Sun Yunwei , Bao Yue , Jiang Wenbo , Song Zuoyan , Wang Yongyi , Liu Mingxing , Wang Weimin , Li Tong , Li Luo
Published: March 2022

Objectives

Cerebral ischemic complications are common after revascularization in patients with moyamoya disease (MMD). Risk factors from specific laboratory variables have only been assessed by limited research. This study was to investigate the association between postoperative cerebral ischemia and nutritional blood parameters and examine predictive values of such risk factors in adults.

Methods

Preoperative demographics and nutritional blood parameters of patients with MMD who received revascularization at our institution from 2012 to 2021 were retrospectively reviewed. Univariate analysis and multivariable logistic regression were used to identify independent risk factors for the onset of postoperative cerebral ischemic complications. Predictive values were tested and a model incorporating these independent risk factors was created using the R program. Area under the receiver operating characteristic curve (AUC) was used for testing its discriminability.

Results

Postoperative cerebral ischemic complications occurred in 32 patients of 100 included procedures. Surgery on the left hemisphere, lower admission modified Rankin Scale (mRS) score, aberrant nutritional parameters including low white blood cell (WBC), and high total cholesterol (TC) were significantly associated with cerebral ischemic complications after revascularization. The intriguing role of WBC might be explained by altered immunomodulation. The AUC of this model with novel nutritional parameters yielded a value of 0.811, presenting better predictive accuracy. Additionally, the model was visualized in the form of a nomogram and translated into a user-friendly calculator to generate individual risk.

Conclusions

Surgical side, admission mRS score, WBC, and TC were independent risk factors for postoperative cerebral ischemic complications. The model composed of these four parameters was promising to be adopted in clinical practice.
The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling
Authors: Beiriger Jamison , Habib Ahmed , Jovanovich Nicolina , Kodavali Chowdari V. , Edwards Lincoln , Amankulor Nduka , Zinn Pascal O.
Published: March 2022

Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.
Interaction Analysis of Adenovirus L5 Protein With Pancreatic Cancer Cell Surface Receptor to Analyze Its Affinity for Oncolytic Virus Therapy
Authors: Nisar Maryum , Paracha Rehan Zafar , Gul Alvina , Arshad Iqra , Ejaz Saima , Murad Didar , Khan Shahzeb , Mustansar Zartasha
Published: March 2022

This study seeks to investigate the interaction profile of the L5 protein of oncolytic adenovirus with the overexpressed surface receptors of pancreatic cancer. This is an important area of research because pancreatic cancer is one of the most fatal malignancies with a very low patient survival rate. Multiple therapies to date to improve the survival rate are reported; however, they show a comparatively low success rate. Among them, oncolytic virus therapy is a type of immunotherapy that is currently under deliberation by researchers for multiple cancer types in various clinical trials. Talimogene laherparepvec (T-VEC) is the first oncolytic virus approved by the US Food and Drug Administration (FDA) for melanoma. The oncolytic virus not only kills cancer cells but also activates the anticancer immune response. Therefore, it is preferred over others to deal with aggressive pancreatic cancer. The efficacy of therapy primarily depends on how effectively the oncolytic virus enters and infects the cancer cell. Cell surface receptors and their interactions with virus coat proteins are a crucial step for oncolytic virus entry and a pivotal determinant. The L5 proteins of the virus coat are the first to interact with host cell surface receptors. Therefore, the objective of this study is to analyze the interaction profile of the L5 protein of oncolytic adenovirus with overexpressed surface receptors of pancreatic cancer. The L5 proteins of three adenovirus serotypes HAdV2, HAdV5, and HAdV3 were utilized in this study. Overexpressed pancreatic cancer receptors include SLC2A1, MET, IL1RAP, NPR3, GABRP, SLC6A6, and TMPRSS4. The protein structures of viral and cancer cell protein were docked using the High Ambiguity Driven protein–protein DOCKing (HADDOCK) server. The binding affinity and interaction profile of viral proteins against all the receptors were analyzed. Results suggest that the HAdV3 L5 protein shows better interaction as compared to HAdV2 and HAdV5 by elucidating high binding affinity with 4 receptors (NPR3, GABRP, SLC6A6, and TMPRSS4). The current study proposed that HAdV5 or HAdV2 virus pseudotyped with the L5 protein of HAdV3 can be able to effectively infect pancreatic cancer cells. Moreover, the current study surmises that the affinity maturation of HAdV3 L5 can enhance virus attachment with all the receptors of cancer cells.
Trends in Disease Burden of Chronic Lymphocytic Leukemia at the Global, Regional, and National Levels From 1990 to 2019, and Projections Until 2030: A Population-Based Epidemiologic Study
Authors: Ou Yang , Long Yichen , Ji Lili , Zhan Yanxia , Qiao Tiankui , Wang Xiangdong , Chen Hao , Cheng Yunfeng
Published: March 2022

Background

The prognosis of chronic lymphocytic leukemia (CLL) has been improved dramatically, but there are limited studies focusing on CLL disease burden on a global scale. We aimed to evaluate the accurate assessment of the disease burden of CLL that may provide more detailed epidemiological information for rational policies.

Methods

The main source of the data was the Global Burden of Disease (GBD) study 2019. Incident cases, death cases, disability-adjusted life years (DALYs), and their corresponding age-standardized rates (ASRs) from 1990 to 2019 were used to describe the burden of CLL. Data about attributable risk factors were also extracted and analyzed. Bayesian age-period-cohort (BAPC) models were used to assess and project the incidence and mortality rates till 2030.

Results

Globally, the incidence of CLL had been increasing. Deaths and DALYs decreased slightly. The burden of death and DALY is affected by socio-demographic index (SDI). The incidence rate, death rate, and DALY rate of CLL increased significantly with age. Male-to-female ratios of incidence rates varied in different SDI quintiles. Smoking, high body mass index, and occupational exposure to benzene or formaldehyde were the potential risk factors related to CLL. Global ASIRs might tend to increase until 2030, while ASDR would decrease until 2030.

Conclusion

The disease burden of CLL decreased in higher SDI countries but increased in lower ones. Strategies for early detection of asymptomatic CLL, development of novel drugs, and measures against attributable factors should be implemented to combat CLL burden.
The Signaling Pathways Associated With Breast Cancer Bone Metastasis
Authors: Song Xuelian , Wei Changran , Li Xiangqi
Published: March 2022

Background

Breast cancer (BC) is now the leading cause of cancer in women, and bone is the primary site of distant BC metastasis. BC bone metastasis seriously affects the quality of life of patients and increases the mortality rate. However, the mechanism of BC bone metastasis is not fully understood.

Main Body

Paget’s “seed and soil” hypothesis led experts to explore the relationship between surface markers and receptors in breast tumors and various growth factors in bone. The relevant breast tumor markers serve as “seeds”, and the bone microenvironment that is suitable for the survival of the tumor serves as the “soil”. These factors interact to make up an entire system and form feedback pathways that accelerate the production of various cytokines, attracting BC cells to migrate to bone tissue, which worsens the development of BC and seriously affects the prognosis of patients. This process is a vicious cycle. At present, there are seven major signaling pathways involved in BC bone metastasis: the OPG/RANK/RANKL signaling pathway, TGF-β signaling pathway, IGF system, PI3K-AKT-mTOR signaling pathway, Wnt signaling pathway and Hippo signaling pathway. In addition, FGF-FGFR signaling pathway, androgen-AR/LSD1-target gene pathway, Notch signaling pathway, JAK-STAT signaling pathway and CaN/NFATC1 signaling pathway also seem to be associated with BC bone metastasis.

Conclusion

This review focuses on the signaling pathways related to BC bone metastasis and explores the interactions among these pathways, which will lay a solid theoretical foundation for further understanding the mechanism of BC bone metastasis and developing effective targeted therapeutic drugs.
Endometrioid Cancer Associated With Endometriosis: From the Seed and Soil Theory to Clinical Practice
Authors: Farolfi Alberto , Altavilla Amelia , Morandi Luca , Capelli Laura , Chiadini Elisa , Prisinzano Giovanna , Gurioli Giorgia , Molari Marianna , Calistri Daniele , Foschini Maria Pia , De Giorgi Ugo
Published: March 2022

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. It is still debated whether endometriosis is a disease that can predispose to the pathogenesis of endometrial cancer outside the uterus. Deficiencies in mismatch repair (MMR) genes are a known risk factor for developing endometrioid cancer. Starting from two cases of patients with abnormal MMR endometrioid carcinoma of the uterus and synchronous endometrioid carcinoma in non-ovarian and ovarian endometriosis, we performed a somatic mutation profile and phylogenetic analysis of the lesions in order to identify if they were metastasis or primary de novo tumors. In the first case, we identified de novo activating mutations in PIK3CA and KRAS in endometrioid cancer lesions but not in endometriosis. Although the acquisition of a de novo mutation in ESR1 and a decrease in mutant allele fraction (MAF) from the endometrial tumor to the localizations in the endometriosis lesions, the clonal relationship was confirmed by the limited number of heteroplasmic mutations in D-loop mitochondrial DNA region. In the other case, the clonal behavior was demonstrated by the overlap of MAF at each site. Our data support the hypothesis of a retrograde dissemination of tumor cells, moving from the primary carcinoma in the endometrium to ectopic sites of endometriosis where localizations of tumor arise.
Is There Any Mosaicism in REarranged During Transfection Variant in Hirschsprung Disease’s Patients?
Authors: Iskandar Kristy , Simanjaya Susan , Indrawan Taufik , Kalim Alvin Santoso , Marcellus  , Heriyanto Didik Setyo , Gunadi
Published: March 2022

Background

Hirschsprung disease (HSCR) is a heterogeneous genetic disease characterized by the absence of ganglion cells in the intestinal tract. The REarranged during Transfection (RET) is the most responsible gene for its pathogenesis. RET’s somatic mosaicisms have been reported for HSCR; however, they are still under-recognized. Therefore, we determined the frequency of somatic mutation of RET rs2435357 in HSCR patients at our institution.

Methods

We performed RET rs2435357 genotyping from 73 HSCR formalin-fixed and paraffin-embedded (FFPE) rectal and 60 non-HSCR controls using the PCR-RFLP method. Subsequently, we compared those frequencies of genotypes for RET rs2435357 with our previous genotyping data from 93 HSCR blood specimens.

Results

The frequencies of genotypes for RET rs2435357 in HSCR paraffin-embedded rectal were CC 0, CT 11 (15%), and TT 62 (85%), whereas their frequencies in HSCR blood samples were CC 4 (4.3%), CT 22 (23.7%), and TT 67 (72%). Those frequencies differences almost reached a significant level (p = 0.06). Moreover, the frequency of RET rs2435357 risk allele (T) was significantly higher in HSCR patients (135/146, 92.5%) than controls (46/120, 38.3%) (p = 3.4 × 10–22), with an odds ratio of 19.74 (95% confidence interval = 9.65–40.41).

Conclusion

Our study suggests somatic mosaicism in HSCR patients. These findings further imply the complexity of the pathogenesis of HSCR. Moreover, our study confirms the RET rs2435357 as a significant genetic risk factor for HSCR patients.
Neonatal Applications of Heliox: A Practical Review
Authors: Szczapa Tomasz , Kwapień Patryk , Merritt T. Allen
Published: March 2022

Heliox is a mixture of helium and oxygen that may be utilized as an alternative to air-oxygen during the ventilatory support in the neonate. Special physical properties of Heliox, particularly low density, allow for improved gas flow and diffusion. First reports of Heliox use in the pediatric population were published in 1930s; however, this therapy has never gained widespread popularity despite its described beneficial effects. Historically, this was largely due to technical challenges associated with Heliox ventilation that significantly limited its use and realization of large-scale clinical trials. However, nowadays several commercially available ventilators allow easy and safe ventilation with both conventional and non-invasive modes. In the era of minimally invasive respiratory interventions in the newborn Heliox could be seen as a therapy that may potentially decrease the risk of non-invasive ventilation failure. This review presents pathophysiologic rationale for the use of Heliox in the newborn, and summarizes available data regarding applications of Heliox in the setting of neonatal intensive care unit based on clinical studies and findings from animal models. Mechanisms of action and practical aspects of Heliox delivery are thoroughly discussed. Finally, future research directions for neonatal use of Heliox are proposed.
New Insights Into PTBP3 in Human Cancers: Immune Cell Infiltration, TMB, MSI, PDCD1 and m6A Markers
Authors: Fang Zhen , Li Peijuan , Li Han , Chong Wei , Li Leping , Shang Liang , Li Fei
Published: March 2022

Polypyrimidine tract binding protein 3 (PTBP3) plays a critical role in post-transcriptional regulation. The role of PTBP3 in various human tumours was explored and analysed in this study based on the Cancer Genome Atlas and Gene Expression Omnibus datasets. PTBP3 was highly expressed in most tumours, such as breast invasive carcinoma, colon adenocarcinoma and hepatocellular carcinoma. PTBP3 overexpression generally predicts poor overall survival and disease-free survival in patients with adrenocortical carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma. However, low PTBP3 expression predicts poor prognosis in kidney renal clear cell carcinoma. We also explored PTBP3 genetic alterations in different tumour tissues. The result found that the frequency of PTBP3 alteration (>4%) was the highest in uterine tumours with “mutation” as the primary type. Furthermore, we found a significant correlation between PTBP3 expression and tumour mutational burden and microsatellite instability in various human tumours, and found that PTBP3 expression was positively correlated with TMB in ACC, STAD, PAAD, LUAD, and SARC. Two enhanced phosphorylation levels of S30 and S426 in colon cancer, ovarian cancer, and uterine corpus endometrial carcinoma were found. Further analysis indicated that PTBP3 expression was positively correlated with the cancer-associated fibroblasts for most tumour types. This study also found a relationship between immune checkpoints and N6-methyladenosine-related markers and PTBP3 expression. Moreover, the “mRNA surveillance pathway” and “RNA degradation” were involved in the functional mechanisms of PTBP3. These results provide new insights for molecular studies, and integrative analysis provided a framework for determining the predictive, prognostic, and therapeutic relevance of PTBP3 in cancer patients.
Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations
Authors: Gerhart Jacqueline G. , Balevic Stephen , Sinha Jaydeep , Perrin Eliana M. , Wang Jian , Edginton Andrea N. , Gonzalez Daniel
Published: March 2022

Childhood obesity is an alarming public health problem. The pediatric obesity rate has quadrupled in the past 30 years, and currently nearly 20% of United States children and 9% of children worldwide are classified as obese. Drug distribution and elimination processes, which determine drug exposure (and thus dosing), can vary significantly between patients with and without obesity. Obesity-related physiological changes, such as increased tissue volume and perfusion, altered blood protein concentrations, and tissue composition can greatly affect a drug’s volume of distribution, which might necessitate adjustment in loading doses. Obesity-related changes in the drug eliminating organs, such as altered enzyme activity in the liver and glomerular filtration rate, can affect the rate of drug elimination, which may warrant an adjustment in the maintenance dosing rate. Although weight-based dosing (i.e., in mg/kg) is commonly practiced in pediatrics, choice of the right body size metric (e.g., total body weight, lean body weight, body surface area, etc.) for dosing children with obesity still remains a question. To address this gap, the interplay between obesity-related physiological changes (e.g., altered organ size, composition, and function), and drug-specific properties (e.g., lipophilicity and elimination pathway) needs to be characterized in a quantitative framework. Additionally, methodological considerations, such as adequate sample size and optimal sampling scheme, should also be considered to ensure accurate and precise top-down covariate selection, particularly when designing opportunistic studies in pediatric drug development. Further factors affecting dosing, including existing dosing recommendations, target therapeutic ranges, dose capping, and formulations constraints, are also important to consider when undergoing dose selection for children with obesity. Opportunities to bridge the dosing knowledge gap in children with obesity include modeling and simulating techniques (i.e., population pharmacokinetic and physiologically-based pharmacokinetic [PBPK] modeling), opportunistic clinical data, and real world data. In this review, key considerations related to physiology, drug parameters, patient factors, and methodology that need to be accounted for while studying the influence of obesity on pharmacokinetics in children are highlighted and discussed. Future studies will need to leverage these modeling opportunities to better describe drug exposure in children with obesity as the childhood obesity epidemic continues.
Anti-Seizure Medication Treatment of Benign Childhood Epilepsy With Centrotemporal Spikes: A Systematic Review and Meta-analysis
Authors: Cheng Wenwen , Yang Yan , Chen Ying , Shan Sharui , Li Changhui , Fang Ling , Zhang Weiguo , Lan Song , Zhang Xiong
Published: March 2022

Background: This study aimed to evaluate the efficacy and tolerability of Anti-Seizure medication (ASM) treatment in patients with BECTS.

Method: We searched PubMed, Cochrane Library, Embase, MEDLINE, Web of Science, China National Knowledge Infrastructure (CNKI), WANFANG DATA, and China Science and Technology Journal Database (VIP) between 1 Jan 1990, and 1 Sep 2021, for randomized controlled studies. Data on seizure freedom rate, rate of treatment withdrawal due to serious adverse events, rate of any adverse events and dropout, 50% remission rate, the proportion of patients whose EEG to be normalized, and improvement in cognitive function were extracted by two authors independently. The pooled data were meta-analyzed using a random effects model.

Results: A total of 27 studies evaluating 9 ASMs were included, 19 of which were suitable for meta-analysis. Compared with sulthiame (STM), levetiracetam (LEV) was associated with a higher probability of treatment withdrawal due to serious adverse events [RR = 5.12, 95% CI (1.19, 22.01), I2 = 0.0%], experiencing any adverse events [RR = 5.12, 95% CI (1.19, 22.01)], and dropping out for any reason [RR = 3.17, 95% CI (1.36, 10.11)], while it did not affect the seizure freedom rate [RR = 0.90, 95% CI (0.75, 1.06)]. LEV significantly improved cognitive performance relative to carbamazepine (CBZ) but had no effect on the proportion of any adverse events [RR = 0.62, 95% CI (0.25, 1.59)] and EEG to be normalized [RR = 1.27, 95% CI (0.94, 1.71)]. There was no higher probability of a 50% remission rate when comparing valproic acid (VPA) to LEV [RR = 0.96, 95% CI (0.57, 1.61)] and oxcarbazepine (OXC) [RR = 0.61, 95% CI (0.31, 1.20)]. In addition, STM was related to a higher probability of EEG normalization than placebo [RR = 4.61, 95% CI (2.12, 10.01)]. The included single studies also provided some evidence for the efficacy and/or tolerability of other ASMs in BECTS, including topiramate, lamotrigine, clobazam, and clonazepam. The risk of bias of the included studies was frequently low or unclear.

Conclusion: This study indicated some discrepancies in efficacy and tolerability among ASMs used in patients with BECTS. More randomized controlled trials (RCTs) comparing ASMs with larger populations are required to ascertain the optimum antiepileptic drug treatment to guide clinicians.
Elucidating a Complicated Enantioselective Metabolic Profile: A Study From Rats to Humans Using Optically Pure Doxazosin
Authors: Kong Dezhi , Tian Yuan , Duan Kunfeng , Guo Wenyan , Zhang Qingning , Zhang Panpan , Yang Zuxiao , Qin Xia , Ren Leiming , Zhang Wei
Published: March 2022

Doxazosin (DOX) is prescribed as a racemic drug for the clinical treatment of benign prostatic hyperplasia and hypertension. Recent studies found that the two enantiomers of DOX exhibit differences in blood concentration and pharmacological effects. However, the stereoselective metabolic characteristics and mechanisms for DOX are not yet clear. Herein, we identified 34 metabolites of DOX in rats based on our comprehensive and effective strategy. The relationship among the metabolites and the most discriminative metabolites between (−)-DOX and (+)-DOX administration was analyzed according to the kinetic parameters using state-of-the-art multivariate statistical methods. To elucidate the enantioselective metabolic profile in vivo and in vitro, we carefully investigated the metabolic characteristics of metabolites after optically pure isomers administration in rat plasma, rat liver microsomes (RLMs) or human liver microsomes (HLMs), and recombinant human cytochrome P450 (CYP) enzymes. As a result, the differences of these metabolites were found based on their exposure and elimination rate, and the metabolic profile of (±)-DOX was more similar to that of (+)-DOX. Though the metabolites identified in RLMs and HLMs were the same, the metabolic profiles of the metabolites from (−)-DOX and (+)-DOX were greatly different. Furthermore, four human CYP enzymes could catalyze DOX to produce metabolites, but their preferences seemed different. For example, CYP3A4 highly specifically and selectively catalyzed the formation of the specific metabolite (M22) from (−)-DOX. In conclusion, we established a comprehensive metabolic system using pure optical isomers from in vivo to in vitro, and the complicated enantioselectivity of the metabolites of DOX was clearly shown. More importantly, the comprehensive metabolic system is also suitable to investigate other chiral drugs.
Omalizumab and IgE in the Control of Severe Allergic Asthma
Authors: Gon Yasuhiro , Maruoka Shuichiro , Mizumura Kenji
Published: March 2022

Omalizumab, a human immunoglobulin (Ig)G1 antibody against IgE, is a therapeutic agent for bronchial asthma. The Global Initiative for Asthma guidelines indicate that the use of omalizumab should be considered as an option in step 5 of treatment for patients with the most severe type of bronchial asthma. In patients with atopic asthma who are at a high risk of exacerbation, and in whom symptoms are poorly controlled despite treatment with inhaled corticosteroids, omalizumab is one of the few drugs that improves symptoms, reduces the risk of exacerbation, and improves the quality of life while offering a high level of safety. On the other hand, the associated treatment costs are high, and there are no clear methods to identify responders. A recent study suggested that evaluating the therapeutic effects and monitoring the pharmacokinetics of omalizumab could improve the success of omalizumab therapy. This review outlines the relationship between IgE-targeted therapy and the serum level of IgE to enhance the current understanding of the mechanism of omalizumab therapy. It also describes the clinical significance of measuring serum free IgE levels and monitoring omalizumab therapy.
Unveiling Dynamic Changes of Chemical Constituents in Raw and Processed Fuzi With Different Steaming Time Points Using Desorption Electrospray Ionization Mass Spectrometry Imaging Combined With Metabolomics
Authors: Liu Yue , Yang Xuexin , Zhou Chao , Wang Zhang , Kuang Tingting , Sun Jiayi , Xu Binjie , Meng Xianli , Zhang Yi , Tang Ce
Published: March 2022

Fuzi is a famous toxic traditional herbal medicine, which has long been used for the treatment of various diseases in China and many other Asian countries because of its extraordinary pharmacological activities and high toxicity. Different processing methods to attenuate the toxicity of Fuzi are important for its safe clinical use. In this study, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) with a metabolomics-combined multivariate statistical analysis approach was applied to investigate a series of Aconitum alkaloids and explore potential metabolic markers to understand the differences between raw and processed Fuzi with different steaming time points. Moreover, the selected metabolic markers were visualized by DESI-MSI, and six index alkaloids’ contents were determined through HPLC. The results indicated visible differences among raw and processed Fuzi with different steaming times, and 4.0 h is the proper time for toxicity attenuation and efficacy reservation. A total of 42 metabolic markers were identified to discriminate raw Fuzi and those steamed for 4.0 and 8.0 h, which were clearly visualized in DESI-MSI. The transformation from diester-diterpenoid alkaloids to monoester-diterpenoid alkaloids and then to non-esterified diterpene alkaloids through hydrolysis is the major toxicity attenuation process during steaming. DESI-MSI combined with metabolomics provides an efficient method to visualize the changeable rules and screen the metabolic markers of Aconitum alkaloids during steaming. The wide application of this technique could help identify markers and reveal the possible chemical transition mechanism in the “Paozhi” processes of Fuzi. It also provides an efficient and easy way to quality control and ensures the safety of Fuzi and other toxic traditional Chinese medicine.