bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathological Significance and Prognostic Roles of Indirect Bilirubin/Albumin Ratio in Hepatic Encephalopathy
Authors: Li Yanling , Liu Huiyuan , Chen Keng , Wu Xueheng , Wu Jiawen , Yang Zhenjun , Yao Leyi , Wen Guanmei , Zhang Change , Chen Xin , Chen Xiaohui , Tang Daolin , Wang Xuejun , Liu Jinbao
Published: September 2021

Background and Aim: Hepatic encephalopathy (HE) is a neurological disease caused by severe liver disease. Early identification of the risk factor is beneficial to the prevention and treatment of HE. Free bilirubin has always been considered to be the culprit of neonatal kernicterus, but there is no research to explore its role in HE. In this study, we aim to study the clinical significance of the indirect bilirubin-albumin ratio in HE.

Methods: A retrospective case-control study of 204 patients with liver failure was conducted. Human serum albumin (HSA) or heme oxygenase-1 (HO-1) inhibitor SnPP (Tin protoporphyrin IX dichloride) was injected intraperitoneally into Ugt1−/− mice to establish a treatment model for endogenous hyperbilirubinemia.

Results: IBil/albumin ratio (OR = 1.626, 95% CI1.323–2.000, P < 0.001), white blood cell (WBC) (OR = 1.128, 95% CI 1.009–1.262, P = 0.035), ammonia (OR = 1.010, 95% CI 1.001–1.019, P = 0.027), platelet (OR=1.008, 95% CI 1.001–1.016, P = 0.022), Hb (OR = 0.977, 95% CI 0.961–0.994, P = 0.007), and PTA (OR = 0.960, 95% CI 0.933–0.987, P = 0.005) were independent factors of HE. Patients with a history of liver cirrhosis and severe HE (OR = 12.323, 95% CI 3.278–47.076, P < 0.001) were more likely to die during hospitalization. HSA or SnPP treatment improved cerebellum development and reduced apoptosis of cerebellum cells.

Conclusion: The IBil/albumin ratio constitutes the most powerful risk factor in the occurrence of HE, and reducing free bilirubin may be a new strategy for HE treatment.
The Impact of Artificial Intelligence and Deep Learning in Eye Diseases: A Review
Authors: Nuzzi Raffaele , Boscia Giacomo , Marolo Paola , Ricardi Federico
Published: September 2021

Artificial intelligence (AI) is a subset of computer science dealing with the development and training of algorithms that try to replicate human intelligence. We report a clinical overview of the basic principles of AI that are fundamental to appreciating its application to ophthalmology practice. Here, we review the most common eye diseases, focusing on some of the potential challenges and limitations emerging with the development and application of this new technology into ophthalmology.
High Central Venous Pressure and Right Ventricle Size Are Related to Non-decreased Left Ventricle Stroke Volume After Negative Fluid Balance in Critically Ill Patients: A Single Prospective Observational Study
Authors: Hua Zhao , Xin Ding , Xiaoting Wang , Dawei Liu
Published: September 2021

Background: Optimal adjustment of cardiac preload is essential for improving left ventricle stroke volume (LVSV) and tissue perfusion. Changes in LVSV caused by central venous pressure (CVP) are the most important concerns in the treatment of critically ill patients.

Objectives: This study aimed to clarify the changes in LVSV after negative fluid balance in patients with elevated CVP, and to elucidate the relationship between the parameters of right ventricle (RV) filling state and LVSV changes.

Methods: This prospective cohort study included patients with high central venous pressure (CVP) (≥8 mmHg) within 24 h of ICU admission in the Critical Medicine Department of Peking Union Medical College Hospital. Patients were classified into two groups based on the LVSV changes after negative fluid balance. The cutoff value was 10%. The hemodynamic and echo parameters of the two groups were recorded at baseline and after negative fluid balance.

Results: A total of 71 patients included in this study. Forty in VI Group (LVOT VTI increased ≥10%) and 31 in VNI Group (LVOT VTI increased <10%). Of all patients, 56.3% showed increased LVSV after negative fluid balance. In terms of hemodynamic parameters at T0, patients in VI Group had a higher CVP (p < 0.001) and P(v-a)CO2 (p < 0.001) and lower ScVO2 (p < 0.001) relative to VNI Group, regarding the echo parameters at T0, the RVD/LVD ratio (p < 0.001), DIVC end−expiratory (p < 0.001), and ΔLVOT VTI (p < 0.001) were higher, while T0 LVOT VTI (p < 0.001) was lower, in VI Group patients. The multifactor logistic regression analysis suggested that a high CVP and RVD/LVD ratio ≥0.6 were significant associated with LVSV increase after negative fluid balance in critically patients. The AUC of CVP was 0.894. A CVP >10.5 mmHg provided a sensitivity of 87.5% and a specificity of 77.4%. The AUC of CVP combined with the RVD/LVD ratio ≥0.6 was 0.926, which provided a sensitivity of 92.6% and a specificity of 80.4%.

Conclusion: High CVP and RVD/LVD ratio ≥0.6 were significant associated with RV stressed in critically patients. Negative fluid balance will not always lead to a decrease, even an increase, in LVSV in these patients.
Baseline Neutrophil-to-Lymphocyte Ratio Is Independently Associated With 90-Day Transplant-Free Mortality in Patients With Cirrhosis
Authors: Liu Jing , Li Hai , Xia Jie , Wang Xianbo , Huang Yan , Li Beiling , Meng Zhongji , Gao Yanhang , Qian Zhiping , Liu Feng , Lu Xiaobo , Liu Junping , Deng Guohong , Zheng Yubao , Yan Huadong , Qiao Liang , Xiang Xiaomei , Zhang Qun , Chen Ruochan , Chen Jinjun , Luo Sen , Gao La , Ji Liujuan , Li Jing , Zhou Xinyi , Ren Haotang , Lu Sihong , Li Sumeng , Zhang Weituo , Zheng Xin
Published: September 2021

Background: Patients with cirrhosis have an increased risk of short-term mortality, however, few studies quantify the association between neutrophil-to-lymphocyte ratio (NLR) and 90-day transplant-free mortality in cirrhotic patients.

Methods: We prospectively analyzed 3,970 patients with chronic liver diseases from two multicenter cohorts in China (January 2015 to December 2016 and July 2018 to January 2019). Restricted cubic splines (RCS) were used to analyze the relation of NLR and all-causes 90-day transplant-free mortality in cirrhosis.

Results: A total of 2,583 cirrhotic patients were enrolled in our study. Restricted cubic splines showed that the odds ratio (OR) of all causes 90-day transplant-free mortality started to increase rapidly until around NLR 6.5, and then was relatively flat (p for non-linearity <0.001). The risk of 90-day transplant-free mortality in cirrhotic patients with NLR < 6.5 increased with an increment of 23% for every unit increase in NLR (p < 0.001). The patients with NLR < 4.5 had the highest risk (OR: 2.34, 95% CI 1.66–3.28). In multivariable-adjusted stratified analyses, the increase in the incidence of 90-day transplant-free mortality with NLR increasing was consistent (OR >1.0) across all major prespecified subgroups, including infection group (OR: 1.04, 95% CI 1.00–1.09) and non-infection (OR: 1.06, 95% CI 1.02–1.11) group. The trends for NLR and numbers of patients with organ failure varied synchronously and were significantly increased with time from day 7 to day 28.

Conclusions: We found a non-linear association between baseline NLR and the adjusted probability of 90-day transplant-free mortality. A certain range of NLR is closely associated with poor short-term prognosis in patients with cirrhosis.
Clinical Features of Spontaneous Regression of Retinopathy of Prematurity in China: A 5-Year Retrospective Case Series
Authors: Wang Liang , Li Manhong , Zhu Jun , Yan Hongxiang , Wu Lei , Fan Jing , Zhou Yi , Gou Kaili , Zhang Zifeng , Wang Yusheng
Published: September 2021

Purpose: The aim of this study is to explore the clinical features of spontaneous regression of retinopathy of prematurity (ROP) in China, including fundus appearance, time course, and affecting factors.

Methods: Data of pediatric patients in whom ROP spontaneously regressed without treatment were collected, including general demographics, medical history, zones and stages of ROP, and changes of fundus appearance. The fundus manifestations of spontaneous regression in ROP were systematically summarized. Meanwhile, the time course of spontaneous regression in ROP was further analyzed, including the onset time, completion time, and duration of regression, which were all compared across different ROP zones and stages. The associated factors were analyzed by survival analysis for their correlation with delayed regression for the first time.

Results: Two hundred thirty-seven eyes of 237 pediatric patients were included. The fundus manifestations of regression differed across stages. Lesions gradually subsided, and the retinal vessels gradually vascularized completely. However, despite ROP regression, some abnormalities remained. We observed avascular retina in the temporal periphery (19.0%), increased vascular branching (6.8%), retinal pigmentary changes (6.8%), and smaller angle between the upper and lower temporal retinal vessel trunks (3.0%). Acute ROP started to regress at a median 40 weeks of postmenstrual age (PMA) and completely regressed by median 49.0 weeks of PMA. The median duration for regression was 8.5 weeks. The zone II ROP and stage 3 ROP had a later time for onset and completion of regression, and longer duration. Anemia and retinal hemorrhage (RH) were identified as independent risk factors for delayed regression by survival analysis.

Conclusions: During spontaneous regression, the fundus appearance is diverse, and the retinal vessels gradually vascularized completely. The time course of regression differs depending on the ROP zone and stage. Anemia and RH are independent risk factors for delayed regression. Further research of the natural course of the regression of ROP is needed to help design effective screening and follow-up plans.
Animal Models for COVID-19: Hamsters, Mouse, Ferret, Mink, Tree Shrew, and Non-human Primates
Authors: Shou Shuyu , Liu Menghui , Yang Yang , Kang Ning , Song Yingying , Tan Dan , Liu Nannan , Wang Feifei , Liu Jing , Xie Youhua
Published: September 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus causing acute respiratory tract infection in humans. The virus has the characteristics of rapid transmission, long incubation period and strong pathogenicity, and has spread all over the world. Therefore, it is of great significance to select appropriate animal models for antiviral drug development and therapeutic effect evaluation. Here, we review and compare the current animal models of SARS-CoV-2.
Models and Processes to Extract Drug-like Molecules From Natural Language Text
Authors: Hong Zhi , Pauloski J. Gregory , Ward Logan , Chard Kyle , Blaiszik Ben , Foster Ian
Published: September 2021

Researchers worldwide are seeking to repurpose existing drugs or discover new drugs to counter the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A promising source of candidates for such studies is molecules that have been reported in the scientific literature to be drug-like in the context of viral research. However, this literature is too large for human review and features unusual vocabularies for which existing named entity recognition (NER) models are ineffective. We report here on a project that leverages both human and artificial intelligence to detect references to such molecules in free text. We present 1) a iterative model-in-the-loop method that makes judicious use of scarce human expertise in generating training data for a NER model, and 2) the application and evaluation of this method to the problem of identifying drug-like molecules in the COVID-19 Open Research Dataset Challenge (CORD-19) corpus of 198,875 papers. We show that by repeatedly presenting human labelers only with samples for which an evolving NER model is uncertain, our human-machine hybrid pipeline requires only modest amounts of non-expert human labeling time (tens of hours to label 1778 samples) to generate an NER model with an F-1 score of 80.5%—on par with that of non-expert humans—and when applied to CORD’19, identifies 10,912 putative drug-like molecules. This enriched the computational screening team’s targets by 3,591 molecules, of which 18 ranked in the top 0.1% of all 6.6 million molecules screened for docking against the 3CLPro protein.
Conformational Characterization of the Co-Activator Binding Site Revealed the Mechanism to Achieve the Bioactive State of FXR
Authors: Kumari Anita , Mittal Lovika , Srivastava Mitul , Pathak Dharam Pal , Asthana Shailendra
Published: September 2021

FXR bioactive states are responsible for the regulation of metabolic pathways, which are modulated by agonists and co-activators. The synergy between agonist binding and ‘co-activator’ recruitment is highly conformationally driven. The characterization of conformational dynamics is essential for mechanistic and therapeutic understanding. To shed light on the conformational ensembles, dynamics, and structural determinants that govern the activation process of FXR, molecular dynamic (MD) simulation is employed. Atomic insights into the ligand binding domain (LBD) of FXR revealed significant differences in inter/intra molecular bonding patterns, leading to structural anomalies in different systems of FXR. The sole presence of an agonist or ‘co-activator’ fails to achieve the essential bioactive conformation of FXR. However, the presence of both establishes the bioactive conformation of FXR as they modulate the internal wiring of key residues that coordinate allosteric structural transitions and their activity. We provide a precise description of critical residue positioning during conformational changes that elucidate the synergy between its binding partners to achieve an FXR activation state. Our study offers insights into the associated modulation occurring in FXR at bound and unbound forms. Thereafter, we also identified hot-spots that are critical to arrest the activation mechanism of FXR that would be helpful for the rational design of its agonists.
Ligand Binding Introduces Significant Allosteric Shifts in the Locations of Protein Fluctuations
Authors: Kumar Ambuj , Jernigan Robert L.
Published: September 2021

Allostery is usually considered to be a mechanism for transmission of signals associated with physical or dynamic changes in some part of a protein. Here, we investigate the changes in fluctuations across the protein upon ligand binding based on the fluctuations computed with elastic network models. These results suggest that binding reduces the fluctuations at the binding site but increases fluctuations at remote sites, but not to fully compensating extents. If there were complete conservation of entropy, then only the enthalpies of binding would matter and not the entropies; however this does not appear to be the case. Experimental evidence also suggests that energies and entropies of binding can compensate but that the extent of compensation varies widely from case to case. Our results do however always show transmission of an allosteric signal to distant locations where the fluctuations are increased. These fluctuations could be used to compute entropies to improve evaluations of the thermodynamics of binding. We also show the allosteric relationship between peptide binding in the GroEL trans-ring that leads directly to the release of GroES from the GroEL-GroES cis-ring. This finding provides an example of how calculating these changes to protein dynamics induced by the binding of an allosteric ligand can regulate protein function and mechanism.
Transduction Efficiency and Immunogenicity of Viral Vectors for Cochlear Gene Therapy: A Systematic Review of Preclinical Animal Studies
Authors: Verdoodt Dorien , Peeleman Noa , Van Camp Guy , Van Rompaey Vincent , Ponsaerts Peter
Published: September 2021

Background: Hearing impairment is the most frequent sensory deficit, affecting 466 million people worldwide and has been listed by the World Health Organization (WHO) as one of the priority diseases for research into therapeutic interventions to address public health needs. Inner ear gene therapy is a promising approach to restore sensorineural hearing loss, for which several gene therapy applications have been studied and reported in preclinical animal studies.

Objective: To perform a systematic review on preclinical studies reporting cochlear gene therapy, with a specific focus on transduction efficiency.

Methods: An initial PubMed search was performed on April 1st 2021 using the PRISMA methodology. Preclinical in vivo studies reporting primary data regarding transduction efficiency of gene therapy targeting the inner ear were included in this report.

Results: Thirty-six studies were included in this review. Transduction of various cell types in the inner ear can be achieved, according to the viral vector used. However, there is significant variability in the applied vector delivery systems, including promoter, viral vector titer, etc.

Conclusion: Although gene therapy presents a promising approach to treat sensorineural hearing loss in preclinical studies, the heterogeneity of methodologies impedes the identification of the most promising tools for future use in inner ear therapies.
Comparison of Microvascular Decompression and Two Isocenters Gamma Knife for the Treatment of Trigeminal Neuralgia Caused by Vertebrobasilar Dolichoectasia
Authors: Zhao Zhen , Chai SongShan , Wang JiaJing , Jiang XiaoBing , Nie ChuanSheng , Zhao HongYang
Published: September 2021

Background: Vertebrobasilar dolichoectasia (VBD) is one of the rare causes of trigeminal neuralgia (TN). The common surgical treatments for patients with TN caused by VBD (VBD-TN) are microvascular decompression (MVD) and Gamma Knife radiosurgery (GKRS). However, the therapeutic effects of the two methods have not been clinically compared, so this study was performed to evaluate the treatment outcomes of MVD and GKRS for patients with VBD-TN.

Methods: The retrospective study was performed from March 2011 to March 2019 in Wuhan Union Hospital. A total of 80 patients diagnosed with VBD-TN were included in this study, and they were divided into the MVD group (n = 46) and GKRS group (n = 34) according to the surgical methods. The imaging data, intraoperative findings, treatment outcomes, and complications of the two groups were analyzed and compared. Meanwhile, the influencing factors of the treatment effect are also explored on the two groups.

Results: Patients who underwent MVD were younger than patients who underwent GKRS (median ages were 61.1 and 65.4 years old, respectively, p = 0.03). The median follow-up was 61.1 months for the MVD group and 56.8 months for the GKRS group. The favorable outcomes [Barrow Neurological Institute (BNI) pain score, BNI scores I–II] occurred in 97.8% of patients treated with MVD and in 78.9% of patients treated with GKRS (p = 0.009). The favorable outcomes in the percentage of patients after MVD 1, 3, 5, and 7 years were 95.7, 85.1, 74.2, and 74.2%, respectively, whereas the corresponding percentages after GKRS were 76.5, 66.2, 56.6, and 47.2%, respectively (p = 0.031). The postoperative complications (except facial numbness) in the MVD group were higher than those in the GKRS group (p = 0.036), but the incidence of new and worsening facial numbness was lower in the GKRS group (p < 0.001).

Conclusions: MVD is superior to GKRS in obtaining and maintaining favorable outcomes for patients with VBD-TN, but it also comes with more complications other than facial numbness. Thus, the treatment program can be tailored to a patient's unique condition and wishes.
Dynamic Ultrasound Assessment of Median Nerve Mobility Changes Following Corticosteroid Injection and Carpal Tunnel Release in Patients With Carpal Tunnel Syndrome
Authors: Lo I-Ning , Hsu Po-Cheng , Huang Yi-Chao , Yeh Chih-Kuang , Yang Yi-Chiang , Wang Jia-Chi
Published: September 2021

Decreased median nerve (MN) mobility was found in patients with carpal tunnel syndrome (CTS) and was inversely associated with symptom severity. It is unclear whether MN mobility can be restored with interventions. This study compared the changes in MN mobility and clinical outcomes after interventions. Forty-six patients with CTS received an injection (n = 23) or surgery (n = 23). Clinical outcomes [Visual Analogue Scale; Boston Carpal Tunnel Questionnaire (BCTQ), which includes the Symptom Severity Scale and Functional Status Scale; median nerve cross-sectional area; and dynamic ultrasound MN mobility parameters (amplitude, and R2 value and curvature of the fitted curves of MN transverse sliding)] were assessed at baseline and 12 weeks after the interventions. At baseline, the BCTQ-Functional Status Scale and median nerve cross-sectional area showed significant inter-treatment differences. At 12 weeks, both treatments had significant improvements in BCTQ-Symptom Severity Scale and Visual Analogue Scale scores and median nerve cross-sectional area, but with greater improvements in BCTQ-Functional Status Scale scores observed in those who received surgery than in those who received injections. MN mobility was insignificantly affected by both treatments. The additional application of dynamic ultrasound evaluation may help to discriminate the severity of CTS initially; however, its prognostic value to predict clinical outcomes after interventions in patients with CTS is limited.
Promoting the Calcium-Uptake Bioactivity of Casein Phosphopeptides in vitro and in vivo
Authors: Liu Guo , Guo Baoyan , Sun Shengwei , Luo Minna , Liu Fei , Miao Jianyin , Tang Jian , Huang Yahui , Cao Yong , Song Mingyue
Published: September 2021

Casein phosphopeptides have been studied widely for their ability to chelate calcium. However, systematic studies on the effects of casein phosphopeptides (CPP) on calcium absorption in vitro and in vivo are scarce. The purities of two commercially available products, CPP1 and CPP2, are 18.37 and 25.12%, respectively. Here, the in vitro calcium binding capacity of CPP2 was 142.56 ± 7.39 mg/g, which was higher than that of CPP1 (107.15 ± 6.27 mg/g). The calcium transport results in a Caco-2 monolayer model indicated that, relative to controls, CPP1 and CPP2 increased calcium transport by 21.78 and 53.68%, respectively. Subsequent animal experiments showed that the CPP2-Ca-H group (1% Ca, 0.4% CPP2) had significant increases in the femur index, serum Ca2+ and serum osteocalcin levels, and femoral Ca content. The CPP2-Ca-H animal also had decreased serum alkaline phosphatase levels, parathyroid hormone content, and urinary pyridinoline content. Overall, our results demonstrated that CPP2 had stronger effects on promoting calcium uptake than CPP1.
Case Report and Literature Review: Primary Pulmonary NUT-Midline Carcinoma
Authors: Zhang Yunxiang , Han Kai , Dong Xiaotong , Hou Qian , Li Tianbao , Li Li , Zhou Gengyin , Liu Xia , Zhao Guifeng , Li Wei
Published: September 2021

Nuclear protein of the testis (NUT) carcinoma is a very rare and aggressive carcinoma characterized by chromosomal rearrangement. NUT-midline carcinoma (NMC) can occur anywhere in the body, but most of the tumors are found in the midline anatomic structure or mediastinum. Pulmonary-originated NMC is extremely rare and often difficult to be distinguished from other poorly differentiated tumors, making the diagnosis awfully challenged in clinical practice. There are less than 100 cases of NUT carcinoma reported so far. In this study, the diagnosis and molecular mechanisms of reported NUT carcinoma cases were reviewed. Furthermore, a case of primary pulmonary NUT-midline carcinoma and its pathological features was reported. The process of pathological identification and genomic analysis for establishing the diagnosis was discussed. We found that NUT carcinoma could be identified by combining CT, H&E staining, immunohistochemistry (IHC), and molecular tests. The development of NUT carcinoma might be associated with mutation of MYC, p63, and MED24 genes and the Wnt, MAPK, and PI3K signaling pathways. Our study provided a detailed molecular mechanistic review on NMC and established a procedure to identify pulmonary NMC.
High Counts of CD68+ and CD163+ Macrophages in Mantle Cell Lymphoma Are Associated With Inferior Prognosis
Authors: Li Philippa , Yuan Ji , Ahmed Fahad Shabbir , McHenry Austin , Fu Kai , Yu Guohua , Cheng Hongxia , Xu Mina L. , Rimm David L. , Pan Zenggang
Published: September 2021

Background

Lymphoma-associated macrophages (LAMs) are key components in the lymphoma microenvironment, which may impact disease progression and response to therapy. There are two major subtypes of LAMs, CD68+ M1 and CD163+ M2. M2 LAMs can be transformed from M1 LAMs, particularly in certain diffuse large B-cell lymphomas (DLBCL). While mantle cell lymphoma (MCL) is well-known to contain frequent epithelioid macrophages, LAM characterization within MCL has not been fully described. Herein we evaluate the immunophenotypic subclassification, the expression of immune checkpoint molecule PD-L1, and the prognostic impact of LAMs in MCL.

Materials and Methods

A total of 82 MCL cases were collected and a tissue microarray block was constructed. Immunohistochemical staining was performed using CD68 and CD163, and the positive cells were recorded manually in four representative 400× fields for each case. Multiplexed quantitative immunofluorescence assays were carried out to determine PD-L1 expression on CD68+ M1 LAMs and CD163+ M2 LAMs. In addition, we assessed Ki67 proliferation rate of MCL by an automated method using the QuPath digital imaging analysis. The cut-off points of optimal separation of overall survival (OS) were analyzed using the X-Tile software, the SPSS version 26 was used to construct survival curves, and the log-rank test was performed to calculate the p-values.

Results

MCL had a much higher count of M1 LAMs than M2 LAMs with a CD68:CD163 ratio of 3:1. Both M1 and M2 LAMs were increased in MCL cases with high Ki67 proliferation rates (>30%), in contrast to those with low Ki67 (<30%). Increased number of M1 or M2 LAMs in MCL was associated with an inferior OS. Moreover, high expression of PD-L1 on M1 LAMs had a slightly better OS than the cases with low PD-L1 expression, whereas low expression of PD-L1 on M2 LAMs had a slightly improved OS, although both were not statistically significant.

Conclusions

In contrast to DLBCL, MCL had a significantly lower rate of M1 to M2 polarization, and the high levels of M1 and M2 LAMs were associated with poor OS. Furthermore, differential PD-L1 expressions on LAMs may partially explain the different functions of tumor-suppressing or tumor-promoting of M1 and M2 LAMs, respectively.
Immunotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck
Authors: Hsieh Ronan W. , Borson Steven , Tsagianni Anastasia , Zandberg Dan P.
Published: September 2021

Head and neck cancer is the 6thmost common cancer worldwide with the most common histology being squamous cell carcinoma (HNSCC). While the majority of patients present at a stage where curative intent therapy is possible, when patients recur and/or develop metastatic disease, outcomes are generally poor, especially with systemic therapy alone, and they lag behind other solid tumors. Over the last decade immunotherapy has revolutionized the field of oncology, and anti-PD-1-based therapy has changed the standard of care in recurrent/metastatic (R/M) HNSCC as well. With these gains have come new questions to continue to move the field forward. In this review, we discuss the tumor immune microenvironment and predictive biomarkers and current status and future directions for immunotherapy in recurrent/metastatic head and neck cancer.
S100 Proteins in Pancreatic Cancer: Current Knowledge and Future Perspectives
Authors: Wu Yu , Zhou Qi , Guo Fangyue , Chen Mingming , Tao Xufeng , Dong Deshi
Published: September 2021

Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC.
Non-Small Cell Lung Cancer: Challenge and Improvement of Immune Drug Resistance
Authors: Kong Fanming , Wang Ziwei , Liao Dongying , Zuo Jinhui , Xie Hongxia , Li Xiaojiang , Jia Yingjie
Published: September 2021

Lung cancer is the leading cause of cancer deaths in the world. At present, immunotherapy has made a great breakthrough in lung cancer treatment. A variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4. However, in the actual clinical process, about 30%–50% of patients still do not receive long-term benefits. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the immune mechanism of immune checkpoint inhibitor resistance, various combination strategies, and prediction of biomarkers to overcome resistance in order to accurately screen out the advantageous population, expand the beneficiary population, and enable precise and individualized medicine.
Association Between Assisted Reproductive Technology and White Matter Injury in Premature Infants: A Case-Control Study
Authors: Huang Xuejiao , Fu JianHua
Published: September 2021

Objectives: Whether there is a link between assisted reproductive technology (ART) and brain damage in premature infants remains unclear. The aim of this study was to determine whether premature infants conceived by ART are at a greater risk of developing white matter injury (WMI), as detected by magnetic resonance imaging (MRI) or diffusion-weighted imaging (DWI) within 14 days, than those naturally conceived (NC).

Methods: A retrospective case-control study was conducted on singleton premature infants with a gestational age of ≥28 weeks and <34 weeks delivered between 2017 and 2019 at Shengjing Hospital, China Medical University. This study included 638 live births that were stratified into case group (n = 218) and control group (n = 420), depending on the presence or absence of WMI. The exposure proportion of ART was compared between the case and control groups, and a logistic regression model was used to identify whether ART was an independent risk factor for WMI.

Results: In the univariate analysis, the exposure proportion of ART conception was higher in cases than in controls (12.84 vs. 7.38%, p = 0.024). According to the multivariable analysis, after adjustment for other variables, the association between ART and WMI remained significant (1.82; 95% confidence interval, 1.04–3.21; P = 0.038).

Conclusions: Singleton premature infants conceived by ART have a higher risk of WMI than NC infants. Given that ART is an independent risk factor for WMI in premature infants, more attention should be paid to neurodevelopmental outcomes in this group.
Case Report: Clinical Features of a Chinese Boy With Epileptic Seizures and Intellectual Disabilities Who Carries a Truncated NUS1 Variant
Authors: Zhang Pingli , Cui Di , Liao Peiyuan , Yuan Xiang , Yang Nuan , Zhen Yuanyuan , Yang Jing , Huang Qikun
Published: September 2021

The mental retardation-55 with seizures (MRD55) is a rare genetic disease characterized by developmental delay, intellectual disability, language delay and multiple types of epileptic seizures. It is caused by pathogenic variants of the NUS1 gene, which encodes Nogo-B receptor (NgBR), a necessary subunit for the glycosylation reactions in mammals. To date, 25 disease-causing mutations of NUS1 have been reported, which are responsible for various diseases, including dystonia, Parkinson's disease, developmental and epileptic encephalopathy as well as congenital disorder of glycosylation. In addition, only 9 of these mutations were reported with detailed clinical features. There are no reports about Chinese cases with MRD55. In this study, a novel, de novo pathogenic variant of NUS1 (c.51_54delTCTG, p.L18Tfs*31) was identified in a Chinese patient with intellectual disability and epileptic seizures. This pathogenic variant resulted in truncated NgBR proteins, which might be the cause of the clinical features of the patient. Oxcarbazepine was an effective treatment for improving speech and movement of the patient, who consequently presented with no seizure. With this novel pathogenic variant found in NUS1, we expand the genotype spectrum of MRD55 and provide valuable insights into the potential genotype-phenotype correlation.
Effect of Pharmacogenetics Variations on Praziquantel Plasma Concentrations and Schistosomiasis Treatment Outcomes Among Infected School-Aged Children in Tanzania
Authors: Mnkugwe Rajabu Hussein , Minzi Omary , Kinung’hi Safari , Kamuhabwa Appolinary , Aklillu Eleni
Published: September 2021

Studies on pharmacogenetics of praziquantel (PZQ) and its relevance on plasma drug concentrations and schistosomiasis treatment outcomes are lacking. We investigated the effect of pharmacogenetics variations of PZQ on plasma drug levels and schistosomiasis treatment outcomes among infected Tanzanian school-aged children. A total of 340 Schistosoma mansoni infected children were enrolled and treated with single-dose PZQ. Stool samples analysis was done by thick smear Kato-Katz technique, and treatment efficacy was assessed at 3-weeks post-treatment. Safety was assessed within 4 h after PZQ intake. Plasma samples were collected at 4 h post-dose, and PZQ and trans-4-OH-PZQ concentrations were quantified using UPLCMS/MS. Genotyping for CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), and CYP2C9 (*2, *3) were done by Real-Time PCR. The median age (range) of the study participants was 12 years (7–17). There was a significant association of CYP2C19 genotypes with PZQ concentrations and its metabolic ratio (trans-4-OH-PZQ/PZQ). PZQ concentration was significantly higher among CYP2C19 (*2, *3) carriers than CYP2C19 *1/*1 and CYP2C19 *17 carriers (ultra-rapid metabolizers) (p = 0.04). The metabolic ratio was significantly higher among CYP2C19*17 carriers than CYP2C19 (*2, *3) carriers (p = 0.01). No significant effect of CYP3A4, CYP3A5, CYP2C19, and CYP2C9 genotypes on treatment efficacy or adverse events were observed. Baseline infection intensity and CYP3A5 genotype were significant predictors of treatment associated-adverse events. In conclusion, CYP2C19 genotype significantly affects plasma PZQ concentration and its metabolic ratio. For the first time, we report the importance of pharmacogenetic variation for the treatment of schistosomiasis, a neglected tropical disease.
Huangbai Liniment Ameliorates Skin Inflammation in Atopic Dermatitis
Authors: Zheng Ting , Fan Miao , Wei Yunbo , Feng Jinhong , Zhou Pengcheng , Sun Xin , Xue Anqi , Qin Cheng Xue , Yu Di
Published: September 2021

Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3–4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1β, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.
Pharmacological Properties of 2,4,6-Trihydroxy-3-Geranyl Acetophenone and the Underlying Signaling Pathways: Progress and Prospects
Authors: Chan Yee Han , Liew Kong Yen , Tan Ji Wei , Shaari Khozirah , Israf Daud Ahmad , Tham Chau Ling
Published: September 2021

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a bioactive phloroglucinol compound found in Melicope pteleifolia (Champ. ex Benth.) T.G.Hartley, a medicinal plant vernacularly known as “tenggek burung”. A variety of phytochemicals have been isolated from different parts of the plant including leaves, stems, and roots by using several extraction methods. Specifically, tHGA, a drug-like compound containing phloroglucinol structural core with acyl and geranyl group, has been identified in the methanolic extract of the young leaves. Due to its high nutritional and medicinal values, tHGA has been extensively studied by using various experimental models. These studies have successfully discovered various interesting pharmacological activities of tHGA such as anti-inflammatory, endothelial and epithelial barrier protective, anti-asthmatic, anti-allergic, and anti-cancer. More in-depth investigations later found that these activities were attributable to the modulatory actions exerted by tHGA on specific molecular targets. Despite these findings, the association between the mechanisms and signaling pathways underlying each pharmacological activity remains largely unknown. Also, little is known about the medicinal potentials of tHGA as a drug lead in the current pharmaceutical industry. Therefore, this mini review aims to summarize and relate the pharmacological activities of tHGA in terms of their respective mechanisms of action and signaling pathways in order to present a perspective into the overall modulatory actions exerted by tHGA. Besides that, this mini review will also pinpoint the unexplored potentials of this compound and provide some valuable insights into the potential applications of tHGA which may serve as a guide for the development of modern medication in the future.
The Traditional Chinese Medicine Compound Huangqin Qingre Chubi Capsule Inhibits the Pathogenesis of Rheumatoid Arthritis Through the CUL4B/Wnt Pathway
Authors: Wang Xiao , Chang Jun , Zhou Guoliang , Cheng Chenglong , Xiong Youyi , Dou Jinfeng , Cheng Gen , Miao Chenggui
Published: September 2021

The pathogenesis of rheumatoid arthritis (RA) is still not fully clarified, and the development of therapeutic drugs for RA is particularly urgent. Our group studies a possibility that circ_ 0015756/miR-942-5p may participate in the pathogenesis of RA through disordered Cullin 4B (CUL4B) and the traditional Chinese medicine compound Huangqin Qingre Chubi Capsule (HQC) may inhibit the pathogenesis of RA through the CUL4B/Wnt pathway. Data showed that the expression of circ_0015756 increased not only in fibroblast-like synoviocytes (FLS) of RA, but also in synovium and FLS of CIA mice, and the expression of miR-942-5p decreased. Abnormal circ_0015756 up-regulated the CUL4B expression and activated the canonical Wnt signaling pathway by inhibiting the expression of miR-942-5p. Circ_0015756 participated in the pathogenesis of RA and promoted the abnormal proliferation of FLS. Further, circ_0015756 activated the secretion of IL-1 and IL-8 and promoted the production of RA pathological gene MMP3 and fibronectin. Further analysis showed that HQC inhibited the pathogenesis of RA through the CUL4B/Wnt pathway, and the specific target was CUL4B. HQC interfered with the effects of circ_0015756 on the pathogenesis of RA by inhibiting the CUL4B, showing a good therapeutic effect on RA.
Longitudinal Component Properties of Circularly Polarized Terahertz Vortex Beams
Authors: Wang Miao , Wang Xinke , Han Peng , Sun Wenfeng , Feng Shengfei , Ye Jiasheng , Zhang Yan
Published: September 2021

A circularly polarized vortex beam possesses similar focusing properties as a radially polarized beam. This type of beam is highly valuable for developing optical manufacturing technology, microscopy, and particle manipulation. In this work, a left-hand circularly polarized terahertz (THz) vortex beam (CPTVB) is generated by utilizing a THz quarter wave plate and a spiral phase plate. Focusing properties of its longitudinal component Ez are detailedly discussed on the simulation and experiment. With reducing the F-number of the THz beam and comparing with a transverse component Ex of a general circularly polarized THz beam, the simulation results show that the focal spot size and intensity of its Ez component can reach 87 and 50% of Ex under a same focusing condition. In addition, the experimental results still demonstrate that the left-hand CPTVB can always maintain fine Ez focusing properties in a broad bandwidth, which manifest the feasibility of this class of THz beams.
MSCs Therapy Reverse the Gut Microbiota in Hypoxia-Induced Pulmonary Hypertension Mice
Authors: Luo Lingjie , Chen Qinhua , Yang Lei , Zhang Zhenxia , Xu Jihong , Gou Deming
Published: September 2021

Mesenchymal stem cell (MSC) therapy is a promising therapeutic approach based on its strong effect on pulmonary hypertension (PH) in rats. However, the detailed mechanism of MSC therapy remains unknown. Alterations in the gut microbiota were found in both type 1 pulmonary arterial hypertension patients and hypoxia/SU5416- or monocrotaline (MCT)-induced PH rats. However, whether the therapeutic mechanism of MSCs is associated with the gut microbiota is poorly understood. Here, we found that gut microbiota homeostasis was disrupted in hypoxia-induced PH mice due to the increased Firmicutes-to-Bacteroidetes (F/B) ratio; enhanced abundances of harmful Marinifilaceae, Helicobacteraceae, and Lactobacillaceae; and decreased abundances of beneficial Bacteroidaceae, Prevotellaceae, Tannerellaceae, and Lachnospiraceae. Unexpectedly, reverses of the increase in disease-associated microbiota and decrease in anti-inflammatory and immunomodulatory functional microbiota were observed in the MSC-treated group. We also identified harmful Erysipelotrichaceae, Alphaproteobacteria, Christensenella timonensis, Coriobacteriales, and Rhodospirillales that may serve as gut microbiota biomarkers of hypoxia-induced PH mice. Micrococcaales, Nesterenkonia, Anaerotruncus, and Tyzzerella may serve as gut microbiota biomarkers of MSC-treated mice. In summary, MSC treatment suppresses hypoxia-induced pulmonary hypertension in mice, and alterated gut microbiota may play a role in the development and progression of PH. The mechanism of MSC therapy is associated with various metabolic pathways of the gut microbiota in hypoxia model PH mice.
Improvement of Phosphorus Use Efficiency in Rice by Adopting Image-Based Phenotyping and Tolerant Indices
Authors: Bhatta Bishal Binaya , Panda Rajendra Kumar , Anandan Annamalai , Pradhan Nirakar Susanta Narayan , Mahender Anumalla , Rout Kumbha Karna , Patra Bhaskar Chandra , Ali Jauhar
Published: September 2021

Phosphorus is one of the second most important nutrients for plant growth and development, and its importance has been realised from its role in various chains of reactions leading to better crop dynamics accompanied by optimum yield. However, the injudicious use of phosphorus (P) and non-renewability across the globe severely limit the agricultural production of crops, such as rice. The development of P-efficient cultivar can be achieved by screening genotypes either by destructive or non-destructive approaches. Exploring image-based phenotyping (shoot and root) and tolerant indices in conjunction under low P conditions was the first report, the epicentre of this study. Eighteen genotypes were selected for hydroponic study from the soil-based screening of 68 genotypes to identify the traits through non-destructive (geometric traits by imaging) and destructive (morphology and physiology) techniques. Geometric traits such as minimum enclosing circle, convex hull, and calliper length show promising responses, in addition to morphological and physiological traits. In 28-day-old seedlings, leaves positioned from third to fifth played a crucial role in P mobilisation to different plant parts and maintained plant architecture under P deficient conditions. Besides, a reduction in leaf angle adjustment due to a decline in leaf biomass was observed. Concomitantly, these geometric traits facilitate the evaluation of low P-tolerant rice cultivars at an earlier stage, accompanying several stress indices. Out of which, Mean Productivity Index, Mean Relative Performance, and Relative Efficiency index utilising image-based traits displayed better responses in identifying tolerant genotypes under low P conditions. This study signifies the importance of image-based phenotyping techniques to identify potential donors and improve P use efficiency in modern rice breeding programs.
Opportunity or Risk? Appraisal and Affect Mediate the Effect of Task Framing on Working Memory Performance in University Students
Authors: Chen Luxi , Qu Li
Published: September 2021

Working memory (WM) is crucial for reasoning, learning, decision-making and academic achievement. In diverse contexts, how a task is framed pertaining to its demands and consequences can influence participants' task performance by modifying their cognitive appraisals. However, less is known about the effect of task framing on WM performance and the mechanisms. This study examined whether opportunity- and risk-focused task framing would influence university students' WM performance by altering their cognitive appraisals and affective experiences. Ninety-seven university students were randomly assigned to one of the three framing conditions (Opportunity, Risk, vs. Null), and received instructions that differed in consequences (gain for top performers, loss for poor performers, vs. null), goals (approach, avoidance, vs. neutral), and feedback on personal competence (adequate, inadequate, vs. null). Challenge and threat appraisals, affect, and WM performance were measured before and after task framing. Results showed that opportunity-focused task framing improved students' WM performance, whilst risk-focused task framing increased threat appraisal and decreased positive affect, and that challenge appraisal was not altered in any condition. Female students were influenced by task framing to a greater extent than were male students. Mediation analysis revealed that the alteration of threat appraisal and the change in positive affect mediated the effect of task framing on WM performance. Findings highlight the important role of modifying cognitive appraisals and affective responses in optimizing cognitive performance.