bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic Review and Meta-Analysis on the Number of Adjuvant Temozolomide Cycles in Newly Diagnosed Glioblastoma
Authors: Attarian Fahimeh , Taghizadeh-Hesary Farzad , Fanipakdel Azar , Javadinia Seyed Alireza , Porouhan Pejman , PeyroShabany Babak , Fazilat-Panah Danial
Published: November 2021

Background

In newly diagnosed glioblastoma, radiation with concurrent and adjuvant (six cycles) temozolomide (TMZ) is the established standard of postsurgical care. However, the benefit of extending adjuvant TMZ therapy beyond six cycles has remained unknown.

Methods

We searched PubMed, Web of Science, Scopus, and Embase up to October 1, 2021. The search keywords were “glioblastoma,” “adjuvant chemotherapy,” and their synonyms. The data of randomized clinical trials were extracted and included in this meta-analysis if they had reported patients’ median overall survival (OS) or median progression-free survival (PFS). The standard and extended chemotherapy regimens were considered as adjuvant TMZ up to six cycles and beyond six cycles (up to a total of 12 cycles), respectively. The median OS and median PFS were pooled and compared.

Results

Four studies consisting of 882 patients (461 patients for the standard chemotherapy group and 421 patients for the extended chemotherapy group) were included in this meta-analysis. The extended TMZ regimen was associated with a nonsignificant improvement in PFS [12.0 months (95% CI 9.0 to 15.0) vs. 10.0 months (95% CI 7.0 to 12.0), P = 0.27] without corresponding improvement in OS [23.0 months (95% CI 19.0 to 27.0) and 24.0 months (95% CI 20.0 to 28.0), P = 0.73].

Conclusions

In newly diagnosed glioblastoma, continuing adjuvant TMZ beyond six cycles did not shown an increase neither in PFS nor OS.
Investigation of Suitable Detection Angles for Carbon-Ion Radiotherapy Monitoring in Depth by Means of Secondary-Ion Tracking
Authors: Ghesquière-Diérickx Laura , Schlechter Annika , Félix-Bautista Renato , Gehrke Tim , Echner Gernot , Kelleter Laurent , Martišíková Mária
Published: December 2021

The dose conformity of carbon-ion beam radiotherapy, which allows the reduction of the dose deposition in healthy tissue and the escalation of the dose to the tumor, is associated with a high sensitivity to anatomical changes during and between treatment irradiations. Thus, the monitoring of inter-fractional anatomical changes is crucial to ensure the dose conformity, to potentially reduce the size of the safety margins around the tumor and ultimately to reduce the irradiation of healthy tissue. To do so, monitoring methods of carbon-ion radiotherapy in depth using secondary-ion tracking are being investigated. In this work, the detection and localization of a small air cavity of 2 mm thickness were investigated at different detection angles of the mini-tracker relative to the beam axis. The experiments were conducted with a PMMA head phantom at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. In a clinic-like irradiation of a single field of 3 Gy (RBE), secondary-ion emission profiles were measured by a 2 cm2 mini-tracker composed of two silicon pixel detectors. Two positions of the cavity in the head phantom were studied: in front and in the middle of the tumor volume. The significance of the cavity detection was found to be increased at smaller detection angles, while the accuracy of the cavity localization was improved at larger detection angles. Detection angles of 20° – 30° were found to be a good compromise for accessing both, the detectability and the position of the air cavity along the depth in the head of a patient.
Prognostic Value of Thyroid Hormone Ratio in Patients With Advanced Metastatic Renal Cell Carcinoma: Results From the Threefour Study (Meet-URO 14)
Authors: Maruzzo Marco , Verzoni Elena , Vitale Maria Giuseppa , Dionese Michele , Buti Sebastiano , Galli Luca , Zivi Andrea , Watutantrige-Fernando Sara , Zielli Teresa , Zanardi Elisa , Sabbatini Roberto , Basso Umberto , Zagonel Vittorina , Procopio Giuseppe
Published: November 2021

Background

Thyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet.

Materials and Methods

We recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS.

Results

We analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p<0.001); median OS in the three groups were 36.5, 48.6, and 70.5 months respectively (p =0.006). The low fT3/fT4 ratio maintained its prognostic role at the multivariate analysis independently from IMDC and other well-established prognostic factors. The development of iatrogenic hypothyroidism was not associated with a better outcome.

Conclusion

We found that baseline thyroid hormone impairment, represented by a low fT3/fT4 ratio, is a strong prognostic factor in patients treated for mRCC in first line setting and is independent of other parameters currently used in clinical practice.
The Role of Decorin and Biglycan Signaling in Tumorigenesis
Authors: Diehl Valentina , Huber Lisa Sophie , Trebicka Jonel , Wygrecka Malgorzata , Iozzo Renato V. , Schaefer Liliana
Published: December 2021

The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
Predictive Validity of Developmental Screening Questionnaires for Identifying Children With Later Cognitive or Educational Difficulties: A Systematic Review
Authors: Schonhaut Luisa , Maturana Andres , Cepeda Olenkha , Serón Pamela
Published: November 2021

Context: Parent/caregiver completing developmental screening questionnaires (DSQs) for children before 5 years of age is currently recommended. The DSQs recommended by the American Academy of Pediatrics (AAP) are the Ages and Stages Questionnaires (ASQ), Parents' Evaluation of Developmental Status (PEDS), and the Survey of Well-being of Young Children (SWYC). Nevertheless, their predictive validity has not been well-established.

Objective: To assess in the current literature, the value of AAP-recommended DSQs (ASQ, PEDS, SWYC) administered between 0 and 5 years of age, for predicting long-term cognitive achievement and/or school performance (CA/SP), after 1 year or more of evaluation and at/or after age 5 years, in the general population.

Data Sources: Cochrane, MEDLINE PubMed, CINAHL, EMBASE, Web of Science, Scielo, and Scopus databases (until March 2021).

Study Selection: Two authors selected the studies. Forward and backward citation follow-up was done; authors of DSQ were contacted to identify additional studies.

Data Extraction: Cohorts were identified, and authors of selected studies were contacted to corroborate and complete extracted data.

Results: Thirty-two publications, corresponding to 10 cohorts, were included. All cohorts used ASQ. Only cohort using PEDS was identified but did not meet the inclusion criteria. No cohorts conducted with SWYC were identified. Associations between ASQ and CA/SP were extracted for eight cohorts. The odds ratios were >3, and the area under the curve was 0.66–0.87. A trade-off between sensitivity and specificity was observed.

Limitations: Heterogeneity in population characteristics and in DSQ adaptations.

Conclusions: A positive association between ASQ and later CA/SP was found in different social, cultural, and economic settings. Additional studies are necessary to determine the impact factors in the predictive capacity of DSQs.

Systematic Review Registration: PROSPERO, identifier: CRD42020183883.
Increased Frequency of CTLA-4 and PD-1 Expressing Regulatory T Cells and Basophils With an Activating Profile in Infants With Moderate-to-Severe Atopic Dermatitis Hypersensitized to Food Allergens
Authors: Bilbao Agurtzane , Pérez-Garay Raquel , Rius Idoia , Irurzun Alex , Terrén Iñigo , Orrantia Ane , Astarloa-Pando Gabirel , Borrego Francisco , Zenarruzabeitia Olatz
Published: December 2021

Background: Infants with severe atopic dermatitis (AD) may be sensitized to foods that have not been introduced into their diet, posing a risk for developing an immediate hypersensitivity reaction on the first exposure to the food to which they are sensitized. The aim of this work was to perform an analysis of the sensitization profile in infants with moderate-to-severe AD and to identify cellular and molecular markers for food allergy (FA).

Methods: Blood samples from healthy donors and children with moderate-to-severe AD were studied. Specific IgE to several allergens were determined using ImmunoCAP FEIA system and ISAC technology. Furthermore, using flow cytometry-based studies, basophils and regulatory T (Treg) cells were phenotypically characterized.

Results: 90% of children with AD were sensitized to food antigens before introducing them into the diet, and 100% developed FA. Phenotypic analysis showed a significantly higher percentage of CTLA-4 and PD-1 expressing Treg cells in AD patients than in healthy controls. Basophils from patients exhibited a marked reduction in the expression of CD300a, higher expression of FcεRI and CXCR4, and to some extent higher expression of CD63 and CD300c.

Conclusions: Infants with moderate-to-severe AD are at high risk of being sensitized to food allergens. Therefore, to avoid allergic reactions, broad-spectrum sensitization studies are necessary before introducing complementary diet. Increased expression of CTLA-4 and PD-1 suggests greater suppressive potential of Treg cells in infants with AD than healthy controls. Furthermore, our results suggest a role for CD300 molecules on circulating basophils as possible biomarkers for FA susceptibility.
The Characteristics of Natural Killer Cells and T Cells Vary With the Natural History of Chronic Hepatitis B in Children
Authors: Zhou Yingzhi , He Yi , Chang Yunan , Peng Xiaorong , Zhao Ruiqiu , Peng Mingli , Hu Peng , Ren Hong , Chen Min , Xu Hongmei
Published: December 2021

Background and Aims: The immune status of children with chronic hepatitis B (CHB) in different phases is still unclear. The aim of this study was to investigate the phenotype and cytokine-producing ability of natural killer (NK) and T cells and to better understand the immune characteristics of children with different phases of CHB.

Methods: Treatment-naive children with CHB were divided into groups with different clinical phases of CHB. Fresh peripheral blood drawn from hepatitis B virus (HBV)-infected and healthy children was processed to perform flow cytometric analysis.

Results: A total of 112 treatment-naive children with CHB and 16 comparable healthy controls were included in this study. The expression of HLA-DR on NK cells and CD38 on T cells were upregulated, especially in the IA phase, in children with CHB compared with healthy controls. The ability of circulating NK cells instead of CD8+ T cells to produce IFN-γ in children with CHB was slightly increased, but TNF-α production seemed to be decreased compared with that in healthy controls. The expression of some activation markers varied among children with different phases of CHB, especially the higher CD38 expression found on T cells in the IA phase. Regression analysis revealed that IFN-γ and TNF-α production by NK cells and CD8+ T cells seemed to have positive correlations with ALT elevation and an activated status of NK cells or T cells.

Conclusion: NK cells and T cells tended to be phenotypically activated (especially in the IA phase) in children with CHB compared with healthy controls. However, their cytokine-producing function was not obviously elevated, especially IFN-γ production by CD8+ T cells. More studies investigating the mechanism and observing the longitudinal changes in the immune status in children with CHB are needed.
Prognostic Value of Biomarkers in Children and Adolescents With Orthostatic Intolerance
Authors: Yan Huijuan , Wang Shuo , Cai Hong , Zhang Juan , Liu Ping , Wang Yuwen , Zou Runmei , Wang Cheng
Published: November 2021

Orthostatic intolerance (OI) refers to a series of symptoms that occur during upright standing, which can be relieved when returned to the supine position. OI is a common cause of syncope in children and adolescents. In recent years, more and more studies have been carried out to assess the prognosis of OI by using biomarkers, among which, flow-mediated vasodilation, left ventricular ejection fraction and fractional shortening, hemodynamic change during head-up tilt test, detection of 24-h urinary sodium excretion, body mass index, midregional pro-adrenomedullin, and erythrocytic H2S producing rate are relatively stable, inexpensive, and easy to obtain. With the help of biomarkers, individualized treatment can be carried out to improve the long-term prognosis of children and adolescents with OI. This article reviews the prognostic value of biomarkers in children and adolescents with OI.
High Rate of Cytomegalovirus Detection in Cholestatic Preterm Infants
Authors: Teng Jonas , Elwin Anne , Omarsdottir Soley , Aquilano Giulia , Vanpee Mireille , Nemeth Antal , Rahbar Afsar , Bohlin Kajsa , Fischler Björn , Söderberg-Nauclér Cecilia
Published: November 2021

Objectives: To evaluate the prevalence of cytomegalovirus (CMV) infection in preterm infants with cholestasis.

Study design: Preterm infants (<37 weeks gestational age) with cholestasis were tested for CMV DNA using Taqman PCR in blood cells from sedimented whole blood, plasma, and urine. Infants were regarded as positive for CMV if any sample was tested positive. Their mothers were tested for CMV serostatus simultaneously. A control group of non-cholestatic preterm infants, and their mothers, were tested at a similar age.

Results: A total of 69 preterm infants with a median gestational age of 26 weeks and 5 days were included, 45 cholestatic and 24 non-cholestatic. Of the cholestatic infants, 31/45 (69%) were CMV positive vs. 3/24 (13%) of the non-cholestatic infants (p < 0.001). Cholestatic infants were equally preterm as the non-cholestatic ones, but were more severely ill. After adjusting for the risk factors necrotizing enterocolitis, prolonged parenteral nutrition, and gestational age, being CMV positive remained significantly associated with cholestasis in a multivariable logistic regression model. Characteristics of CMV-positive and -negative cholestatic infants showed differences only for necrotizing enterocolitis, occurring in 55% (17/31) of CMV positive vs. 21% (3/14) of CMV negative (p = 0.054), and mortality. Eight cholestatic CMV-positive infants died (26%) vs. none of the CMV-negative infants (p = 0.044).

Conclusions: CMV DNA was detected in two out of three cholestatic preterm infants, by far more often than in the non-cholestatic control group. Cholestasis with simultaneous detection of CMV DNA may be associated with increased mortality.
Feeding Difficulty Among Chinese Toddlers Aged 1–3 Years and Its Association With Health and Development
Authors: Ren Zhongxia , Lan Hanglian , Szeto Ignatius Man-Yau , Yang Chenlu , Zhang Jian , Li Pin , Li Jingwen , Wang Peiyu , Zhang Yumei , Zhao Ai
Published: November 2021

Feeding problems are biopsychosocial in nature and have a great influence on children's growth. The aim of this study was to profile the status and possible influencing factors of feeding difficulty among normal Chinese toddlers, and to investigate its association with health and development. This study is a part of the Young Investigation (YI study) conducted in 10 cities in China. Data from 924 children aged 1–3 years were analyzed. Data on socio-demographic factors, feeding behaviors, self-reported diseases, and anthropometry parameters were collected. Blood samples were drawn to determine hemoglobin levels. Feeding difficulty was evaluated by the Montreal Children's Hospital Feeding Scale (MCH-FS). Ages and Stages Questionnaires, Third Edition (ASQ-3) were used to assess developmental progress. Multivariable analyses were performed to explore the potential associations. The mean total score of the MCH-FS was 35.21 ± 12.90 and the highest scored item was “acting up/making a big fuss during mealtimes.” Feeding difficulty occurred more often among children with picky eating behavior or whose caregivers once used the strategy of pre-mastication. Children with feeding difficulty had lower intakes of cereals, vegetables, and fruits, and were more likely to suffer from diarrhea (OR, 2.04; 95%CI: 1.32, 3.11) or constipation (OR, 2.04; 95%CI: 1.27, 3.24), but not anemia. Feeding difficulty was also negatively associated with weight, height, head circumference and mid-upper-arm circumference-related Z-scores (P all < 0.05). In addition, it was related to poorer fine motor skills, personal and social skills, and total scores of ASQ-3 (β, −9.00; 95%CI: −15.11, −2.89). Feeding difficulty assessed by MCH-FS showed a negative association with children's health and development, supporting the need for early identification.
A Novel Mutation c.841C>T in COPA Syndrome of an 11-Year-Old Boy: A Case Report and Short Literature Review
Authors: Zeng Jingxia , Hao Jing , Zhou Wei , Zhou Zhaoqun , Miao Hongjun
Published: November 2021

COPA syndrome is a rare autosomal dominant disorder with auto-immune and auto-inflammatory abnormalities. This disease is caused by mutations of COPα, a protein that functions in the retrograde transport from the Golgi to the ER. Here we report the first COPA case of an 11-year-old boy with c.841C>T, p.R281W mutation. The arginine at position 281 was located in a highly evolutionary-conserved region. Immunosuppressive drugs and corticosteroids might not improve the long-term outcome of COPA patients. For patients with pulmonary disease, polyarthritis and/or kidney disorder, and suspected of COPA, genetic analysis should be conducted promptly for early diagnosis.
Late Effects After Haematopoietic Stem Cell Transplantation in ALL, Long-Term Follow-Up and Transition: A Step Into Adult Life
Authors: Diesch-Furlanetto Tamara , Gabriel Melissa , Zajac-Spychala Olga , Cattoni Alessandro , Hoeben Bianca A. W. , Balduzzi Adriana
Published: November 2021

Haematopoietic stem cell transplant (HSCT) can be a curative treatment for children and adolescents with very-high-risk acute lymphoblastic leukaemia (ALL). Improvements in supportive care and transplant techniques have led to increasing numbers of long-term survivors worldwide. However, conditioning regimens as well as transplant-related complications are associated with severe sequelae, impacting patients' quality of life. It is widely recognised that paediatric HSCT survivors must have timely access to life-long care and surveillance in order to prevent, ameliorate and manage all possible adverse late effects of HSCT. This is fundamentally important because it can both prevent ill health and optimise the quality and experience of survival following HSCT. Furthermore, it reduces the impact of preventable chronic illness on already under-resourced health services. In addition to late effects, survivors of paediatric ALL also have to deal with unique challenges associated with transition to adult services. In this review, we: (1) provide an overview of the potential late effects following HSCT for ALL in childhood and adolescence; (2) focus on the unique challenges of transition from paediatric care to adult services; and (3) provide a framework for long-term surveillance and medical care for survivors of paediatric ALL who have undergone HSCT.
Histopathologic Findings Associated With Matrix Metalloproteinases Proceeding to Recurrence of Primary Spontaneous Pneumothorax in Adolescents
Authors: Chiu Chih-Yung , Chen Jim-Ray , Yin Shun-Ying , Wang Chia-Jung , Chen Tzu-Ping , Hsieh Tsan-Yu
Published: December 2021

Background:Primary spontaneous pneumothorax is potentially life-threatening, and its recurrence is always a serious problem. Pathological examination provides molecular insights into the pathophysiology of primary spontaneous pneumothorax.

Objectives:To investigate the association of histopathologic features of primary spontaneous pneumothorax with matrix metalloproteinase expression and their relevance to the recurrence.

Methods:A total of 217 tissue section slides in 172 adolescent patients with primary spontaneous pneumothorax were retrospectively reviewed from January 2001 to June 2020. All histopathologic features were recorded and pathologic findings related to ipsilateral recurrence and second surgery were analyzed. Serum levels of matrix metalloproteinases were prospectively measured in 25 primary spontaneous pneumothorax patients receiving surgery and 18 healthy controls. Their relevance to the histopathologic features of primary spontaneous pneumothorax related to its recurrence was also examined.

Results:The major presenting histopathologic findings of primary spontaneous pneumothorax were bleb/bulla (98%) followed by fibrosis (68%). Low prevalence of the pathologic findings of granulation tissue and macrophage accumulation were significantly associated with recurrent primary spontaneous pneumothorax, whereas fibrosis was significantly higher in patients receiving more than once surgery. Furthermore, the ratios of matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were significantly higher in theses pathological findings as well as multinucleated giant cells and mesothelial cell hyperplasia in comparison with healthy controls.

Conclusions:Low prevalence of macrophage accumulation and granulation tissue related to the overexpression of matrix metalloproteinase-2 and−9 activities may contribute to healing impairment and primary spontaneous pneumothorax recurrence.
Efficacy and Safety of Traditional Chinese Medicine Injections for Heart Failure With Reduced Ejection Fraction: A Bayesian Network Meta-Analysis of Randomized Controlled Trials
Authors: Lin Shanshan , Shi Qingyang , Ge Zhao , Liu Yangxi , Cao Yawen , Yang Ying , Zhao Zhiqiang , Bi Yingfei , Hou Yazhu , Wang Shuai , Wang Xianliang , Mao Jingyuan
Published: December 2021

Background: Heart failure as an important issue in global public health, has brought a heavy economic burden. Traditional Chinese medicine injections (TCMIs) have significant effects on heart failure with reduced ejection fraction (HFrEF). However, it is difficult for clinicians to identify the differences in clinical efficacy and safety of various TCMIs. The purpose of this study is to compare the efficacy and safety of various TCMIs for treating HFrEF by conducting a Bayesian network meta-analysis (NMA) and to further provide references for clinical decision-making.

Methods: The clinical randomized controlled trials of TCMIs for treating HFrEF were searched in seven database from inception to August 3rd, 2021. The Cochrane collaboration’s tool was used to assess the risk of bias. NMA was performed in a Bayesian hierarchical framework. The surface under the cumulative ranking curve (SUCRA), the multi-dimensional efficacy analysis, the comparison-adjusted funnel plot, and the node-splitting analysis were conducted using R software.

Results: A total of 107 eligible RCTs involving 9,073 HFrEF patients and 6 TCMIs were included. TCMIs include Huangqi injection (HQ) also called Astragalus injection, Shenfu injection (SF), Shengmai injection (SGM), Shenmai injection (SM), Xinmailong injection (XML), and Yiqifumai lyophilized injection (YQFM). The results of NMA and SUCRA showed that with conventional treatment (CT) as a common control, in terms of clinical efficacy, CT + XML was most effective in New York Heart Association cardiac functional classification efficiency, brain natriuretic peptide, and N-terminal pro-brain natriuretic peptide; the CT + SM was most effective in 6-min walking test, left ventricular end-diastolic diameter, left ventricular end-systolic diameter and cardiac output; the CT + YQFM was most effective in left ventricular ejection fraction; the CT + HQ was most effective in stroke volume; the CT + SF was most effective in Minnesota Living with Heart Failure Questionnaire. In terms of safety, there was no significant difference between CT + TCMIs and CT.

Conclusion: This Bayesian network meta-analysis results show that the combination of qualified TCMIs and CT is more effective for HFrEF patients than CT alone, and CT + XML and CT + SM may be one of the potential optimal treatments. Also, the safety of these TCMIs needs to be further observed. However, due to some limitations, the conclusions need to be verified by more large-sample, double-blind, multi-center RCTs.
Tripterygium hypoglaucum (Lévl.) Hutch and Its Main Bioactive Components: Recent Advances in Pharmacological Activity, Pharmacokinetics and Potential Toxicity
Authors: Zhao Junqi , Zhang Fangling , Xiao Xiaolin , Wu Zhao , Hu Qichao , Jiang Yinxiao , Zhang Wenwen , Wei Shizhang , Ma Xiao , Zhang Xiaomei
Published: November 2021

Tripterygium hypoglaucum(Lévl.) Hutch (THH) is believed to play an important role in health care and disease treatment according to traditional Chinese medicine. Moreover, it is also the representative of medicine with both significant efficacy and potential toxicity. This characteristic causes THH hard for embracing and fearing. In order to verify its prospect for clinic, a wide variety of studies were carried out in the most recent years. However, there has not been any review about THH yet. Therefore, this review summarized its characteristic of components, pharmacological effect, pharmacokinetics and toxicity to comprehensively shed light on the potential clinical application. More than 120 secondary metabolites including terpenoids, alkaloids, glycosides, sugars, organic acids, oleanolic acid, polysaccharides and other components were found in THH based on phytochemical research. All these components might be the pharmacological bases for immunosuppression, anti-inflammatory and anti-tumour effect. In addition, recent studies found that THH and its bioactive compounds also demonstrated remarkable effect on obesity, insulin resistance, fertility and infection of virus. The main mechanism seemed to be closely related to regulation the balance of immune, inflammation, apoptosis and so on in various disease. Furthermore, the study of pharmacokinetics revealed quick elimination of the main component triptolide. The feature of celastrol was also investigated by several models. Finally, the side effect of THH was thought to be the key for its limitation in clinical application. A series of reports indicated that multiple organs or systems including liver, kidney and genital system were involved in the toxicity. Its potential serious problem in liver was paid specific attention in recent years. In summary, considering the significant effect and potential toxicity of THH as well as its components, the combined medication to inhibit the toxicity, maintain effect might be a promising method for clinical conversion. Modern advanced technology such as structure optimization might be another way to reach the efficacy and safety. Thus, THH is still a crucial plant which remains for further investigation.
Prediction of the Molecular Mechanisms Underlying Erlong Zuoci Treatment of Age-Related Hearing Loss via Network Pharmacology-Based Analyses Combined with Experimental Validation
Authors: Liu Qing , Li Ning , Yang Yifang , Yan Xirui , Dong Yang , Peng Yinting , Shi Jianrong
Published: November 2021

Background: The traditional Chinese medicine formula ErLong ZuoCi (ELZC) has been extensively used to treat age-related hearing loss (ARHL) in clinical practice in China for centuries. However, the underlying molecular mechanisms are still poorly understood.

Objective: Combine network pharmacology with experimental validation to explore the potential molecular mechanisms underlying ELZC with a systematic viewpoint.

Methods: The chemical components of ELZC were collected from the Traditional Chinese Medicine System Pharmacology database, and their possible target proteins were predicted using the SwissTargetPrediction database. The putative ARHL-related target proteins were identified from the database: GeneCards and OMIM. We constructed the drug-target network as well as drug-disease specific protein-protein interaction networks and performed clustering and topological property analyses. Functional annotation and signaling pathways were performed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Finally, in vitro experiments were also performed to validate ELZC’s key target proteins and treatment effects on ARHL.

Results: In total, 63 chemical compounds from ELZC and 365 putative ARHL-related targets were identified, and 1860 ARHL-related targets were collected from the OMIM and GeneCards. A total of 145 shared targets of ELZC and ARHL were acquired by Venn diagram analysis. Functional enrichment analysis suggested that ELZC might exert its pharmacological effects in multiple biological processes, such as cell proliferation, apoptosis, inflammatory response, and synaptic connections, and the potential targets might be associated with AKT, ERK, and STAT3, as well as other proteins. In vitro experiments revealed that ELZC pretreatment could decrease senescence-associated β-galactosidase activity in hydrogen peroxide-induced auditory hair cells, eliminate DNA damage, and reduce cellular senescence protein p21 and p53. Finally, Western blot analysis confirmed that ELZC could upregulate the predicted target ERK phosphorylation.

Conclusion: We provide an integrative network pharmacology approach, in combination with in vitro experiments to explore the underlying molecular mechanisms governing ELZC treatment of ARHL. The protective effects of ELZC against ARHL were predicted to be associated with cellular senescence, inflammatory response, and synaptic connections which might be linked to various pathways such as JNK/STAT3 and ERK cascade signaling pathways. As a prosperous possibility, our experimental data suggest phosphorylation ERK is essential for ELZC to prevent degeneration of cochlear.
Circular RNA CREBBP Suppresses Hepatic Fibrosis Via Targeting the hsa-miR-1291/LEFTY2 Axis
Authors: Yang Ya-Ru , Hu Shuang , Bu Fang-Tian , Li Hao , Huang Cheng , Meng Xiao-Ming , Zhang Lei , Lv Xiong-Wen , Li Jun
Published: November 2021

CircRNAs (circRNAs) are commonly dysregulated in a variety of human diseases and are involved in the development and progression of cancer. However, the role of circRNAs in hepatic fibrosis (HF) is still unclear. Our previous high throughput screen revealed changes in many circRNAs in mice with carbon tetrachloride (CCl4)-induced HF. For example, circCREBBP was significantly down-regulated in primary hepatic stellate cells (HSCs) and liver tissue of HF mice induced by CCl4 compared to those in the vehicle group. Overexpression of circCREBBP with AAV8-circCREBBP in vivo prevented CCl4-induced HF worsening by reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) contents, liver hydroxyproline levels, collagen deposition, and levels of pro-fibrosis genes and pro-inflammatory cytokines. Furthermore, in vitro function loss and function gain analysis showed that circCREBBP inhibited HSCs activation and proliferation. Mechanically, circCREBBP acts as a sponge for hsa-miR-1291 and subsequently promotes LEFTY2 expression. In conclusion, our current results reveal a novel mechanism by which circCREBBP alleviates liver fibrosis by targeting the hsa-miR-1291/LEFTY2 axis, and also suggest that circCREBBP may be a potential biomarker for heart failure.
Characterization of Alpelisib in Rat Plasma by a Newly Developed UPLC-MS/MS Method: Application to a Drug-Drug Interaction Study
Authors: Wang Qiong , Lan Xia , Zhao Zhuofei , Su Xiaohang , Zhang Yuji , Zhou Xiao-Yang , Xu Ren-Ai
Published: December 2021

Alpelisib, an oral selective and small-molecule phosphoinositide 3-kinase inhibitor, was lately approved in the United States to treat breast cancer. A sensitive method to quantify alpelisib levels in rat plasma on the basis of ultra-performance liquid chromatography–tandem mass spectrometry technique was established and validated, which was successfully employed to explore the effects of CYP3A4 inhibitors on alpelisib pharmacokinetics in rats. A C18 column named Acquity UPLC BEH C18 was applied to achieve the separation of alpelisib and internal standard duvelisib after protein precipitation with acetonitrile. The mobile phase in this study had two components, namely, acetonitrile and water having 0.1% formic acid, and a program with gradient elution method was used at a flow rate of 0.40 ml/min. Mass spectrometry in a positive multiple reaction monitoring mode was operated. In the scope of 1–5,000 ng/ml, this assay had excellent linearity. Our newly developed assay was verified in all aspects of bioanalytical method validation, involving lower limit of quantification, selectivity, accuracy and precision, calibration curve, extraction recovery, matrix effect, and stability. Then, this assay was used to detect the plasma levels of alpelisib from a drug-drug interaction investigation, where ketoconazole remarkably increased the plasma concentration of alpelisib and changed alpelisib pharmacokinetics more than itraconazole. This study will help better understand the pharmacokinetic properties of alpelisib, and further clinical studies should be done to confirm this result in patients.
In Vitro Selective Antibacterial and Antiproliferative Effects of Ethanolic Extracts from Cambodian and Philippine Plants Used in Folk Medicine for Diarrhea Treatment
Authors: Kudera Tomas , Fiserova Barbora , Korytakova Marie , Doskocil Ivo , Salmonova Hana , Tulin Edgardo E. , Nguon Samnang , Bande Marlito M. , Kokoska Ladislav
Published: December 2021

Bacterial diarrhea remains a global health problem, especially in developing tropical countries. Moreover, dysbiosis caused by diarrheagenic bacteria and inappropriate antimicrobial treatment has been associated with intestinal carcinogenesis. Despite the rich tradition of the use of herbs for the treatment of gastrointestinal disorders in Cambodian and Philippine folk medicine, many of them have not yet been systematically studied for their in vitro selective inhibitory effects on intestinal bacteria and cells. In the present study, in vitro inhibitory activities of 35 ethanolic extracts derived from 32 Cambodian and Philippine medicinal plants were determined by broth microdilution method against 12 pathogenic bacteria. Furthermore, cytotoxicity against intestinal cancer cells (Caco-2 and HT-29) using thiazolyl blue tetrazolium bromide cytotoxicity assay and safety to six beneficial intestinal bacteria (bifidobacteria and lactobacilli) and intestinal normal cells (FHs 74 Int) were determined for the antimicrobially active extracts. Selectivity indices (SIs) were calculated among the averages of minimum inhibitory concentrations (MICs), half-maximal inhibitory concentrations (IC50), and 80% inhibitory concentrations of proliferation (IC80) for each type of the tested agents. The extracts of Artocarpus blancoi (Elmer) Merr. (Moraceae), Ancistrocladus tectorius (Lour.) Merr. (Ancistrocladaceae), and Pentacme siamensis (Miq.) Kurz (Dipterocarpaceae) produced significant growth-inhibitory effects (MICs = 32–512 μg/ml) against intestinal pathogenic bacteria at the concentrations nontoxic to normal intestinal cells (IC80 values >512 μg/ml; SIs = 0.11–0.2). Moreover, the extract of P. siamensis (Miq.) Kurz was relatively safe to beneficial bacteria (MICs ≥512 μg/ml; SI = 0.1), and together with A. blancoi (Elmer) Merr., they selectively inhibited intestinal cancer cells (IC50 values ≥51.98 ± 19.79 μg/ml; SIs = 0.3 and 0.6). Finally, a strong selective antiproliferative effect on cancer cells (IC50 values 37.89 ± 2.68 to 130.89 ± 13.99 μg/ml; SIs = 0.5) was exerted by Ehretia microphylla Lam. (Boraginaceae), Lagerstroemia cochinchinensis Pierre ex Gagnep. (Lythraceae), and Melastoma saigonense (Kuntze) Merr. (Melastomataceae) (leaves with flower buds). The results suggest that the above-mentioned species are promising materials for the development of new selective antibacterial and antiproliferative agents for the treatment of infectious diarrhea and associated intestinal cancer diseases. However, further research is needed regarding the isolation and identification of their active constituents.
The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation
Authors: Pilarzyk Katy , Farmer Reagan , Porcher Latarsha , Kelly Michy P.
Published: November 2021

Phosphodiesterase 11A (PDE11A), an enzyme that degrades cyclic nucleotides (cAMP and cGMP), is the only PDE whose mRNA expression in brain is restricted to the hippocampal formation. Previously, we showed that chronic social isolation changes subsequent social behaviors in adult mice by reducing expression of PDE11A4 in the membrane fraction of the ventral hippocampus (VHIPP). Here we seek extend these findings by determining 1) if isolation-induced decreases in PDE11A4 require chronic social isolation or if they occur acutely and are sustained long-term, 2) if isolation-induced decreases occur uniquely in adults (i.e., not adolescents), and 3) how the loss of PDE11 signaling may increase neuroinflammation. Both acute and chronic social isolation decrease PDE11A4 expression in adult but not adolescent mice. This decrease in PDE11A4 is specific to the membrane compartment of the VHIPP, as it occurs neither in the soluble nor nuclear fractions of the VHIPP nor in any compartment of the dorsal HIPP. The effect of social isolation on membrane PDE11A4 is also selective in that PDE2A and PDE10A expression remain unchanged. Isolation-induced decreases in PDE11A4 expression appear to be functional as social isolation elicited changes in PDE11A-relevant signal transduction cascades (i.e., decreased pCamKIIα and pS6-235/236) and behavior (i.e., increased remote long-term memory for social odor recognition). Interestingly, we found that isolation-induced decreases in membrane PDE11A4 correlated with increased expression of interleukin-6 (IL-6) in the soluble fraction, suggesting pro-inflammatory signaling for this cytokine. This effect on IL-6 is consistent with the fact that PDE11A deletion increased microglia activation, although it left astrocytes unchanged. Together, these data suggest that isolation-induced decreases in PDE11A4 may alter subsequent social behavior via increased neuroinflammatory processes in adult mice.
An Analysis of Medical Care Services for Children With Rare Diseases in the Russian Federation
Authors: Volgina Svetlana Ya. , Sokolov Alexey A.
Published: November 2021

Rare diseases continue to present numerous challenges for the medical field worldwide. Understanding innovative mechanisms of service provision for patients with rare conditions through shared communication across different healthcare systems should be encouraged. This study presents the organization of medical care for people with rare diseases in Russia, while also exploring the epidemiology of both life-threatening and chronic, progressive, rare diseases. Further, the regulation of medical care provision is examined, including the preferential provision of medicines in different Russian regions and potential role of compulsory medical insurance. The principles guiding patient referrals to appropriate specialist centres for rare diseases are outlined, including considering the increased role that public-patient organizations have in developing healthcare systems. In reviewing the specialized resources available for patients with rare diseases, medical genetics services offering diagnostics and counselling are discussed. Additionally, population-level preventive care necessitates significant investment, principally in diagnostic technology and screening programs. As seen elsewhere, these initiatives involve forming reference centres and tertiary-level pediatric departments staffed by multidisciplinary specialists in rare diseases. Numerous challenges are highlighted relating to Russian healthcare systems, including the financing of expensive treatments and ensuring equitable access to medical care for those patients with rare diseases outside of State-subsidized programs. Recommendations are made on creating international registries for knowledge sharing, quality appraisal, newborn screening, diagnostic challenges, available treatments and rehabilitation services. Given the high cost of rare diseases, cost-effective interventions are advisable, particularly developing preventive programs and targeting the most common and severe mutations in patients planning pregnancies.
The Protective Effects of Zornia diphylla (L.) Pers. Against Acute Liver Injury Induced by Carbon Tetrachloride in Mice
Authors: Xie Su-Zhi , Zhai Xiang-Yang , Xi Sheng-Yan , Qiu Ying-Kun , Zhang Yu-Mei , Kong Xiang-Jun , Li Yun-Hong , Zhu Lin , Wang Zheng , Zhang Shan-Gang , Huang Shu-Qiong , Lu Da-Wei , Wang Zheng
Published: November 2021

Background:Zornia diphylla (L.) Pers. (ZDP) is a traditional Chinese herbal medicine that has been used for several decades to treat patients with liver diseases. Whether ZDP is best administered as a single agent or adjunctive therapy has yet to be determined as does the mechanism whereby it exerts its effects on antagonizing acute liver injury (ALI).

Aim of the study: To investigate the protective effects of ZDP on ALI induced by carbon tetrachloride (CCl4) and the potential underlying mechanisms.

Materials and Methods: Sixty adult mice were randomized into six study groups (n = 10/group). Three groups were treated with different concentrations of ZDP (2.5, 1.25, 0.625 g/kg), one with bifendate (0.0075 g/kg) alone (positive control) and one with physiologic saline (normal, negative control). All groups were treated for 14 days. Two hours after the last administration, the normal group received an intraperitoneal injection of peanut oil, and the other five groups received an intraperitoneal injection of an equal dose of CCl4 peanut oil solution. At 24 h, the liver index, histology and serum or tissue levels and/or protein expression of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), alkaline phosphatase (ALP), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione (GSH), Akt, phosphorylated Akt (p-Akt), nuclear factor kappa B p65 (NF-κB p65), inhibitor of NF-κB α (IκB-α), interleukin-1 β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), E-cadherin and vimentin were determined.

Results: Compared to the model controls, the degree of inflammatory cell infiltration and hepatocyte injury of liver tissue was relieved in the bifendate and three ZDP groups; liver index in the ZDP (2.5, 1.25 g/kg) groups and serum liver function indices in the ZDP (2.5, 1.25 and 0.625 g/kg) groups were decreased; antioxidants SOD, CAT and GSH in liver tissue were increased but the lipid peroxidation index MDA was decreased; protein expression of inflammatory cytokines Akt, p-Akt, NF-κB p65, IκB-α, IL-1β, IL-6 and TNF-α in the liver was ameliorated, and E-cadherin expression was increased. The results of liver histopathology also showed that ZDP had a significant effect on ALI.

Conclusion: ZDP has obvious protective effects on CCl4-induced ALI as a single therapy and appears to act by inhibiting oxidation, reducing the release of inflammatory factors and promoting hepatocyte repair.
Ferruginol Restores SIRT1-PGC-1α-Mediated Mitochondrial Biogenesis and Fatty Acid Oxidation for the Treatment of DOX-Induced Cardiotoxicity
Authors: Li Weili , Cao Jing , Wang Xiaoping , Zhang Yawen , Sun Qianbin , Jiang Yanyan , Yao Junkai , Li Chun , Wang Yong , Wang Wei
Published: November 2021

Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, has life-threatening cardiotoxicity. Therefore, searching cardioprotective drugs for DOX-induced cardiotoxicity (DIC) is urgently needed.

Objectives: This study aimed to explore cardioprotective effect and specific mechanism by which Ferruginol (FGL) attenuated DIC in vivo and in vitro.

Methods: We evaluated the cardioprotection of FGL and performed high-throughput RNA-Seq on a DIC mouse. Whereafter, multiple methods, including western blot, RT-qPCR, a transmission electron microscope, CO-IP, immunofluorescence, and other staining methods, and antagonist of SIRT1 and PGC-1α were utilized to confirm the cardioprotection and molecular mechanism of FGL.

Results: FGL-exerted cardioprotection manifested as enhanced cardiac function and reduced structural damage and apoptosis. The transcriptome and other results revealed that FGL facilitated PGC-1α-mediated mitochondrial biogenesis and fatty acid oxidation (MB and FAO) by increasing the expression of PGC-1α and concurrently promoting the expression of SIRT1-enhancing deacetylase SIRT1 deacetylating and activating PGC-1α.

Conclusions: These results documented that FGL exerted cardioprotective effects restoring MB&FAO via the SIRT1–PGC-1α axis.
Proton Sensing on the Ocular Surface: Implications in Eye Pain
Authors: Comes Núria , Gasull Xavier , Callejo Gerard
Published: November 2021

Protons reaching the eyeball from exogenous acidic substances or released from damaged cells during inflammation, immune cells, after tissue injury or during chronic ophthalmic conditions, activate or modulate ion channels present in sensory nerve fibers that innervate the ocular anterior surface. Their identification as well as their role during disease is critical for the understanding of sensory ocular pathophysiology. They are likely to mediate some of the discomfort sensations accompanying several ophthalmic formulations and may represent novel targets for the development of new therapeutics for ocular pathologies. Among the ion channels expressed in trigeminal nociceptors innervating the anterior surface of the eye (cornea and conjunctiva) and annex ocular structures (eyelids), members of the TRP and ASIC families play a critical role in ocular acidic pain. Low pH (pH 6) activates TRPV1, a polymodal ion channel also activated by heat, capsaicin and hyperosmolar conditions. ASIC1, ASIC3 and heteromeric ASIC1/ASIC3 channels present in ocular nerve terminals are activated at pH 7.2–6.5, inducing pain by moderate acidifications of the ocular surface. These channels, together with TRPA1, are involved in acute ocular pain, as well as in painful sensations during allergic keratoconjunctivitis or other ophthalmic conditions, as blocking or reducing channel expression ameliorates ocular pain. TRPV1, TRPA1 and other ion channels are also present in corneal and conjunctival cells, promoting inflammation of the ocular surface after injury. In addition to the above-mentioned ion channels, members of the K2P and P2X ion channel families are also expressed in trigeminal neurons, however, their role in ocular pain remains unclear to date. In this report, these and other ion channels and receptors involved in acid sensing during ocular pathologies and pain are reviewed.