bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Hippocampal Subfield Asymmetry at 7T With Automated Segmentation in Epilepsy Patients With Normal Clinical Strength MRIs
Authors: Pai Akila , Marcuse Lara V. , Alper Judy , Delman Bradley N. , Rutland John W. , Feldman Rebecca E. , Hof Patrick R. , Fields Madeline , Young James , Balchandani Priti
Published: November 2021

While the etiology of hippocampal sclerosis (HS) in epilepsy patients remains unknown, distinct phenotypes of hippocampal subfield atrophy have been associated with different clinical presentations and surgical outcomes. The advent of novel techniques including ultra-high field 7T magnetic resonance imaging (MRI) and automated subfield volumetry have further enabled detection of hippocampal pathology in patients with epilepsy, however, studies combining both 7T MRI and automated segmentation in epilepsy patients with normal-appearing clinical MRI are limited. In this study, we present a novel application of the automated segmentation of hippocampal subfields (ASHS) software to determine subfield volumes of the CA1, CA2/3, CA4/DG, and the subiculum using ultra high-field 7T MRI scans, including T1-weighted MP2RAGE and T2-TSE sequences, in 27 patients with either mesial temporal lobe epilepsy (mTLE) or neocortical epilepsy (NE) compared to age and gender matched healthy controls. We found that 7T improved visualization of structural abnormalities not otherwise seen on clinical strength MRIs in patients with unilateral mTLE. Additionally, our automated segmentation algorithm was able to detect structural differences in volume and asymmetry across hippocampal subfields in unilateral mTLE patients compared to controls. Specifically, amongst unilateral mTLE patients with longer disease durations, volume loss was observed in the ipsilateral CA1 and CA2/3 subfields and contralateral CA1. There were no differences in subfield volumes in patients with NE compared to controls. We report the first application of 7T with automated segmentation to characterize the relationship between disease duration burden and asymmetry across specific hippocampal subfields in this population. Disease duration was found to have a statistically significant positive relationship with subfield asymmetry within the unilateral mTLE cohort. These findings highlight the ability of 7T MRI and automated segmentation to provide novel qualitative and quantitative information in epilepsy patients who are otherwise MRI-negative at clinical field strengths.
The Psychiatric Misdiagnosis of Behavioral Variant Frontotemporal Dementia in a Colombian Sample
Authors: Zapata-Restrepo Lina , Rivas Juan , Miranda Carlos , Miller Bruce L. , Ibanez Agustín , Allen Isabel E. , Possin Katherine
Published: November 2021

Objective: To describe the demographic characteristics, initial psychiatric diagnoses, and the time to reach a diagnosis of probable behavioral variant frontotemporal dementia (bvFTD) in a public psychiatric hospital in Cali, Colombia.

Methods: We retrospectively reviewed the medical records of 28 patients who were diagnosed with probable bvFTD based on a multidisciplinary evaluation that included a structural MRI, neuropsychological testing, functional assessment, and neurological exam. Prior to this evaluation, all patients were evaluated by a psychiatrist as part of their initial consultation at the hospital. The initial consultation included the Neuropsychiatric Inventory and diagnoses based on the DSM-V. Demographics, clinical features, and initial psychiatric misdiagnoses were extracted from clinical records and summarized in the full sample and by gender.

Results: The study sample had a mean education of 10.0 years (SD = 4.9) and 68.0% were female. In the full sample, 28.6% were initially diagnosed with dementia, and 71.4% with a psychiatric disorder. The psychiatric diagnosis at initial consultation differed by gender. Women were most likely to be diagnosed with depression (26.3%) or bipolar disorder (26.3%), while the men were most likely to be diagnosed with anxiety (33.3%) or a psychotic disorder (22.2%). Psychotic symptoms were common (delusions, 60.7% and hallucinations, 39.3%), and the pattern of neuropsychiatric symptoms did not differ by gender.

Conclusions: This is one of few case series of bvFTD in a Colombian population, where bvFTD is a recognizable and prevalent disorder. In this psychiatric hospital, the majority of patients with bvFTD were initially diagnosed with a primary psychiatric condition. There was a gender difference in psychiatric diagnosis, but not in neuropsychiatric symptoms. In this sample, the rate of psychiatric misdiagnosis, as well as the psychotic symptoms, were higher compared to rates described in other countries. These results highlight the need for interventions to improve bvFTD diagnosis in under-represented populations.
Development and Validation of a Predictive Model for Spontaneous Hemorrhagic Transformation After Ischemic Stroke
Authors: Wei Chenchen , Liu Junfeng , Guo Wen , Jin Yuxi , Song Quhong , Wang Yanan , Ye Chen , Li Jing , Zhang Shanshan , Liu Ming
Published: November 2021

Background: Hemorrhagic transformation (HT) after reperfusion therapy for acute ischemic stroke (AIS) has been well studied; however, there is scarce research focusing on spontaneous HT (sHT). Spontaneous HT is no less important with a relatively high incidence and could be associated with neurological worsening. We aimed to develop and validate a simple and practical model to predict sHT after AIS (SHAIS) and compared the predictive value of the SHAIS score against the models of post-Reperfusion HT for sHT.

Methods: Patients with AIS admitted within 24 h of onset were prospectively screened to develop and validate the SHAIS score. The primary outcome was sHT during hospitalization (within 30 days after onset), and the secondary outcomes were symptomatic sHT and parenchymal hematoma (PH). Clinical information, laboratory, and neuroimaging data were screened to construct the SHAIS score. We selected six commonly used scales for predicting HT after reperfusion therapy and compared their predictive ability for sHT with the SHAIS score using Delong's test.

Results: The derivation cohort included 539 patients (mean age, 68.1 years; men, 61.4%), of whom 91 (16.9%) patients developed sHT with 25.3% (23/91) being symptomatic sHT and 62.6% (57/91) being PH. Five variables (atrial fibrillation, NIHSS score ≥ 10, hypodensity > 1/3 of middle cerebral artery territory, hyperdense artery sign, and anterior circulation infarction) composed the SHAIS score, which ranged from 0 to 11 points. The area under the receiver-operating characteristic curve (AUC) was 0.86 (95% CI 0.82–0.91, p < 0.001) for the overall sHT, 0.85 (95% CI 0.76–0.92, p < 0.001) for symptomatic sHT, and 0.89 (95% CI 0.85–0.94, p < 0.001) for PH. No evidence of miscalibration of the SHAIS score was found to predict the overall sHT (p = 0.19), symptomatic sHT (p = 0.44), and PH (p = 0.22). The internal (n = 245) and external validation cohorts (n = 200) depicted similar predictive performance compared to the derivation cohort. The SHAIS score had a higher AUC to predict sHT than any of the six pre-Existing models (p < 0.05).

Conclusions: The SHAIS score provides an easy-to-use model to predict sHT, which could help providers with decision-making about treatments with high bleeding risk, and to counsel patients and families on the baseline risk of HT, aligning expectations with probable outcomes.
Association Between Migraine Complicated With Restless Legs Syndrome and Vitamin D
Authors: Sun Shuning , Liu Chunling , Jia Yanlu , Wu Jun , Li Hui , Li Xiaonan , Zhao Yimin
Published: November 2021

Background: This study aimed to evaluate the prevalence of restless legs syndrome (RLS) in patients with migraine and explore its association with vitamin D deficiency, aiming to provide biological support for the comorbidity of migraine with RLS, and shed new lights into clinical diagnosis and treatment.

Methods: A case-control study was performed on 175 migraine patients and 151 non-headache controls. The information of all subjects concerning headache severity [visual analog scale (VAS) score], RLS, RLS severity [International Restless Legs Scale (IRLS) score], sleep quality [Pittsburgh sleep quality index (PSQI)], anxiety and depression symptoms [hospital anxiety and depression scale (HADS)], and demographic data were collected. At the same time, serum 25-(OH) D levels were also measured (concentration <20 ng/ml was defined deficiency). Afterward, the logistic regression model was adopted to explore the risk factors for RLS in patients with migraines.

Results: Compared with control group, migraine group had lower vitamin D levels [(21.10 ± 6.58) vs. (16.42 ± 5.6) ng/ml, P < 0.001], a higher rate of vitamin D deficiency (45.03 vs. 72%, P <0001), higher prevalence of RLS (6.62 vs. 22.29%, P < 0.001). Compared with the pure RLS group, RLS with the migraine group had lower vitamin D levels and higher IRLS score (P < 0.05). Compared with pure migraine group, migraine with RLS group had lower vitamin D levels [(17.36 ± 5.56) vs. (13.15 ± 4.42) ng/ml, P < 0.001], higher incidence of vitamin D deficiency (66.18 vs. 92.31%, P = 0.001), higher frequency of headache attacks (P = 0.004). Thereafter, the multivariate logistic regression model was employed to adjust confounding factors such as age, gender, season, frequency of headache attacks, PSQI score, and HADS scores. According to the results vitamin D deficiency in patients with migraines was an independent risk factor for RLS (OR = 5.03, 95%CI: 1.2–21.16, P = 0.027).

Conclusions: The prevalence of RLS in migraine patients was significantly higher than that in the non-headache population. Besides, vitamin D levels decreased, while the incidence of vitamin D deficiency increased in the migraine patients complicated with RLS. Finally, the occurrence of RLS in migraine patients was significantly related to vitamin D deficiency.
Intrahippocampal Adeno-Associated Virus–Mediated Overexpression of Nerve Growth Factor Reverses 192IgG-Saporin–Induced Impairments of Hippocampal Plasticity and Behavior
Authors: Dobryakova Yulia V. , Spivak Yulia S. , Zaichenko Maria I. , Koryagina Alena A. , Markevich Vladimir A. , Stepanichev Mikhail Yu. , Bolshakov Alexey P.
Published: November 2021

One of the aspects of Alzheimer disease is loss of cholinergic neurons in the basal forebrain, which leads to development of cognitive impairment. Here, we used a model of cholinergic deficit caused by immunotoxin 192IgG-saporin to study possible beneficial effects of adeno-associated virus (AAV)–mediated overexpression of nerve growth factor (NGF) in the hippocampus of rats with cholinergic deficit. Suspension of recombinant AAV carrying control cassette or cassette with NGF was injected into both hippocampi of control rats or rats with cholinergic deficit induced by intraseptal injection of 192IgG-saporin. Analysis of choline acetyltransferase (ChAT) immunostaining showed that NGF overexpression in the hippocampus did not prevent strong loss of ChAT-positive neurons in the septal area caused by the immunotoxin. Induction of cholinergic deficit in the hippocampus led to impairments in Y-maze and beam-walking test but did not affect behavioral indices in the T-maze, open field test, and inhibitory avoidance training. NGF overexpression in the rats with cholinergic deficit restored normal animal behavior in Y-maze and beam-walking test. Recording of field excitatory postsynaptic potentials in vivo in the hippocampal CA1 area showed that induction of cholinergic deficit decreased magnitude of long-term potentiation (LTP) and prevented a decrease in paired-pulse ratio after LTP induction, and NGF overexpression reversed these negative changes in hippocampal synaptic characteristics. The beneficial effect of NGF was not associated with compensatory changes in the number of cells that express NGF receptors TrkA and NGFR in the hippocampus and medial septal area. NGF overexpression also did not prevent a 192IgG-saporin–induced decrease in the activity of acetylcholine esterase in the hippocampus. We conclude that NGF overexpression in the hippocampus under conditions of cholinergic deficit induces beneficial effects which are not related to maintenance of cholinergic function.
Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption
Authors: Hayashi Takashi
Published: November 2021

Glutamate is the major excitatory neurotransmitter in the vertebrate brain and various modifications have been established in the glutamatergic synapses. Generally, many neuronal receptors and ion channels are regulated by S-palmitoylation, a reversible post-translational protein modification. Genome sequence databases show the evolutionary acquisition and conservation concerning vertebrate-specific palmitoylation of synaptic proteins including glutamate receptors. Moreover, palmitoylation of some glutamate receptor-binding proteins is subsequently acquired only in some mammalian lineages. Recent progress in genome studies has revealed that some palmitoylation-catalyzing enzymes are the causative genes of neuropsychiatric disorders. In this review, I will summarize the evolutionary development of palmitoylation-dependent regulation of glutamatergic synapses and their dysfunctions which are caused by the disruption of palmitoylation mechanism.
OLFML2B Is a Robust Prognostic Biomarker in Bladder Cancer Through Genome-Wide Screening: A Study Based on Seven Cohorts
Authors: Lin Jiaxing , Xu Xiao , Li Tianren , Yao Jihang , Yu Meng , Zhu Yuyan , Sun Dan
Published: November 2021

Background

Bladder cancer lacks useful and robust prognostic markers to stratify patients at risk. Our study is to identify a robust prognostic marker for bladder cancer.

Methods

The transcriptome and clinical data of bladder cancer were downloaded from multiple databases. We searched for genes with robust prognosis by Kaplan-Meier analysis of the whole genome. CIBERSORT and TIMER algorithm was used to calculate the degree of immune cell infiltration.

Results

We identified OLFML2B as a robust prognostic marker for bladder cancer in five cohorts. Kaplan-Meier analysis showed that patients with a high level of OLFML2B expression had a poor prognosis. The expression of OLFML2B increased with the increase of stage and grade. We found that patients with high expression of OLFML2B still had a poor prognosis in two small bladder cancer cohorts. OLFML2B also has the prognostic ability in ten other tumors, and the prognosis is poor in high expression. The correlation analysis between OLFML2B and immune cells showed that it was positively correlated with the degree of macrophage infiltration and highly co-expressed with tumor-associated macrophage markers. Finally, the Wound-healing assay and Colony formation assay results showed that the migration and proliferation ability of bladder cancer cell lines decreased after the knockdown of OLFML2B.

Conclusions

In summary, OLFML2B is a robust risk prognostic marker, and it can help patients with bladder cancer improve individualized treatment.
Transcriptome-Wide Map of N6-Methyladenosine Methylome Profiling in Human Bladder Cancer
Authors: Li Aolin , Gan Ying , Cao Congcong , Ma Binglei , Zhang Quan , Zhang Qian , Yao Lin
Published: November 2021

N6-Methyladenosine (m6A) is the most widespread internal RNA modification in several species. In spite of latest advances in researching the biological roles of m6A, its function in the development and progression of bladder cancer remains unclear. In this study, we used MeRIPty -55-seq and RNA-seq methods to obtain a comprehensive transcriptome-wide m6A profiling and gene expression pattern in bladder cancer and paired normal adjacent tissues. Our findings showed that there were 2,331 hypomethylated and 3,819 hypermethylated mRNAs, 32 hypomethylated and 105 hypermethylated lncRNAs, and 15 hypomethylated and 238 hypermethylated circRNAs in bladder cancer tissues compared to adjacent normal tissues. Furthermore, m6A is most often harbored in the coding sequence (CDS), with some near the start and stop codons between two groups. Functional enrichment analysis revealed that differentially methylated mRNAs, lncRNAs, and circRNAs were mostly enriched in transcriptional misregulation in cancer and TNF signaling pathway. We also found that different m6A methylation levels of gene might regulate its expression. In summary, our results for the first time provide an m6A landscape of human bladder cancer, which expand the understanding of m6A modifications and uncover the regulation of mRNAs, lncRNAs, and circRNAs through m6A modification in bladder cancer.
Targeting miR-185-3p Inhibits Head and Neck Squamous Cell Carcinoma by Modulating RAB25
Authors: Wang Xueping , Zhu Xiaoyuan , Zhao Yulin
Published: November 2021

Cancer cell-derived exosomes regulate tumor growth and progression. However, the effects of exosomes and its contents on head and neck squamous cell carcinoma (HNSCC) and its underlying mechanisms remain unclear. Here, we found HNSCC displayed a dysregulation of exosomes biogenesis. miR-185-3p was one of the most upregulated exosome-derived miRNAs in HNSCC. Functional assay showed that RAB25 is a direct downstream target of miR-185-3p. miR-185-3p/RAB25 signaling controlled tumor progression and correlated with disease prognosis. Targeting miR-185-3p/RAB25 significantly inhibited tumor growth and promoted drug response to chemotherapy. To conclude, the findings demonstrate exosomal miR-185-3p promotes tumor growth by mediating RAB25 that could be effectively targeted for HNSCC treatment.
Upfront Treatment of Pediatric High-Risk Neuroblastoma With Chemotherapy, Surgery, and Radiotherapy Combination: The CCCG-NB-2014 Protocol
Authors: Zhang Dongdong , Kaweme Natasha Mupeta , Duan Peng , Dong Youhong , Yuan Xiaojun
Published: November 2021

Purpose

The Chinese Children’s Cancer Group developed the CCCG-NB-2014 study to formulate optimal treatment strategies for high-risk (HR) neuroblastoma (NB). The safety and efficacy of this protocol were evaluated.

Method

Patients with newly diagnosed neuroblastoma and defined as HR according to the Children’s Oncology Group study were included. They were treated with a combination of chemotherapy, surgery, and radiotherapy. The treatment-related toxicities, response rate, 3-year progression-free survival (PFS), and overall survival (OS) were analyzed.

Results

Of 159 patients enrolled between 2014 and 2018, 80 were eligible, including 19 girls and 61 boys, with a median age of 3.9 years (range 0.9–11). After a median follow-up of 24 months (range 3–40), the median OS was 31.8 months, and 3-year OS was 83.8%. In multivariate analyses, the OS was affected by N-MYC amplification (hazard ratio 0.212, 95% confidence interval (CI) 0.049–0.910; p = 0.037) and giant tumor mass (hazard ratio 0.197, 95% CI 0.071–0.552; p = 0.002). The median 3-year PFS was 25.8 months, and 3-year PFS was 57.5%. The univariate analysis showed that only the giant tumor mass was associated with the outcome. Of the 13 deaths, 11 died from the rapid progression of the disease and two from treatment-related toxicities. The most common adverse reaction was chemotherapy-induced hematological toxicity.

Conclusion

The PFS and OS reported in our study were similar to Western countries. The CCCG-NB-2014 protocol proved to be an efficient regimen with tolerable side-effect for the treatment of pediatric HR-NB.
3D Quantitative Ablation Margins for Prediction of Ablation Site Recurrence After Stereotactic Image-Guided Microwave Ablation of Colorectal Liver Metastases: A Multicenter Study
Authors: Ruiter Simeon J. S. , Tinguely Pascale , Paolucci Iwan , Engstrand Jennie , Candinas Daniel , Weber Stefan , de Haas Robbert J. , de Jong Koert P. , Freedman Jacob
Published: November 2021

Background

Three-dimensional (3D) volumetric ablation margin assessment after thermal ablation of liver tumors using software has been described, but its predictive value on treatment efficacy when accounting for other factors known to correlate ablation site recurrence (ASR) remains unknown.

Purpose

To investigate 3D quantitative ablation margins (3D-QAMs) as an algorithm to predict ASR within 1 year after stereotactic microwave ablation (SMWA) for colorectal liver metastases (CRLM).

Materials and Methods

Sixty-five tumors in 47 patients from a prospective multicenter study of patients undergoing SMWA for CRLM were included in this retrospective 3D-QAM analysis. Using a previously developed algorithm, 3D-QAM defined as the distribution of tumor to ablation surface distances was assessed in co-registered pre- and post-ablation CT scans. The discriminatory power and optimal cutoff values for 3D-QAM were assessed using receiver operating characteristic (ROC) curves. Multivariable logistic regression analysis using generalized estimating equations was applied to investigate the impact of various 3D-QAM outputs on 1-year ASR while accounting for other known influencing factors.

Results

Ten of the 65 (15.4%) tumors included for 3D-QAM analysis developed ASR. ROC analyses identified i) 3D-QAM <1 mm for >23% of the tumor surface, ii) 3D-QAM <5 mm for >45%, and iii) the minimal ablation margin (MAM) as the 3D-QAM outputs with optimal discriminatory qualities. The multivariable regression model without 3D-QAM yielded tumor diameter and KRAS mutation as 1-year ASR predictors. When adding 3D-QAM, this factor became the main predictor of 1-year ASR [odds ratio (OR) 21.67 (CI 2.48, 165.21) if defined as >23% <1 mm; OR 0.52 (CI 0.29, 0.95) if defined as MAM].

Conclusions

3D-QAM allows objectifiable and standardized assessment of tumor coverage by the ablation zone after SMWA. Our data shows that 3D-QAM represents the most important factor predicting ASR within 1 year after SMWA of CRLM.
RETRACTED: Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation
Authors: Zhao Ziyi , Zeng Jinhao , Guo Qiang , Pu Kunming , Yang Yi , Chen Nianzhi , Zhang Gang , Zhao Maoyuan , Zheng Qiao , Tang Jianyuan , Hu Qiongying
Published: November 2021

Background

Cancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkaloid extracted from the Chinese herbal medicine Coptis chinensis, was found to have antitumor activities against colorectal cancer, without knowing whether it exerts inhibitory effects on colorectal CSCs and the potential mechanisms.

Methods

In this study, we examined the inhibitory roles of Berberine on CSCs derived from HCT116 and HT29 by culturing in serum-free medium. We also examined the effects of Berberine on m6A methylation via regulating fat mass and obesity-associated protein (FTO), by downregulating β-catenin.

Results

We examined the effects of Berberine on the tumorigenicity, growth, and stemness of colorectal cancer stem-like cells. The regulatory effect of Berberine on N6-methyladenosine (m6A), an abundant mRNA modification, was also examined. Berberine treatment decreased cell proliferation by decreasing cyclin D1 and increasing p27 and p21 and subsequently induced cell cycle arrest at the G1/G0 phase. Berberine treatment also decreased colony formation and induced apoptosis. Berberine treatment transcriptionally increased FTO and thus decreased m6A methylation, which was reversed by both FTO knockdown and the addition of the FTO inhibitor FB23-2. Berberine induced FTO-related decreases in stemness in HCT116 and HT29 CSCs. Berberine treatment also increased chemosensitivity in CSCs and promoted chemotherapy agent-induced apoptosis. Moreover, we also found that Berberine treatment increased FTO by decreasing β-catenin, which is a negative regulator of FTO.

Conclusions

Our observation that Berberine effectively decreased m6A methylation by decreasing β-catenin and subsequently increased FTO suggests a role of Berberine in modulating stemness and malignant behaviors in colorectal CSCs.
Synergistic Cascade Strategy Based on Modifying Tumor Microenvironment for Enhanced Breast Cancer Therapy
Authors: Zhang Huan , Xu Jinshun , Gao Binyang , Wang Hong , Huang Jianbo , Zhou Jie , Yang Rui , Yan Feng , Peng Yulan
Published: November 2021

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with very few treatment options. Although tumor-targeted nanomedicines hold great promise for the treatment of TNBC, the tumor microenvironment (TME) continues to be a major cause of failure in nanotherapy and immunotherapy. To overcome this barrier, we designed a new synergistic cascade strategy (SCS) that uses mild hyperthermia and smart drug delivery system (SDDS) to alter TME resistance in order to improve drug delivery and therapeutic efficacy of TNBC.

Methods: Mild hyperthermia was produced by microwave (MW) irradiation. SDDS were formulated with thermosensitive polymer-lipid nanoparticles (HA-BNPs@Ptx), composed of polymer PLGA, phospholipid DPPC, hyaluronic acid (HA, a differentiation-44-targeted molecule, also known as CD44), 1-butyl-3-methylimidazolium-L-lactate (BML, a MW sensitizer), and paclitaxel (Ptx, chemotherapy drug). 4T1 breast tumor-bearing mice were treated with two-step MW combined with HA-BNPs@Ptx. Tumors in mice were pretreated with first MW irradiation prior to nanoparticle injection to modify and promote TME and promoting nanoparticle uptake and retention. The second MW irradiation was performed on the tumor 24 h after the injection of HA-BNPs@Ptx to produce a synergistic cascade effect through activating BML, thus, enhancing a hyperthermia effect, and instantly releasing Ptx at the tumor site.

Results: Multifunctional CD44-targeted nanoparticles HA-BNPs@Ptx were successfully prepared and validated in vitro. After the first MW irradiation of tumors in mice, the intratumoral perfusion increased by two times, and the nanoparticle uptake was augmented by seven times. With the second MW irradiation, remarkable antitumor effects were obtained with the inhibition rate up to 88%. In addition, immunohistochemical analysis showed that SCS therapy could not only promote tumor cell apoptosis but also significantly reduce lung metastasis.

Conclusion: The SCS using mild hyperthermia combined with SDDS can significantly improve the efficacy of TNBC treatment in mice by modifying TME and hyperthermia-mediated EPR effects.
Isoliquiritigenin Alleviates Semen Strychni-Induced Neurotoxicity by Restoring the Metabolic Pathway of Neurotransmitters in Rats
Authors: Wang Lu , Zhang Min , Wen Jing , Xiang Yalan , Duan Xiaoyu , Yu Changwei , Yan Miao , Zhang Bikui , Fang Pingfei
Published: November 2021

Acute neurotoxicity of Semen Strychni can result in sudden death in epilepsy. The detoxification method and mechanism of Semen Strychni acute poisoning have not been clarified. This experiment focused on the mechanism of Semen Strychni neurotoxicity and the alleviation effects of isoliquiritigenin. The rats were intraperitoneally injected with Semen Strychni extract (125 mg/kg), followed by oral administration of isoliquiritigenin (50 mg/kg) for 7 days. FJ-B staining was used to evaluate the degree of injury on hippocampus neurons. The concentration of monoamines, amino acids, and choline neurotransmitters, the Dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolic pathway in the hippocampus, cerebellum, striatum, prefrontal cortex, hypothalamus, serum, and plasma were detected by LC-MS/MS. The expression of neurotransmitter metabolic enzymes [catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO)] and neurotransmitter receptors [glutamate N-methyl-D-aspartic acid receptors (NMDARs) and gamma-aminobutyric acid type A receptor (GABRs)] were, respectively determined using ELISA and qRT-PCR. The results indicated that Semen Strychni induced neuronal degeneration in the hippocampal CA1 region. Meanwhile, Semen Strychni inhibited the mRNA expression of NMDAR1, NMDAR2A, NMDAR2B, GABRa1, GABRb2 and reduced the level of MAO, which disrupted the DA and 5-HT metabolic pathway. However, isoliquiritigenin reversed these effects. In summary, isoliquiritigenin showed alleviation effects on Semen Strychni-induced neurotoxicity, which could be attributed to restoring neurotransmitters metabolic pathway, most likely through the activation of NMDA receptors.
Effects of Diminished NADPH:cytochrome P450 Reductase in Human Hepatocytes on Lipid and Bile Acid Homeostasis
Authors: Heintze Tamara , Wilhelm Denise , Schmidlin Thierry , Hofmann Ute , Zanger Ulrich M. , Schwab Matthias , Klein Kathrin
Published: November 2021

NADPH:cytochrome P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450 (CYP) enzymes involved in the biosynthesis of endogenous substances like bile acids and other steroids as well as in the oxidative metabolism of xenobiotics. P450 oxidoreductase also supports other redox enzymes in fatty acid and cholesterol pathways. Recently, we have established CRISPR/Cas9-mediated POR knockdown in a human hepatic cell model, HepaRG, and demonstrated the differential effects of limited POR expression on CYP activity. The aim of the present work was to systematically investigate the impact of POR knockdown with a focus on the expression of ADME (absorption, distribution, metabolism, and excretion) genes and related regulators. Functional consequences have been assessed using quantitative mass spectrometry for targeted metabolomics covering bile acids, and cholesterol and its precursors, and for untargeted proteomics. In addition to the previously described alteration of RNA expression of CYP genes, we showed significant downregulation of transcriptional regulators of drug metabolism and transport, including NR1I3 (CAR), NR1I2 (PXR), NR1H4 (FXR), and NR1H3 (LXRα) in cells with POR gene disruption. Furthermore, POR knockdown resulted in deregulated bile acid and cholesterol biosynthesis demonstrated by low levels of cholic acid derivates and increased concentrations of chenodeoxycholic acid derivates, respectively. Systemic effects of POR knockdown on global protein expression were indicated by downregulation of several metabolic pathways including lipid metabolism and biological oxidation reactions. The deduced protein network map corroborates CYP enzymes as direct interaction partners, whereas changes in lipid metabolism and homeostasis are the result of indirect effects. In summary, our results emphasize a widespread role of POR in various metabolic pathways and provide the first human data on the effects of diminished POR expression on drug and endogenous metabolism in a genomeedited HepaRG cell model.
Therapeutic Development by Targeting the cGAS-STING Pathway in Autoimmune Disease and Cancer
Authors: Li Qiumei , Tian Shuoran , Liang Jiadi , Fan Jiqiang , Lai Junzhong , Chen Qi
Published: November 2021

DNA immune recognition regulation mediated by the cGAS-STING pathway plays an important role in immune functions. Under normal physiological conditions, cGAS can recognize and bind to invading pathogen DNA and activate the innate immune response. On the other hand, abnormal activation of cGAS or STING is closely related to autoimmune diseases. In addition, activation of STING proteins as a bridge connecting innate immunity and adaptive immunity can effectively restrain tumor growth. Therefore, targeting the cGAS-STING pathway can alleviate autoimmune symptoms and be a potential drug target for treating cancer. This article summarizes the current progress on cGAS-STING pathway modulators and lays the foundation for further investigating therapeutic development in autoimmune diseases and tumors.
Dihydromyricetin Reverses Thioacetamide-Induced Liver Fibrosis Through Inhibiting NF-κB-Mediated Inflammation and TGF-β1-Regulated of PI3K/Akt Signaling Pathway
Authors: Zhao Yingchun , Liu Xinglong , Ding Chuanbo , Gu Yan , Liu Wencong
Published: November 2021

As a natural active substance, dihydromyricetin (DHM) has been proven to have good hepatoprotective activity. However, the therapeutic effect of DHM on liver fibrosis, which has become a liver disease threatening the health of people around the world, has not been studied to date. The purpose of this study was to investigate the effect of DHM as a new nutritional supplement on thioacetamide (TAA)-induced liver fibrosis. The liver fibrosis model was established by intraperitoneal injection of TAA (200 mg/kg, every 3 days) for 8 weeks, and oral administration of DHM (20 mg/kg and 40 mg/kg, daily) after 4 weeks of TAA-induced liver fibrosis. The results showed that DHM treatment significantly inhibited the activities of alanine aminotransferase (ALT) (37.81 ± 7.62 U/L) and aspartate aminotransferase (AST) (55.18 ± 10.94 U/L) in serum of liver fibrosis mice, and increased the levels of superoxide dismutase (SOD) and glutathione (GSH) while reversed the level of malondialdehyde (MDA). In addition, histopathological examination illustrated that TAA induced the inflammatory infiltration, apoptosis and fibroatherosclerotic deposition in liver, which was further confirmed by western-blot and immunofluorescence staining. Moreover, DHM inhibited hepatocyte apoptosis by regulating the phosphorylation level of phosphatidylinositol 3-kinase (PI3K), protein kinase-B (AKT) and its downstream apoptotic protein family. Interestingly, immunofluorescence staining showed that DHM treatment significantly inhibited alpha smooth muscle actin (α-SMA), which was a marker of hepatic stellate cell activation, and regulated the expression of transforming growth factor (TGF-β1). Importantly, supplementation with DHM significantly inhibited the release of nuclear factor kappa-B (NF-κB) signaling pathway and pro-inflammatory factors in liver tissue induced by TAA, and improved liver fiber diseases, such as tumor necrosis factor alpha (TNF-α) and recombinant rat IL-1β (IL-1β). In conclusion, the evidence of this study revealed that DHM is a potential hepatoprotective and health factor, and which also provides the possibility for the treatment of liver fibrosis.
Calorie Restriction With Exercise Intervention Improves Inflammatory Response in Overweight and Obese Adults: A Systematic Review and Meta-Analysis
Authors: Liu Yubo , Hong Feng , Lebaka Veeranjaneya Reddy , Mohammed Arifullah , Ji Lei , Zhang Yean , Korivi Mallikarjuna
Published: November 2021

Background/Purpose: In this systematic review and meta-analysis, we assessed the effects of exercise (EX) combined with calorie restriction (CR) intervention on inflammatory biomarkers, and correlations between biomarkers and participants’ characteristics were calculated in overweight and obese adults.

Methods: An article search was conducted through PubMed, Web of Science, EMBASE, the Cochrane database, Scopus, and Google Scholar to identify articles published up to April 2021. Studies that examined the effect of EX + CR intervention on inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and compared them with a CR trial in overweight and obese adults were included. We calculated the pooled effect by meta-analysis, identified the correlations (between inflammatory biomarkers and participants’ characteristics) through meta-regression, and explored the beneficial variable through subgroup analysis. The Cochrane risk of bias tool and Methodological Index for Non-randomized Studies were used to assess the risk of bias for the included trials.

Results: A total of 23 trials, including 1196 overweight and obese adults, were included in the meta-analysis. The pooled effect showed that EX + CR intervention significantly decreased CRP levels (P = 0.02), but had no effect on IL-6 (P = 0.62) and TNF-α (P = 0.11). Meta-regression analysis showed that the effect of EX + CR on CRP, IL-6, and TNF-α changes was correlated with lifestyle behavior of adults (Coef. = −0.380, P = 0.018; Coef. = −0.359, P = 0.031; Coef. = −0.424, P = 0.041, respectively), but not with age and BMI. The subgroup analysis results revealed that participants with sedentary lifestyle behavior did not respond to EX + CR intervention, as we found no changes in CRP, IL-6, and TNF-α concentrations (P = 0.84, P = 0.16, P = 0.92, respectively). However, EX + CR intervention significantly decreased CRP (P = 0.0003; SMD = −0.39; 95%CI: −0.60 to −0.18), IL-6 (P = 0.04; SMD = −0.21; 95%CI: −0.40 to −0.01) and TNF-α (P = 0.006; SMD = −0.40, 95%CI: −0.68 to −0.12) in adults without a sedentary lifestyle or with a normal lifestyle. Furthermore, the values between sedentary and normal lifestyle subgroups were statistically significant for CRP, IL-6, and TNF-α.

Conclusion: Our findings showed that combination EX + CR intervention effectively decreased CRP, IL-6, and TNF-α in overweight and obese adults with active lifestyles, but not with sedentary lifestyle behavior. We suggest that ‘lifestyle behavior’ is a considerable factor when designing new intervention programs for overweight or obese adults to improve their inflammatory response.
Unsaturated Fatty Acid Intake During Periconception and Incidence of Achieving Pregnancy: A Systematic Review and Meta-Analysis
Authors: Gatti Cintia Romina , Gomez Ribot Dalmiro , Mariani Javier , Jawerbaum Alicia
Published: November 2021

Background: Previous studies suggest that maternal diets enriched in unsaturated fatty acids may have a positive effect on pregnancy success. The aim of the present study was to conduct a systematic review and meta-analysis to evaluate whether increased dietary intake of polyunsaturated fatty acids (PUFAs) or monounsaturated fatty acids (MUFAs) during the periconception period has beneficial effects on the achievement of pregnancy in women.

Methods: The electronic databases PubMed, Medline and Cochrane Central Register, as well as references in related review articles, were searched to find studies assessing the effects of unsaturated fatty acid dietary intake during the periconception period on the achievement of pregnancy in women. Pregnancy was confirmed by high levels of hCG (biochemical means) and ultrasound confirmation of a gestational sac and heartbeat (clinical means).

Results: For the meta-analysis evaluating the effects of periconceptional diets enriched in PUFAs on pregnancy, four articles, providing data on 2,121 patients, were included. Results showed that periconceptional intake of PUFAs has no significant effects on achieving pregnancy compared to controls, according to both the fixed effects and random effects models (RR = 0.99, 95% CI 0.98–1.00). Further secondary analysis considering ω-6 and ω-3 PUFAs separately showed no significant effects on achieving pregnancy compared to controls. On the other hand, for the meta-analysis evaluating the effects of periconceptional diets enriched in MUFAs on achieving pregnancy, five articles, providing data on 2,473 patients, were included. Results showed that periconceptional dietary intake of MUFAs has significant effects on achieving pregnancy compared to controls according to the fixed effects model (RR = 1.03, 95% CI 1.01–1.06, p < 0.02) but not to the random effects model, due to heterogeneity. A secondary meta-analysis excluding one study which led to heterogeneity showed significant effects of MUFAs on achieving pregnancy compared to controls, according to both the fixed effects and random effects models (RR = 1.03, 95% CI 1.01–1.05, p < 0.02).

Conclusion: The meta-analysis of published clinical studies suggests that diets enriched in MUFAs, although not those enriched in PUFAs, may have a positive effect on pregnancy success as determined by HCG and ultrasonography.

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42021239355, identifier: CRD42021239355.
The Impact of ACTN3 Gene Polymorphisms on Susceptibility to Exercise-Induced Muscle Damage and Changes in Running Economy Following Downhill Running
Authors: de Lima Leonardo Coelho Rabello , Bueno Junior Carlos Roberto , de Oliveira Assumpção Claudio , de Menezes Bassan Natália , Barreto Renan Vieira , Cardozo Adalgiso Coscrato , Greco Camila Coelho , Denadai Benedito Sérgio
Published: November 2021

This study aimed to investigate if ACTN3 gene polymorphism impacts the susceptibility to exercise-induced muscle damage (EIMD) and changes in running economy (RE) following downhill running. Thirty-five healthy men were allocated to the two groups based on theirACTN3gene variants: RR and X allele carriers. Neuromuscular function [knee extensor isometric peak torque (IPT), rate of torque development (RTD), and countermovement, and squat jump height], indirect markers of EIMD [muscle soreness, mid-thigh circumference, knee joint range of motion, and serum creatine kinase (CK) activity], and RE (oxygen uptake, minute ventilation, blood lactate concentration, and perceived exertion) for 5-min of running at a speed equivalent to 80% of individual maximal oxygen uptake speed were assessed before, immediately after, and 1–4 days after a 30-min downhill run (−15%). Neuromuscular function was compromised (P< 0.05) following downhill running with no differences between the groups, except for IPT, which was more affected in the RR individuals compared with the X allele carriers immediately (−24.9 ± 6.9% vs. −16.3 ± 6.5%, respectively) and 4 days (−16.6 ± 14.9% vs. −4.2 ± 9.5%, respectively) post-downhill running. EIMD manifested similarly for both the groups except for serum CK activity, which was greater for RR (398 ± 120 and 452 ± 126 U L–1at 2 and 4 days following downhill running, respectively) compared with the X allele carriers (273 ± 121 and 352 ± 114 U L–1at the same time points). RE was compromised following downhill running (16.7 ± 8.3% and 11 ± 7.5% increases in oxygen uptake immediately following downhill running for the RR and X allele carriers, respectively) with no difference between the groups. We conclude that although RR individuals appear to be more susceptible to EIMD following downhill running, this does not extend to the changes in RE.
Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets
Authors: Navarro-García José Alberto , González-Lafuente Laura , Fernández-Velasco María , Ruilope Luis M. , Ruiz-Hurtado Gema
Published: November 2021

Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.
Soybean Yield Formation Physiology – A Foundation for Precision Breeding Based Improvement
Authors: Vogel Jonathan T. , Liu Weidong , Olhoft Paula , Crafts-Brandner Steven J. , Pennycooke Joyce C. , Christiansen Nicole
Published: November 2021

The continued improvement of crop yield is a fundamental driver in agriculture and is the goal of both plant breeders and researchers. Plant breeders have been remarkably successful in improving crop yield, as demonstrated by the continued release of varieties with improved yield potential. This has largely been accomplished through performance-based selection, without specific knowledge of the molecular mechanisms underpinning these improvements. Insight into molecular mechanisms has been provided by plant molecular, genetic, and biochemical research through elucidation of the function of genes and pathways that underlie many of the physiological processes that contribute to yield potential. Despite this knowledge, the impact of most genes and pathways on yield components have not been tested in key crops or in a field environment for yield assessment. This gap is difficult to bridge, but field-based physiological knowledge offers a starting point for leveraging molecular targets to successfully apply precision breeding technologies such as genome editing. A better understanding of both the molecular mechanisms underlying crop yield physiology and yield limiting processes under field conditions is essential for elucidating which combinations of favorable alleles are required for yield improvement. Consequently, one goal in plant biology should be to more fully integrate crop physiology, breeding, genetics, and molecular knowledge to identify impactful precision breeding targets for relevant yield traits. The foundation for this is an understanding of yield formation physiology. Here, using soybean as an example, we provide a top-down review of yield physiology, starting with the fact that yield is derived from a population of plants growing together in a community. We review yield and yield-related components to provide a basic overview of yield physiology, synthesizing these concepts to highlight how such knowledge can be leveraged for soybean improvement. Using genome editing as an example, we discuss why multiple disciplines must be brought together to fully realize the promise of precision breeding-based crop improvement.