bluuebunny/crossref_metadata_2025 huggingface dataset:
EHBP1, TUBB, and WWOX SNPs, Gene-Gene and Gene-Environment Interactions on Coronary Artery Disease and Ischemic Stroke
Authors: Liu Chun-Xiao , Yin Rui-Xing , Cao Xiao-Li , Shi Zong-Hu , Huang Feng , Wei Bi-Liu , Deng Guo-Xiong , Zheng Peng-Fei , Guan Yao-Zong
Published: April 2022

The associations among the EH domain-binding protein 1 (EHBP1), tubulin beta class I (TUBB), and WW domain-containing oxidoreductase (WWOX) single nucleotide polymorphisms (SNPs) and coronary artery disease (CAD) and ischemic stroke (IS) are not yet understood. This study aimed to detect the associations of these SNPs, gene-gene and gene-environment interactions and CAD and IS in the Guangxi Han population. A total of 1853 unrelated subjects were recruited into normal control (n = 638), CAD (n = 622), and IS (n = 593) groups. Related genotypes were determined by high-throughput sequencing. The genotypic and minor allelic frequencies of rs2278075 were different between the CAD and control groups, and those of rs2710642, rs3130685, and rs2278075 were also different between the IS and control groups. The rs2278075T allele, rs3130685-rs2222896-rs2278075, rs3130685-rs2222896-diabetes, rs3130685-rs2222896-drinking, and haplotype rs2710642A-rs10496099C-diabetes interactions were associated with increased risk, while G-T-G-C-G-A and G-T-T-T-G-T-drinking were associated with reduced risk of CAD. The rs2278075T and rs2710642G alleles, rs2710642G-rs10496099C haplotype, rs3130685-rs2278075-rs2222896, and rs2710642-rs2278075-hypertension interactions aggravated the association with IS, whereas the rs3130685T allele, rs2710642A-rs10496099C haplotype and the interactions of H1 (s2710642A-rs10496099C)-H2 (rs2710642G-rs10496099C)-drinking and I1 (A-C-G-C-A-A)-I3 (A-C-G-T-A-A)-I4 (A-C-G-T-G-A)-I5 (G-T-G-C-G-A) diminished the association with IS. Carrying WWOX rs2278075T was strongly associated with CAD or IS, while EHBP1 rs2710642 and TUBB rs3130685 might alter the association of IS by modifying the serum lipid profile. This study demonstrates that the EHBP1, TUBB, and WWOX SNPs, gene-gene and gene-environment interactions are associated with the risk of CAD and IS in the Guangxi Han population.
Organoids as Model Systems to Investigate Circadian Clock-Related Diseases and Treatments
Authors: Lee Suengwon , Hong Christian I.
Published: April 2022

Circadian rhythms exist in most cell types in mammals regulating temporal organization of numerous cellular and physiological processes ranging from cell cycle to metabolism. The master clock, suprachiasmatic nucleus (SCN) in the hypothalamus, processes light input and coordinates peripheral clocks optimizing organisms’ survival and functions aligning with external conditions. Intriguingly, it was demonstrated that circadian rhythms in the mouse liver can be decoupled from the master clock under time-restricted feeding regimen when food was provided during their inactive phase. Furthermore, mouse liver showed clock-controlled gene expression even in the absence of the master clock demonstrating independent functions of peripheral clocks apart from the SCN. These findings suggest a dynamic relationship between the master and peripheral clocks and highlight potential functions of peripheral clocks independent of the master clock. Importantly, disruption of circadian rhythms correlates with numerous human ailments including cancer and metabolic diseases, suggesting that diseases may be exacerbated by disruption of circadian rhythms in the SCN and/or peripheral clocks. However, molecular mechanisms providing causative links between circadian rhythms and human diseases remain largely unknown. Recent technical advances highlighted PCS- and tissue-derived 3-dimensional organoids as in vitro organs that possess numerous applications ranging from disease modeling to drug screening. In this mini-review, we highlight recent findings on the importance and contributions of peripheral clocks and potential uses of 3D organoids investigating complex circadian clock-related diseases.
Homologous Recombination Related Signatures Predict Prognosis and Immunotherapy Response in Metastatic Urothelial Carcinoma
Authors: Li Pan , Chen Chaohu , Li Jianpeng , Yang Li , Wang Yuhan , Dong Zhilong , Mi Jun , Zhang Yunxin , Wang Juan , Wang Hanzhang , Rodriguez Ronald , Tian Junqiang , Wang Zhiping
Published: April 2022

Objective: This study used homologous recombination (HR) related signatures to develop a clinical prediction model for screening immune checkpoint inhibitors (ICIs) advantaged populations and identify hub genes in advanced metastatic urothelial carcinoma.

Methods: The single-sample gene enrichment analysis and weighted gene co-expression network analysis were applied to identify modules associated with immune response and HR in IMvigor210 cohort samples. The principal component analysis was utilized to determine the differences in HR-related module gene signature scores across different tissue subtypes and clinical variables. Risk prediction models and nomograms were developed using differential gene expression analysis associated with HR scores, least absolute shrinkage and selection operator, and multivariate proportional hazards model regression. Additionally, hub genes were identified by analyzing the contribution of HR-related genes to principal components and overall survival analysis. Finally, clinical features from GSE133624, GSE13507, the TCGA, and other data sets were analyzed to validate the relationship between hub genes and tumor growth and mutation.

Results: The HR score was significantly higher in the complete/partial response group than in the stable/progressive disease group. The majority of genes associated with HR were discovered to be involved in the cell cycle and others. Genomically unstable, high tumor level, and high immune level samples all exhibited significantly higher HR score than other sample categories, and higher HR scores were related to improved survival following ICIs treatment. The risk scores for AUNIP, SEPT, FAM72D, CAMKV, CXCL9, and FOXN4 were identified, and the training and verification groups had markedly different survival times. The risk score, tumor neoantigen burden, mismatch repair, and cell cycle regulation were discovered to be independent predictors of survival time following immunotherapy. Patients with a high level of expression of hub genes such as EME1, RAD51AP1, and RAD54L had a greater chance of surviving following immunotherapy. These genes are expressed at significantly higher levels in tumors, high-grade cancer, and invasive cancer than other categories, and are associated with TP53 and RB1 mutations.

Conclusion: HR-related genes are upregulated in genomically unstable samples, the survival time of mUC patients after treatment with ICIs can be predicted using a normogram model based on HR signature.
Recommendations for Sustainable Ancient DNA Research in the Global South: Voices From a New Generation of Paleogenomicists
Authors: Ávila-Arcos Maria C. , de la Fuente Castro Constanza , Nieves-Colón Maria A. , Raghavan Maanasa
Published: April 2022

Paleogenomics - the study of ancient genomes - has made significant contributions, especially to our understanding of the evolutionary history of humans. This knowledge influx has been a direct result of the coupling of next-generation sequencing with improved methods for DNA recovery and analysis of ancient samples. The appeal of ancient DNA studies in the popular media coupled with the trend for such work to be published in “high impact” journals has driven the amassing of ancestral human remains from global collections, often with limited to no engagement or involvement of local researchers and communities. This practice in the paleogenomics literature has led to limited representation of researchers from the Global South at the research design and subsequent stages. Additionally, Indigenous and descendant communities are often alienated from popular and academic narratives that both involve and impact them, sometimes adversely. While some countries have safeguards against ‘helicopter science’, such as federally regulated measures to protect their biocultural heritage, there is variable oversight in others with regard to sampling and exportation of human remains for destructive research, and differing requirements for accountability or consultation with local researchers and communities. These disparities reveal stark contrasts and gaps in regional policies that lend themselves to persistent colonial practices. While essential critiques and conversations in this sphere are taking place, these are primarily guided through the lens of US-based heritage legislation such as the Native American Graves and Protection Act (NAGPRA). In this article, we aim to expand the scope of ongoing conversations by taking into account diverse regional contexts and challenges drawing from our own research experiences in the field of paleogenomics. We emphasize that true collaborations involve knowledge sharing, capacity building, mutual respect, and equitable participation, all of which take time and the implementation of sustainable research methods; amass-and-publish strategy is simply incompatible with this ethos.
Characterization of the Ferroptosis-Related Genes for Prognosis and Immune Infiltration in Low-Grade Glioma
Authors: Yan Xiuwei , Ji Hang , Liu Zhihui , Ma Shuai , Dong Jiawei , Jiang Xiaoyan , Hu Xueyan , Wang Fang , Zhao Hongtao , Jin Jiaqi , Zhang Jiheng , Wang Nan , Du Jianyang , Hu Shaoshan
Published: April 2022

Background: Although ferroptosis has been validated to play a crucial role in some types of tumors, the influence of ferroptosis-related genes (FRGs) on the immune microenvironment in low-grade glioma (LGG) remains unclear. In this research, we screen the FRGs to assess the prognosis value and immune microenvironment in LGG, to provide reliable diagnosis and treatment evidence for the clinic.

Methods: A total of 1,239 patients of LGG samples were selected for subsequent analyses from The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and the Repository of Molecular Brain Neoplasia Data datasets. Univariate Cox regression analysis was used to screen for prognostic FRGs. Consensus clustering was utilized to determine ferroptosis subtypes of LGG patients. Next, the prognostic model was constructed based on differentially expressed FRGs and validation in the validating datasets. The immune microenvironment, biological pathway, and hypoxia score were explored by single-sample gene set enrichment analysis. The potential response of chemotherapy and immune checkpoint blockade therapy was also estimated. In addition, the correlation between the risk score and autophagy-related genes was examined by the Pearson correlation coefficient.

Results: A total of three ferroptosis subtypes were identified by consensus clustering for prognostic FRGs which exhibited different outcomes, clinicopathological characteristics, and immune microenvironment. Afterward, a prognostic model that performed great predictive ability based on nine prognostic FRGs has been constructed and validated. Moreover, the prognostic model had the potential to screen the sensitivity to chemotherapy and immunotherapy in LGG patients. Finally, we also found that the prognostic model has a great connection to autophagy and hypoxia.

Conclusion: We developed a ferroptosis-related prognostic model which strongly linked to diagnosis, treatment, prognosis, and recurrence of LGG. This study also reveals the connection between ferroptosis and tumor immune microenvironment.
Vaccination With a Gamma Irradiation-Inactivated African Swine Fever Virus Is Safe But Does Not Protect Against a Challenge
Authors: Pikalo Jutta , Porfiri Luca , Akimkin Valerij , Roszyk Hanna , Pannhorst Katrin , Kangethe Richard Thiga , Wijewardana Viskam , Sehl-Ewert Julia , Beer Martin , Cattoli Giovanni , Blome Sandra
Published: April 2022

African swine fever (ASF) is among the most devastating viral diseases of pigs and wild boar worldwide. In recent years, the disease has spread alarmingly. Despite intensive research activities, a commercialized vaccine is still not available, and efficacious live attenuated vaccine candidates raise safety concerns. From a safety perspective, inactivated preparations would be most favourable. However, both historical and more recent trials with chemical inactivation did not show an appreciable protective effect. Under the assumption that the integrity of viral particles could enhance presentation of antigens, we used gamma irradiation for inactivation. To this means, gamma irradiated ASFV “Estonia 2014” was adjuvanted with either Polygen™ or Montanide™ ISA 201 VG, respectively. Subsequently, five weaner pigs per preparation were immunized twice with a three-week interval. Six weeks after the first immunization, all animals were challenged with the highly virulent ASFV strain “Armenia 2008”. Although ASFV p72-specific IgG antibodies were detectable in all vaccinated animals prior challenge, no protection could be observed. All animals developed an acute lethal course of ASF and had to be euthanized at a moderate humane endpoint within six days. Indeed, the vaccinated pigs showed even higher clinical scores and a higher inner body temperature than the control group. However, significantly lower viral loads were detectable in spleen and liver of immunized animals at the time point of euthanasia. This phenomenon suggests an immune mediated disease enhancement that needs further investigation.
The JMJD Family Histone Demethylases in Crosstalk Between Inflammation and Cancer
Authors: Yang Jia , Hu Yuan , Zhang Binjing , Liang Xiao , Li Xin
Published: April 2022

Inflammation has emerged as a key player in regulating cancer initiation, progression, and therapeutics, acting as a double edged sword either facilitating cancer progression and therapeutic resistance or inducing anti-tumor immune responses. Accumulating evidence has linked the epigenetic modifications of histones to inflammation and cancer, and histone modifications-based strategies have shown promising therapeutic potentials against cancer. The jumonji C domain-containing (JMJD) family histone demethylases have exhibited multiple regulator functions in inflammatory processes and cancer development, and a number of therapeutic strategies targeting JMJD histone demethylases to modulate inflammatory cells and their products have been successfully evaluated in clinical or preclinical tumor models. This review summarizes current understanding of the functional roles and mechanisms of JMJD histone demethylases in crosstalk between inflammation and cancer, and highlights recent clinical and preclinical progress on harnessing the JMJD histone demethylases to regulate cancer-related inflammation for future cancer therapeutics.
Clinical and Prognostic Implications of Estimating Glomerular Filtration Rate by Three Different Creatinine-Based Equations in Older Nursing Home Residents
Authors: Paparazzo Ersilia , Geracitano Silvana , Lagani Vincenzo , Soraci Luca , Cozza Annalisa , Cosimo Salvatore , Morelli Francesco , Corsonello Andrea , Passarino Giuseppe , Montesanto Alberto
Published: April 2022

Background

According to the international literature, the percentage of nursing home (NH) residents with renal insufficiency is very high, ranging between 22 and 78%. Diminished kidney function represents a risk factor for drug overdosage, adverse drug reactions, end-stage renal disease, disability, morbidity, and mortality. Several studies suggested that screening for chronic kidney disease (CKD) in high-risk and older populations may represent a cost-effective approach to reducing progression to renal failure and CKD mortality.

Objective

This study aimed (i) to investigate to what extent CKD may be staged interchangeably by three different creatinine-based estimated glomerular filtration rate (eGFR) equations in a sample of older adults living in long-term care facilities; (ii) to investigate factors explaining differences among eGFR equations; and (iii) to compare the predictivity of different creatinine-based eGFR equations with respect to all-cause mortality.

Methods

A total of 522 residents aged 65 years and older participated in a prospective cohort study of 9 long-term care facilities in Calabria. eGFR was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Berlin initiative study (BIS), and full age spectrum (FAS) equations. Disability in at least one activity of daily living (ADL), depression, cognitive impairment, comorbidity, and malnutrition was considered in the analysis. Statistical analysis was carried out by Bland–Altman analysis, and 2-year mortality was investigated by Kaplan–Meier curves and Cox regression analysis.

Results

Depending on the adopted equation, the prevalence of NH residents with impaired renal function (eGFR < 60 ml/min/1.73 m2) ranged between 58.2% for the CKD-EPI and 79.1% for the BIS1 equation. The average difference between BIS and FAS was nearly negligible (0.45 ml/min/1.73 m2), while a significant bias was detected between CKD-EPI and BIS and also between CKD-EPI and FAS (6.21 ml/min/1.73 m2 and 6.65 ml/min/1.73 m2, respectively). Although the eGFR study equations had comparable prognostic accuracy in terms of mortality risk, BIS and FAS were able to reclassify NH residents pertaining to a low-risk group with CKD-EPI, and this reclassification improves the discriminative capacity of CKD-EPI with respect to overall mortality.

Conclusion

Despite the relatively good correlation between eGFRs calculated using all adopted equations, the findings in this study reported clearly demonstrated that CKD-EPI and BIS/FAS equations are not interchangeable to assess eGFR among older people and particularly in institutionalized and frail older subjects.
How Did the Archaellum Get Its Rotation?
Authors: Ortega Davi , Beeby Morgan
Published: April 2022

How new functions evolve fascinates many evolutionary biologists. Particularly captivating is the evolution of rotation in molecular machines, as it evokes familiar machines that we have made ourselves. The archaellum, an archaeal analog of the bacterial flagellum, is one of the simplest rotary motors. It features a long helical propeller attached to a cell envelope-embedded rotary motor. Satisfyingly, the archaellum is one of many members of the large type IV filament superfamily, which includes pili, secretion systems, and adhesins, relationships that promise clues as to how the rotating archaellum evolved from a non-rotary ancestor. Nevertheless, determining exactly how the archaellum got its rotation remains frustratingly elusive. Here we review what is known about how the archaellum got its rotation, what clues exist, and what more is needed to address this question.
Pilot Investigation of SARS-CoV-2 Variants in the Island of Sicily Prior to and in the Second Wave of the COVID-19 Pandemic
Authors: Padilla-Blanco Miguel , Gucciardi Francesca , Guercio Annalisa , Rubio Vicente , Princiotta Antonina , Veses Veronica , Terrana Mariangela , Sheth Chirag C. , Pascual-Ortiz Marina , Maiques Elisa , Purpari Giuseppa , Rubio-Guerri Consuelo
Published: April 2022

After 2 years of the COVID-19 pandemic, we continue to face vital challenges stemming from SARS-CoV-2 variation, causing changes in disease transmission and severity, viral adaptation to animal hosts, and antibody/vaccine evasion. Since the monitoring, characterization, and cataloging of viral variants are important and the existing information on this was scant for Sicily, this pilot study explored viral variants circulation on this island before and in the growth phase of the second wave of COVID-19 (September and October 2020), and in the downslope of that wave (early December 2020) through sequence analysis of 54 SARS-CoV-2-positive samples. The samples were nasopharyngeal swabs collected from Sicilian residents by a state-run one-health surveillance laboratory in Palermo. Variant characterization was based on RT-PCR amplification and sequencing of four regions of the viral genome. The B.1.177 variant was the most prevalent one, strongly predominating before the second wave and also as the wave downsized, although its relative prevalence decreased as other viral variants, particularly B.1.160, contributed to virus circulation. The occurrence of the B.1.160 variant may have been driven by the spread of that variant in continental Europe and by the relaxation of travel restrictions in the summer of 2020. No novel variants were identified. As sequencing of the entire viral genome in Sicily for the period covered here was restricted to seven deposited viral genome sequences, our results shed some light on SARS-CoV-2 variant circulation during that wave in this insular region of Italy which combines its partial insular isolation with being a major entry point for the African immigration.
Insulin and Memory in Invertebrates
Authors: Nakai Junko , Chikamoto Nozomi , Fujimoto Kanta , Totani Yuki , Hatakeyama Dai , Dyakonova Varvara E. , Ito Etsuro
Published: April 2022

Insulin and insulin-like peptides (ILP) help to maintain glucose homeostasis, whereas insulin-like growth factor (IGF) promotes the growth and differentiation of cells in both vertebrates and invertebrates. It is sometimes difficult to distinguish between ILP and IGF in invertebrates, however, because in some cases ILP has the same function as IGF. In the present review, therefore, we refer to these peptides as ILP/IGF signaling (IIS) in invertebrates, and discuss the role of IIS in memory formation after classical conditioning in invertebrates. In the arthropod Drosophila melanogaster, IIS is involved in aversive olfactory memory, and in the nematode Caenorhabditis elegans, IIS controls appetitive/aversive response to NaCl depending on the duration of starvation. In the mollusk Lymnaea stagnalis, IIS has a critical role in conditioned taste aversion. Insulin in mammals is also known to play an important role in cognitive function, and many studies in humans have focused on insulin as a potential treatment for Alzheimer’s disease. Although analyses of tissue and cellular levels have progressed in mammals, the molecular mechanisms, such as transcriptional and translational levels, of IIS function in cognition have been far advanced in studies using invertebrates. We anticipate that the present review will help to pave the way for studying the effects of insulin, ILPs, and IGFs in cognitive function across phyla.
Visual Perceptual Learning Induces Long-Lasting Recovery of Visual Acuity, Visual Depth Perception Abilities and Binocular Matching in Adult Amblyopic Rats
Authors: Consorti Alan , Sansevero Gabriele , Torelli Claudia , Di Marco Irene , Berardi Nicoletta , Sale Alessandro
Published: April 2022

An abnormal visual experience early in life, caused by strabismus, unequal refractive power of the eyes, or eye occlusion, is a major cause of amblyopia (lazy eye), a highly diffused neurodevelopmental disorder severely affecting visual acuity and stereopsis abilities. Current treatments for amblyopia, based on a penalization of the fellow eye, are only effective when applied during the juvenile critical period of primary visual cortex plasticity, resulting mostly ineffective at older ages. Here, we developed a new paradigm of operant visual perceptual learning performed under conditions of conventional (binocular) vision in adult amblyopic rats. We report that visual perceptual learning induced a marked and long-lasting recovery of visual acuity, visual depth perception abilities and binocular matching of orientation preference, and we provide a link between the last two parameters.
Protocol for a Cross-Sectional Study: Effects of a Multiple Sclerosis Relapse Therapy With Methylprednisolone on Offspring Neurocognitive Development and Behavior (MS-Children)
Authors: Kozik Valeska , Schwab Matthias , Thiel Sandra , Hellwig Kerstin , Rakers Florian , Dreiling Michelle
Published: April 2022

Introduction

Multiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the fetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitization of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of fetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behavior.

Methods and Analysis

Eighty children aged 8–18 years of mothers with MS will be recruited. Forty children, exposed to GC in utero will be compared to 40 children without fetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioral difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analyzed using linear regression models. Time-variant outcomes of the stress test will be analyzed in two mixed linear models exploring overall activity and change from baseline.

Ethics and Dissemination

This study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement.

Trial Registration

https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130
The Value of the Correlation Coefficient Between the ICP Wave Amplitude and the Mean ICP Level (RAP) Combined With the Resistance to CSF Outflow (Rout) for Early Prediction of the Outcome Before Shunting in Posttraumatic Hydrocephalus
Authors: Zhang Chao , Long Si-Yu , You Wen-dong , Xu Xu-xu , Gao Guo-Yi , Yang Xiao-Feng
Published: April 2022

Objective

To evaluate the value of the correlation coefficient between the ICP wave amplitude and the mean ICP level (RAP) and the resistance to CSF outflow (Rout) in predicting the outcome of patients with post-traumatic hydrocephalus (PTH) selected for shunting.

Materials and Methods

As a training set, a total of 191 patients with PTH treated with VP shunting were retrospectively analyzed to evaluate the potential predictive value of Rout, collected from pre-therapeutic CSF infusion test, for a desirable recovery level (dRL), standing for the modified rankin scale (mRS) of 0–2. Eventually, there were 70 patients with PTH prospectively included as a validation set to evaluate the value of Rout-combined RAP as a predictor of dRL. We calculated Rout from a CSF infusion test and collected RAP during continuous external lumbar drainage (ELD). Maximum RAP (RAPmax) and its changes relative to the baseline (ΔRAPmax%) served as specific parameters of evaluation.

Results

In the training set, Rout was proved to be a significant predictor of dRL to shunting, with the area under the curve (AUC) of 0.686 (p < 0.001) in receiver-operating characteristic (ROC) analysis. In the validation set, Rout alone did not present a significant value in the prediction of desirable recovery level (dRL). ΔRAPmax% after 1st or 2nd day of ELD both showed significance in predicting of dRL to shunting with the AUC of 0.773 (p < 0.001) and 0.786 (p < 0.001), respectively. Significantly, Rout increased the value of ΔRAPmax% in the prediction of dRL with the AUC of 0.879 (p < 0.001), combining with ΔRAPmax% after the 1st and 2nd days of ELD. RAPmax after the 1st and 2nd days of ELD showed a remarkable predictive value for non-dRL (Levels 3-6 in Modified Rankin Scale) with the AUC of 0.891 (p < 0.001) and 0.746 (p < 0.001).

Conclusion

Both RAP and Rout can predict desirable recovery level (dRL) to shunting in patients with PTH in the early phases of treatment. A RAP-combined Rout is a better dRL predictor for a good outcome to shunting. These findings help the neurosurgeon predict the probability of dRL and facilitate the optimization of the individual treatment plan in the event of ineffective or unessential shunting.
Fast and Accurate Motion Correction for Two-Photon Ca2+ Imaging in Behaving Mice
Authors: Liu Weiyi , Pan Junxia , Xu Yuanxu , Wang Meng , Jia Hongbo , Zhang Kuan , Chen Xiaowei , Li Xingyi , Liao Xiang
Published: April 2022

Two-photon Ca2+ imaging is a widely used technique for investigating brain functions across multiple spatial scales. However, the recording of neuronal activities is affected by movement of the brain during tasks in which the animal is behaving normally. Although post-hoc image registration is the commonly used approach, the recent developments of online neuroscience experiments require real-time image processing with efficient motion correction performance, posing new challenges in neuroinformatics. We propose a fast and accurate image density feature-based motion correction method to address the problem of imaging animal during behaviors. This method is implemented by first robustly estimating and clustering the density features from two-photon images. Then, it takes advantage of the temporal correlation in imaging data to update features of consecutive imaging frames with efficient calculations. Thus, motion artifacts can be quickly and accurately corrected by matching the features and obtaining the transformation parameters for the raw images. Based on this efficient motion correction strategy, our algorithm yields promising computational efficiency on imaging datasets with scales ranging from dendritic spines to neuronal populations. Furthermore, we show that the proposed motion correction method outperforms other methods by evaluating not only computational speed but also the quality of the correction performance. Specifically, we provide a powerful tool to perform motion correction for two-photon Ca2+ imaging data, which may facilitate online imaging experiments in the future.
Different Interactive Effects of Metformin and Acarbose With Dietary Macronutrient Intakes on Patients With Type 2 Diabetes Mellitus: Novel Findings From the MARCH Randomized Trial in China
Authors: An Yu , Li Yinhui , Bian Nannan , Ding Xiaoyu , Chang Xiaona , Liu Jia , Wang Guang
Published: April 2022

Antidiabetic oral agents and nutrition management are frequently used together as first-line therapies for type 2 diabetes mellitus (T2DM). However, less is known about their interaction. The interactive effect of two classic antidiabetic medications, namely, acarbose and metformin, with dietary intakes of macronutrients on glycemic control and cardiometabolic risk factors was investigated in the metformin and acarbose in Chinese as the initial hypoglycemic treatment (MARCH) randomized clinical trial. The patients with newly diagnosed T2DM from China were included in the trial. Participants were randomized to receive either metformin or acarbose monotherapy as the initial treatment, followed by a 24-week treatment phase, during which add-on therapy was used if necessary. Dietary intakes of carbohydrate, protein, fat, and total energy were calculated by a 24-h food diary recall method. Linear mixed-effect models combined with a subgroup analysis were used to investigate independent and interactive effects of drugs and diet on clinical outcomes. A data analysis was performed on 551 of the 788 patients randomly assigned to treatment groups. Metformin therapy was independently associated with higher triglycerides (TGs, β = 0.471, P = 0.003), 2 h postprandial plasma glucose (2hPPG, β = 0.381, P = 0.046) but lower low-density lipoprotein cholesterol (LDL-C, β = −0.149, P = 0.013) compared with acarbose therapy. Higher carbohydrates and lower fat intakes were independently associated with poorer glycemic control, less weight loss, and greater insulin secretion. Higher total energy intake was also independently associated with higher fasting (β = 0.0002, P = 0.001) and postprandial blood glucose (β = 0.0004, P = 0.001). Interaction and subgroup analyses demonstrated that glucagon-like peptide-1 (GLP-1) was positively related to total energy (β = 0.268, P = 0.033), carbohydrates intake, and insulin secretion (β = 2,045.2, P = 0.003) only in the acarbose group, while systolic blood pressure (SBP) was negatively related to protein intake in the metformin group (β = 23.21, P = 0.014). The results of this study showed that metformin and acarbose mainly exerted different interactive effects with dietary energy, carbohydrate, and protein intakes on GLP-1 secretion, insulin release, and SBP. The interaction between drug therapy and nutrition intervention in glycemia highlights the complexity of combination therapy.
Prognostic Factors and Survival Benefits of Antitumor Treatments for Advanced Non-Small Cell Lung Cancer Patients With Central Nervous System Metastasis With or Without Driver Genes: A Chinese Single-Center Cohort Study
Authors: Gao Xiaoxing , Chen Minjiang , Liu Xiaoyan , Shi Yuequan , Liang Hongge , Zhou Qing , Zhao Jing , Pan Ruili , Zhong Wei , Xu Yan , Wang Mengzhao
Published: April 2022

Background

The prognosis of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastasis is poor. The treatment for CNS metastasis could prolong the overall survival of NSCLC patients. We aimed to investigate the prognostic factors of Chinese NSCLC patients with CNS metastasis and the survival benefits of various treatments for CNS metastasis in NSCLC patients with or without driver genes.

Methods

Based on the CAPTRA-Lung database, NSCLC patients with CNS metastasis admitted at the Peking Union Medical College Hospital between January 2010 and October 2018 were enrolled in the study. The prognostic factors were analyzed using univariate and multivariate Cox regression analyses.

Results

Overall, 418 patients were enrolled in the study. A total of 206 patients (49.3%) had CNS metastasis with positive driver genes, while 97 patients (23.2%) had negative driver genes. The median survival time after CNS metastasis was 20.8 months. In the multivariable analysis, an Eastern Cooperative Oncology Group performance status of ≥2 (hazard ratio [HR]: 1.750, 95% confidence interval [CI]: 1.184-2.588, P=0.005), number of CNS metastases ≥5 (HR: 1.448, 95% CI: 1.084 -1.934, P=0.012), and CNS metastasis developed during treatment (HR: 1.619, 95% CI: 1.232-2.129, P=0.001) were independent risk factors for poor survival. Lung adenocarcinoma (HR: 0.490, 95% CI: 0.279-0.861, P=0.013) and driver gene positivity (HR: 0.464, 95% CI: 0.302-0.715, P=0.001) were independent predictors of prolonged survival. Radiotherapy for CNS metastasis showed a survival benefit in NSCLC patients in the entire groups (HR: 0.472, 95% CI: 0.360-0.619, P <0.001), and in patients with positive driver genes.

Conclusion

Performance status, number of CNS metastases, timing of CNS metastasis, histological subtype, and driver gene status are prognostic factors for NSCLC patients with CNS metastasis. Furthermore, radiotherapy improved the survival in NSCLC patients with CNS metastasis.
Network Meta-Analysis of Different Intravenous Glucocorticoid Regimes for the Treatment of Graves’ Orbitopathy
Authors: Jia Jun , Dong Jingjian , Deng Lin
Published: April 2022

Background: Intravenous glucocorticoid (GC) has been proposed to treat moderately severe Graves’ orbitopathy (GO); however, the optimal regime remains debatable. We therefore performed this network meta-analysis to objectively determine the comparative efficacy and safety of different intravenous GC regimes, including daily, weekly, or monthly intravenous regimes, for the treatment of GO.

Methods: We electronically searched Medline (via PubMed), EMBASE (via OVID), and the Cochrane Central Register of Controlled Trials (CENTRAL) (via OVID) to retrieve randomized controlled trials (RCTs) investigating the comparative efficacy and safety of different intravenous GC regimes in GO patients from the inception of each database to March 2021. The latest search was updated in June 2021. The risk of bias of original studies was assessed using the Cochrane risk bias assessment tool. A random-effects Bayesian network meta-analysis was conducted using the Markov chain Monte Carlo (MCMC) simulation. Ranking probabilities of all regimes were calculated to rank all regimes. Statistical analysis was conducted using the ADDIS software.

Results: A total of 10 studies involving 593 patients met the selection criteria. Network meta-analysis suggested that the weekly intravenous GC regime (WR) [response: odds ratio (OR), 4.27; 95% creditable interval (CrI); 1.82 to 11.02; clinical activity score change (CASC): standard mean difference (SMD), −0.59; 95% CrI; −1.19 to −0.03) and monthly intravenous regime (MR) (response: OR, 6.32; 95% CrI; 1.25 to 34.96; CASC: SMD, −1.17; 95% CrI; −2.32 to −0.01) were superior to the oral GC (OGC) regime in response and CASC. Meanwhile, pooled results also indicated that the WR was related to the decreased risk of AEs compared with the OGC regime (OR, 0.22; 95% CrI; 0.08–0.62) and daily intravenous GC regime (DR) (OR, 0.19; 95% CrI; 0.03–0.97). Ranking probabilities indicated that the MR and WR have a relatively higher probability of becoming the best option for response, proptosis, and AEs.

Conclusion: Based on limited evidence, the WR or MR should be preferentially prescribed to treat patients with moderately severe GO. However, more studies with a large sample size should be conducted to further confirm our findings and compare the WR with the MR.
A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics
Authors: Wang Bingjie , Zhang Xiao , Chen Huan , Koh Adrian , Zhao Chan , Chen Youxin
Published: April 2022

Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases. The pathogenesis of RVO is multifactorial and involves a complex interplay among a variety of vascular and inflammatory mediators. Many cytokines, chemokines, growth factors, and cell adhesion molecules have been reported to be implicated. Treatments for RVO are directed at the management of underlying risk factors and vision-threatening complications, including macula edema (ME) and neovascularization. Intravitreal anti-VEGF agents are currently considered as the first-line treatment for ME secondary to RVO (RVO-ME), but a substantial proportion of patients responded insufficiently to anti-VEGF agents. Since RVO-ME refractory to anti-VEGF agents generally responds to corticosteroids and its visual outcome is negatively correlated to disease duration, prediction of treatment response at baseline in RVO-ME may significantly improve both cost-effectiveness and visual prognosis. Several bioactive molecules in the aqueous humor were found to be associated with disease status in RVO. This review aims to present a comprehensive review of intraocular biomolecules reported in RVO, including VEGF, IL-6, IL-8, MCP-1, sICAM-1, IL-12, IL-13, sVEGFR-1, sVEGFR-2, PDGF-AA, etc., highlighting their association with disease severity and/or phenotype, and their potential roles in prognostic prediction and treatment selection. Some of these molecules may serve as biomarkers for aqueous humor-based companion diagnostics for the treatment of RVO in the future.
Comparison of Efficacy and Safety Between Low-Dose Ziprasidone in Combination With Sertraline and Ziprasidone Monotherapy for Treatment-Resistant Patients With Acute Exacerbation Schizophrenia: A Randomized Controlled Trial
Authors: Shi Hui , Xu Jing , Lang Xiaoe , Wu Hanjing Emily , Xiu Mei Hong , Zhang Xiang Yang
Published: April 2022

Treatment-resistant schizophrenia (TRS) is a prevalent clinical problem with heterogeneous presentations. However, the clinical trial designs for new treatments are still lacking. This study aimed to assess the efficacy of ziprasidone plus sertraline in TRS patients as compared to ziprasidone monotherapy. We conducted a 24 weeks, randomized, controlled, double-blinded clinical research trial. 62 treatment-resistant patients with acute exacerbation SZ were randomly allocated to receive a usual dose of ziprasidone (120–160 mg/d) monotherapy (Control group) and 53 TRS inpatients were to receive a low dose of ziprasidone (60–80 mg/d) in combination with sertraline (ZS group). Treatment outcomes were measured by the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and Personal and Social Performance Scale (PSP) at baseline, week 4, 8, 12, and 24. Relative to control group, the patients in ZS group showed greater reductions in the following: PANSS positive symptom, negative symptom, total score, and HAMD total score. Additionally, the patients in ZS group had a greater increase in PSP total score. Notably, the reduction in HAMD was positively correlated with the reduction in PANSS total score. The reduction in CGI-S was a predictor for the improvement of psychosocial functioning in patients. Furthermore, the ZS group had a lower rate of side effects compared to the control group. Our findings suggest that a low dose of ziprasidone in combination with sertraline is an effective therapy for the clinical symptoms as compared to a usual dose of ziprasidone in the treatment-resistant patients with acute exacerbation SZ.

Clinical Trial Registration:ClinicalTrials.gov, identifier NCT04076371.
Methyl 6-O-cinnamoyl-α-d-glucopyranoside Ameliorates Acute Liver Injury by Inhibiting Oxidative Stress Through the Activation of Nrf2 Signaling Pathway
Authors: Xu Qianqian , Deng Yanfang , Ming Jiaxiong , Luo Zengwei , Chen Xia , Chen Tianqi , Wang Yafen , Yan Shan , Zhou Jiajun , Mao Lina , Sun Weiguang , Zhou Qun , Ren Hong , Zhang Yonghui
Published: April 2022

Excessive stimulation of hepatotoxins and drugs often lead to acute liver injury, while treatment strategies for acute liver injury have been limited. Methyl 6-O-cinnamoyl-α-d-glucopyranoside (MCGP) is a structure modified compound from cinnamic acid, a key chemical found in plants with significant antioxidant, anti-inflammatory, and antidiabetic effects. In this study, we investigated the effects and underlying mechanisms of MCGP on acetaminophen (APAP)- or carbon tetrachloride (CCl4)-induced acute liver injury. As a result, MCGP inhibited cell death and apoptosis induced by APAP or CCl4, and suppressed the reactive oxygen species (ROS) generation stimulated by H2O2 in liver AML12 cells. In vivo, MCGP alleviated APAP/CCl4-induced hepatic necrosis and resumed abnormal aminotransferase activities and liver antioxidase activities. In addition, MCGP depressed APAP- or CCl4-induced oxidative stress through the suppression of CYP2E1 and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. MCGP also enhanced the number of PCNA-positive hepatocytes, increased hepatic PCNA and Bcl-XL, and decreased BAX expression in APAP-/CCl4-intoxicated mice. Furthermore, MCGP activated the GSDMD-N/cleaved caspase 1 pathway. In summary, MCGP might act as a potential therapeutic drug against drug-induced and chemical-induced acute liver injuries, and its underlying mechanisms might engage on the pressing of oxidative stress, refraining of hepatocyte apoptosis, and facilitating of liver regeneration.
VRK1 Predicts Poor Prognosis and Promotes Bladder Cancer Growth and Metastasis In Vitro and In Vivo
Authors: Wu Jiacheng , Li Tao , Ji Hao , Chen Zhi , Zhai Baoqian
Published: April 2022

Bladder cancer (BC) is one of the most common malignant tumors in the urinary system with growing morbidity and diagnostic rate in recent years. Therefore, identifying new molecular biomarkers that inhibit the progression of bladder cancer is needed for developing further therapeutics. This study found a new potential treatment target: vaccinia-related kinase 1 (VRK1) and explored the function and mechanism of VRK1 in the development of bladder cancer. First, TCGA database and tissue microarray analysis showed that VRK1 was significantly upregulated in bladder cancer. Kaplan–Meier survival analysis indicates that the OS and PFS of the VRK1 high expression group were significantly lower than the VRK1 low expression group (p = 0.002, p = 0.005). Cox multi-factor analysis results show that VRK1 expression is an independent risk factor affecting tumor progress. The maximum tumor diameter, staging, and adjuvant chemotherapy also have a certain impact on tumor progression (p < 0.05). In internal validation, the column C index is 0.841 (95% CI, 0.803–0.880). In addition, cell functional studies have shown that VRK1 can significantly inhibit the proliferation, migration, and invasiveness of bladder cancer cells. In vivo, nude mice transplanted tumors further prove that low VRK1 can significantly inhibit the proliferation capacity of bladder cancer cells. In summary, VRK1 expression is significantly related to the staging, grade, and poor prognosis of patients with bladder cancer. At the same time, in vivo and in vitro experiments have shown that downregulation of VRK1 can significantly inhibit the proliferation of bladder cancer cells. These findings provide a basis for using VRK1 as a potential therapeutic target for patients with bladder cancer.
Erigeron breviscapus (Vant.) Hand-Mazz.: A Promising Natural Neuroprotective Agent for Alzheimer’s Disease
Authors: Dong Xiaoyu , Qu Shengtao
Published: April 2022

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by progressive cognitive dysfunction and memory loss in the elderly, which seriously affects the quality of their lives. Currently, the pathogenesis of AD remains unclear. Molecular biologists have proposed a variety of hypotheses, including the amyloid-β hypothesis, tau hyperphosphorylation hypothesis, cholinergic neuron injury, inflammation caused by an abnormal immune response, and gene mutation. Drugs based on these pathological studies, including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, have achieved a certain level of efficacy but are far from meeting clinical needs. In the recent years, some important advances have been made in the traditional Chinese medicine treatment of AD. Erigeron breviscapus (Vant.) Hand-Mazz. (EBHM) is an important medicinal plant distributed in Yunnan Province, China. Studies have shown that EBHM and its active ingredients have a variety of pharmacological effects with good therapeutic effects and wide application prospects for cognitive disability-related diseases. However, to our best knowledge, only few review articles have been published on the anti-AD effects of EBHM. Through a literature review, we identified the possible pathogenesis of AD, discussed the cultivation and phytochemistry of EBHM, and summarized the pharmacological mechanism of EBHM and its active ingredients in the treatment of AD to provide suggestions regarding anti-AD therapy as well as a broader insight into the therapeutic potential of EBHM.