bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world clinical treatment outcomes in Chinese non-small cell lung cancer with EGFR exon 20 insertion mutations
Authors: Shi Chao , Xing Ruyue , Li Mengmeng , Feng Junnan , Sun Rui , Wei Bing , Guo Yongjun , Ma Jie , Wang Huijuan
Published: September 2022

Background

EGFR exon 20 insertions (EGFR ex20ins) constitute a heterogeneous subset of EGFR-activating alterations. However, the effectiveness of standard therapy in patients with EGFR ex20ins remains poor.

Methods

In our study, we retrospectively collected next-generation sequencing (NGS) data from 7,831 Chinese NSCLC patients and analyzed the relationship between EGFR ex20ins variations and medical records.

Results

Our data showed that EGFR ex20ins account for up to 3.5% of all EGFR mutation non-small-cell lung cancer (NSCLC) patients and 1.6% of all NSCLC patients in China. Thirty-eight different variants of EGFR ex20ins were identified in 129 NSCLC patients. We observed that the patients with EGFR ex20ins may benefit from the anti-angiogenesis agents significantly (P = 0.027). In the EGFR ex20ins near-loop group, patients who received second-/third-generation EGFR-TKI therapy treatment as first-line treatment had a longer median progression-free survival (PFS) than those who initiated treatment with first-generation EGFR-TKI or chemotherapy. Patients with co-mutations of EGFR ex20ins near-loop and TP53 tended to have a shorter OS in second-/third-generation EGFR-TKI therapy (P = 0.039). Additionally, median PFS was significantly longer in patients harboring EGFR ex20ins far-loop variants who received chemotherapy as a first-line setting (P = 0.037).

Conclusions

Overall survival was significantly longer in EGFR ex20ins patients with anti-angiogenesis agents. For the choice of first-line strategy, NSCLC with EGFR ex20ins near-loop variants may benefit from second-/third-generation EGFR-TKI, while patients harboring EGFR ex20ins far-loop variants might have better outcomes from chemotherapy. TP53 could serve as a potential predictive marker in poor prognosis for EGFR ex20ins near-loop patients.
3D-printed bolus ensures the precise postmastectomy chest wall radiation therapy for breast cancer
Authors: Wang Xiran , Zhao Jianling , Xiang Zhongzheng , Wang Xuetao , Zeng Yuanyuan , Luo Ting , Yan Xi , Zhang Zhuang , Wang Feng , Liu Lei
Published: September 2022

Purpose

To investigate the values of a 3D-printed bolus ensuring the precise postmastectomy chest wall radiation therapy for breast cancer.

Methods and materials

In the preclinical study on the anthropomorphic phantom, the 3D-printed bolus was used for dosimetry and fitness evaluation. The dosimetric parameters of planning target volume (PTV) were assessed, including Dmin, Dmax, Dmean, D95%, homogeneity index (HI), conformity index (CI), and organs at risk (OARs). The absolute percentage differences (|%diff|) between the theory and fact skin dose were also estimated, and the follow-up was conducted for potential skin side effects.

Results

In preclinical studies, a 3D-printed bolus can better ensure the radiation coverage of PTV (HI 0.05, CI 99.91%), the dose accuracy (|%diff| 0.99%), and skin fitness (mean air gap 1.01 mm). Of the 27 eligible patients, we evaluated the radiation dose parameter (median(min–max): Dmin 4967(4789–5099) cGy, Dmax 5447(5369–5589) cGy, Dmean 5236(5171–5323) cGy, D95% 5053(4936–5156) cGy, HI 0.07 (0.06–0.17), and CI 99.94% (97.41%–100%)) and assessed the dose of OARs (ipsilateral lung: Dmean 1341(1208–1385) cGy, V5 48.06%(39.75%–48.97%), V20 24.55%(21.58%–26.93%), V30 18.40%(15.96%–19.16%); heart: Dmean 339(138–640) cGy, V30 1.10%(0%–6.14%), V40 0.38%(0%–4.39%); spinal cord PRV: Dmax 639(389–898) cGy). The skin doses in vivo were Dtheory 208.85(203.16–212.53) cGy, Dfact 209.53(204.14–214.42) cGy, and |%diff| 1.77% (0.89–2.94%). Of the 360 patients enrolled in the skin side effect follow-up study (including the above 27 patients), grade 1 was the most common toxicity (321, 89.2%), some of which progressing to grade 2 or grade 3 (32, 8.9% or 7, 1.9%); the radiotherapy interruption rate was 1.1%.

Conclusion

A 3D-printed bolus can guarantee the precise radiation dose on skin surface, good fitness to skin, and controllable acute skin toxicity, which possesses a great clinical application value in postmastectomy chest call radiation therapy for breast cancer.
Effect of circumferential resection margin status on survival and recurrence in esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy
Authors: Gu Yi-Min , Yang Yu-Shang , Kong Wei-Li , Shang Qi-Xin , Zhang Han-Lu , Wang Wen-Ping , Yuan Yong , Che Guo-Wei , Chen Long-Qi
Published: September 2022

Background

The aim of this study was to investigate whether circumferential resection margin (CRM) status has an impact on survival and recurrence in esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy.

Methods

We screened patients with esophageal squamous cell carcinoma who underwent esophagectomy from January 2017 to December 2019. The CRM was reassessed. Patients were grouped into a CRM of 1 mm or less (0 < CRM ≤ 1 mm) and a CRM greater than 1 mm (CRM>1 mm). The impact of CRM on survival was investigated using Kaplan–Meier analysis and Cox regression modeling. The optimal CRM cut point was evaluated using restricted cubic spline curve.

Results

A total of 89 patients were enrolled in this study. The CRM status was an independent risk factor for the prognosis (HR: 0.35, 95% CI: 0.16-0.73). Compared with a CRM of 1 mm or less, a CRM greater than 1 mm had better overall survival (HR: 0.35, 95% CI: 0.16-0.73, log-rank P = 0.011), longer disease-free survival (HR: 0.51, 95% CI: 0.27-0.95, log-rank P = 0.040), and less recurrence (HR: 0.44, 95% CI: 0.23-0.85, log–rank P = 0.015). We visualized the association between CRM and the hazard ratio of survival and identified the optimal cut point at 1 mm.

Conclusions

A CRM greater than 1 mm had better survival and less recurrence compared to a CRM of 1 mm or less. A more radical resection with adequate CRM could benefit survival in patients with esophageal squamous cell carcinoma after neoadjuvant therapy.
Beyond targeting amplified MDM2 and CDK4 in well differentiated and dedifferentiated liposarcomas: From promise and clinical applications towards identification of progression drivers
Authors: Cassinelli Giuliana , Pasquali Sandro , Lanzi Cinzia
Published: September 2022

Well differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are tumors of the adipose tissue poorly responsive to conventional cytotoxic chemotherapy which currently remains the standard-of-care. The dismal prognosis of the DDLPS subtype indicates an urgent need to identify new therapeutic targets to improve the patient outcome. The amplification of the two driver genes MDM2 and CDK4, shared by WDLPD and DDLPS, has provided the rationale to explore targeting the encoded ubiquitin-protein ligase and cell cycle regulating kinase as a therapeutic approach. Investigation of the genomic landscape of WD/DDLPS and preclinical studies have revealed additional potential targets such as receptor tyrosine kinases, the cell cycle kinase Aurora A, and the nuclear exporter XPO1. While the therapeutic significance of these targets is being investigated in clinical trials, insights into the molecular characteristics associated with dedifferentiation and progression from WDLPS to DDLPS highlighted additional genetic alterations including fusion transcripts generated by chromosomal rearrangements potentially providing new druggable targets (e.g. NTRK, MAP2K6). Recent years have witnessed the increasing use of patient-derived cell and tumor xenograft models which offer valuable tools to accelerate drug repurposing and combination studies. Implementation of integrated “multi-omics” investigations applied to models recapitulating WD/DDLPS genetics, histologic differentiation and biology, will hopefully lead to a better understanding of molecular alterations driving liposarcomagenesis and DDLPS progression, as well as to the identification of new therapies tailored on tumor histology and molecular profile.
HOXA1 is a radioresistance marker in multiple cancer types
Authors: He Lu , Liang Min , Guo Weisheng , Liu Jinquan , Yu Yi
Published: September 2022

Radiotherapy is an important therapeutic method for patients with cancer. However, radioresistance can cause treatment failure. Thus, there is an urgent need to investigate mechanisms of radioresistance and identity markers that could be used to predict radioresistance and prognosis of post-radiotherapy cancer patients. In the present study, we propose HOXA1 as a candidate biomarker of intrinsic radioresistance in multiple cancer types. By analyzing data from The Cancer Genome Atlas (TCGA), we found that HOXA1 was aberrantly upregulated in multiple cancers, and that elevated HOXA1 was significantly associated with poor prognosis of post-radiotherapy head and neck squamous cell carcinoma (HNSCC) and low-grade glioma (LGG) patients. Correlation analysis showed that HOXA1 expression was positively correlated with expression of EGFR, CDK6, and CAV1, which have been reported to enhance radioresistance. In addition, gene set enrichment analysis (GSEA) showed that the oxidative phosphorylation gene set was negatively enriched in HOXA1 high-expression samples in both HNSCC and LGG. Moreover, immunohistochemical assays indicated that high HOXA1 expression was significantly correlated with a high recurrence rate of nasopharyngeal carcinoma (NPC) after radiotherapy. Further in vitro experiments demonstrated that HOXA1 knockdown markedly attenuated the DNA repair capacity of NPC cells and sensibilized NPC cells to irradiation. Taken together, the results of this study demonstrate that HOXA1 has potential to be a predictive marker for radioresistance and post-radiotherapy prognosis that could help to guide individualized treatment in multiple cancer types.
Survival and clinicopathological significance of PYCR1 expression in cancer: A meta-analysis
Authors: Li Yue , Xu Jiahuan , Bao Pengchen , Wei Zhijing , Pan Lei , Zhou Jiawei , Wang Wei
Published: September 2022

Background

Proline metabolism is closely related to the occurrence and development of cancer. Δ1-Pyrroline-5-carboxylate reductase (PYCR) is the last enzyme in proline biosynthesis. As one of the enzyme types, PYCR1 takes part in the whole process of the growth, invasion, and drug resistance of cancer cells. This study investigated PYCR1 expressions in cancers together with their relationship to clinical prognosis.

Methods

A thorough database search was performed in PubMed, EMBASE, and Cochrane Library. RevMan5.3 software was used for the statistical analysis.

Results

Eight articles were selected, and 728 cancer patients were enrolled. The cancer types include lung, stomach, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma. The meta-analysis results showed that the expression of PYCR1 was higher in the clinical stage III–IV group than that in the clinical stage I–II group (OR = 1.67, 95%CI: 1.03–2.71), higher in the lymph node metastasis group than in the non-lymph node metastasis group (OR = 1.57, 95%CI: 1.06–2.33), and higher in the distant metastasis group than in the non-distant metastasis group (OR = 3.46, 95%CI: 1.64–7.29). However, there was no statistical difference in PYCR1 expression between different tumor sizes (OR = 1.50, 95%CI: 0.89–2.53) and degrees of differentiation (OR = 0.82, 95%CI: 0.54–1.24).

Conclusion

PYCR1 had a high expression in various cancers and was associated with cancer volume and metastasis. The higher the PYCR1 expression was, the poorer the cancer prognosis was. The molecular events and biological processes mediated by PYCR1 might be the underlying mechanisms of metastasis.
Endoscopic transorbital avenue to the skull base: Four-step conceptual analysis of the anatomic journey
Authors: Guizzardi Giulia , Di Somma Alberto , de Notaris Matteo , Corrivetti Francesco , Sánchez Juan Carlos , Alobid Isam , Ferres Abel , Roldan Pedro , Reyes Luis , Enseñat Joaquim , Prats-Galino Alberto
Published: September 2022

Background

In the last decades, skull base surgery had passed through an impressive evolution. The role of neuroanatomic research has been uppermost, and it has played a central role in the development of novel techniques directed to the skull base. Indeed, the deep and comprehensive study of skull base anatomy has been one of the keys of success of the endoscopic endonasal approach to the skull base. In the same way, dedicated efforts expended in the anatomic lab has been a powerful force for the growth of the endoscopic transorbital approach to the lateral skull base.

Therefore, in this conceptual paper, the main steps for the anatomic description of the endoscopic transorbital approach to the skull base have been detailed.

Methods

The anatomic journey for the development of the endoscopic transorbital approach to the skull base has been analyzed, and four “conceptual” steps have been highlighted.

Results

As neurosurgeons, the eyeball has always represented a respectful area: to become familiar with this complex and delicate anatomy, we started by examining the orbital anatomy on a dry skull (step 1). Hence, step 1 is represented by a detailed bone study; step 2 is centered on cadaveric dissection; step 3 consists in 3D quantitative assessment of the novel endoscopic transorbital corridor; and finally, step 4 is the translation of the preclinical data in the real surgical scenario by means of dedicated surgical planning.

Conclusions

The conceptual analysis of the anatomic journey for the description of the endoscopic transorbital approach to the skull base resulted in four main methodological steps that should not be thought strictly consequential but rather interconnected. Indeed, such steps should evolve following the drives that can arise in each specific situation. In conclusion, the four-step anatomic rehearsal can be relevant for the description, diffusion, and development of a novel technique in order to facilitate the application of the endoscopic transorbital approach to the skull base in a real surgical scenario.
Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study
Authors: Takada Kohichi , Kubo Tomohiro , Kikuchi Junko , Yoshida Makoto , Murota Ayako , Arihara Yohei , Nakamura Hajime , Nagashima Hiroyuki , Tanabe Hiroki , Sugita Shintaro , Tanaka Yumi , Miura Ayana , Ohhara Yoshihito , Ishiguro Atsushi , Yokouchi Hiroshi , Kawamoto Yasuyuki , Mizukami Yusuke , Ohnishi Hirofumi , Kinoshita Ichiro , Sakurai Akihiro
Published: September 2022

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.
Tissue metabolomics identified new biomarkers for the diagnosis and prognosis prediction of pancreatic cancer
Authors: Liu Chang , Qin Henan , Liu Huiying , Wei Tianfu , Wu Zeming , Shang Mengxue , Liu Haihua , Wang Aman , Liu Jiwei , Shang Dong , Yin Peiyuan
Published: September 2022

Pancreatic cancer (PC) is burdened with a low 5-year survival rate and high mortality due to a severe lack of early diagnosis methods and slow progress in treatment options. To improve clinical diagnosis and enhance the treatment effects, we applied metabolomics using ultra-high-performance liquid chromatography with a high-resolution mass spectrometer (UHPLC-HRMS) to identify and validate metabolite biomarkers from paired tissue samples of PC patients. Results showed that the metabolic reprogramming of PC mainly featured enhanced amino acid metabolism and inhibited sphingolipid metabolism, which satisfied the energy and biomass requirements for tumorigenesis and progression. The altered metabolism results were confirmed by the significantly changed gene expressions in PC tissues from an online database. A metabolites biomarker panel (six metabolites) was identified for the differential diagnosis between PC tumors and normal pancreatic tissues. The panel biomarker distinguished tumors from normal pancreatic tissues in the discovery group with an area under the curve (AUC) of 1.0 (95%CI, 1.000−1.000). The biomarker panel cutoff was 0.776. In the validation group, an AUC of 0.9000 (95%CI = 0.782–1.000) using the same cutoff, successfully validated the biomarker signature. Moreover, this metabolites panel biomarker had a great capability to predict the overall survival (OS) of PC. Taken together, this metabolomics method identifies and validates metabolite biomarkers that can diagnose the onsite progression and prognosis of PC precisely and sensitively in a clinical setting. It may also help clinicians choose proper therapeutic interventions for different PC patients and improve the survival of PC patients.
Unique role of DDX41, a DEAD-box type RNA helicase, in hematopoiesis and leukemogenesis
Authors: Shinriki Satoru , Matsui Hirotaka
Published: September 2022

In myeloid malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), patient selection and therapeutic strategies are increasingly based on tumor-specific genetic mutations. Among these, mutations in DDX41, which encodes a DEAD-box type RNA helicase, are present in approximately 2–5% of AML and MDS patients; this disease subtype exhibits a distinctive disease phenotype characterized by late age of onset, tendency toward cytopenia in the peripheral blood and bone marrow, a relatively favorable prognosis, and a high frequency of normal karyotypes. Typically, individuals with a loss-of-function germline DDX41 variant in one allele later acquire the p.R525H mutation in the other allele before overt disease manifestation, suggesting that the progressive decrease in DDX41 expression and/or function is involved in myeloid leukemogenesis.RNA helicases play roles in many processes involving RNA metabolism by altering RNA structure and RNA-protein interactions through ATP-dependent helicase activity. A single RNA helicase can play multiple cellular roles, making it difficult to elucidate the mechanisms by which mutations in DDX41 are involved in leukemogenesis. Nevertheless, multiple DDX41 functions have been associated with disease development. The enzyme has been implicated in the regulation of RNA splicing, nucleic acid sensing in the cytoplasm, R-loop resolution, and snoRNA processing.Most of the mutated RNA splicing-related factors in MDS are involved in the recognition and determination of 3’ splice sites (SS), although their individual roles are distinct. On the other hand, DDX41 is likely incorporated into the C complex of the spliceosome, which may define a distinctive disease phenotype. This review summarizes the current understanding of how DDX41 is involved in this unique myeloid malignancy.
Hypertensive disorders of pregnancy and neonatal outcomes in twin vs. singleton pregnancies after assisted reproductive technology
Authors: Liu Ting , Gao Rui , Liu Yong , Zhao Ke , Su Xiaolin , Wong Hin Ching , Li Luyao , Xie Binbin , Huang Yuanyan , Qiu Chuhui , He Jiang , Liu Chaoqun
Published: September 2022

Objective

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of adverse neonatal outcomes. Although twin pregnancies had a higher risk of developing HDP, it is not known whether HDP in twins will increase the risk of adverse neonatal outcomes. We aimed to assess whether this association differed in singleton and twin pregnancies in women who conceived with assisted reproductive technology (ART).

Methods

We finally included 193,590 live births born via ART from the National Vital Statistics System (NVSS) for the years 2015–2019. We used Log-binomial regression to evaluate the associations between HDP and the risk of adverse neonatal outcomes in ART mothers.

Results

Among 193,590 ART-treated mothers, there were 140,870 and 52,720 mothers who had singleton pregnancies and twin pregnancies, respectively. Those ART mothers with twin pregnancies had a higher rate of HDP than singleton pregnancies (20.5% vs. 11.0%). In singleton pregnancies, the risks of preterm birth [adjusted risk ratio (aRR)): 2.80, 95% CI 2.67–2.93], low birth weight (aRR: 2.80, 95% CI 2.67–2.93), small for gestational age (aRR: 1.41, 95% CI 1.34–1.49), 5 min Apgar <7 (aRR: 1.66, 95% CI 1.50–1.83) and cesarean section (aRR: 1.23, 95% CI 1.21–1.25) were significantly higher in HDP mothers than in non-HDP mothers respectively. However, in contrast to singleton pregnancies, these associations were weak or reversed in twin pregnancies, after adjusting for confounding factors.

Conclusion

In ART-treated women, although twin pregnancies had a higher HDP rate, the risk of adverse neonatal outcomes associated with HDP was lower than that of singletons.
Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling
Authors: Tang Min , Guo Cheng , Sun Mengxue , Zhou Hao , Peng Xin , Dai Jianli , Ding Qin , Wang Ying , Yang Changqing
Published: September 2022

Objective and aims: Osteopontin (OPN), an oxidant stress sensitive cytokine, plays a central role in liver fibrosis. While OPN expression can be reduced by small interfering RNA (siRNA), the challenge to deliver siRNA safely and effectively into liver remains unresolved. Exosomes are promising natural nanocarriers for drug delivery that are able to enter cells with different biological barriers efficiently. In this study, we used exosomes as a delivery vehicle to target OPN in liver fibrosis.

Methods: Exosomes selectively home to fibrotic liver according to small animal imaging system. Electroporation technique was used to engineer exosomes to carry siRNA targeting OPN (ExosiRNA−OPN). Primary hepatic stellate cells (HSCs) were isolated and treated with ExosiRNA−OPN to assess the effect on activated HSCs (aHSCs). Immunofluorescence for α−SMA, an aHSCs marker, and sirius red staining were performed to assess ECM deposition. Finally, plasma OPN from patients with liver fibrosis was identified by ELISA assay.

Results: Exosome-mediated siRNA delivery systems show high uptake and low toxicity. Besides, ExosiRNA−OPN suppressed HSCs activation and ECM deposition and more efficiently improved liver function when compared to naked siRNA-OPN. Moreover, ExosiRNA−OPN was assumed inhibiting TGF-β1 signaling activation, along with other fibrotic-related genes based on a GEO datasheet of liver fibrosis samples for correlation analyzes. ExosiRNA−OPN inhibited TGF-β1 signaling by decreasing high-mobility group box-1 (HMGB1). Plasma proteins from chronic HBV-induced fibrosis patients were identified that patients with high OPN expression correlates with more advanced fibrosis progression.

Discussion: This study shows that exosome-mediated siRNA-OPN delivery may be an effective option for the treatment of liver fibrosis.
Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl
Authors: Tian Xiangyun , Zhang Junjie , Wang Shaowen , Gao Huan , Sun Yi , Liu Xiaoqian , Fu Wei , Tan Bo , Su Ruibin
Published: September 2022

G protein–coupled receptors can signal through both G proteins and ß-arrestin2. For the µ-opioid receptor (MOR), early experimental evidence from a single study suggested that G protein signaling mediates analgesia and sedation, whereas ß-arrestin signaling mediates respiratory depression and constipation. Then, receptor mutations were used to clarify which residues interact with ligands to selectively regulate signals in a ligand-specific manner. However, there is no systematic study on how to determine these residues and clarify the molecular mechanism of their influence on signal pathways. We have therefore used molecular docking to predict the amino acid sites that affect the binding of ligands and MOR. Then, the corresponding sites were mutated to determine the effect of the structural determinant of MOR on Gi/o protein and ß-arrestin pathways. The pharmacological and animal behavioral experiments in combination with molecular dynamics simulations were used to elucidate the molecular mechanism of key residues governing the signaling. Without affecting ligand binding to MOR, MORY7.43A attenuated the activation of both Gi/o protein and ß-arrestin signaling pathways stimulated by fentanyl, whereas it did not change these two pathways stimulated by morphine. Likewise, the activation peak time of extracellular regulated protein kinases was significantly prolonged at MORY7.43A compared with that at MORwildtype stimulated by fentanyl, but there was no difference stimulated by morphine. In addition, MORY7.43A significantly enhanced analgesia by fentanyl but not by morphine in the mice behavioral experiment. Furthermore, the molecular dynamics simulations showed that H6 moves toward the cellular membrane. H6 of the fentanyl–Y7.43A system moved outward more than that in the morphine–Y7.43A system. Y7.43 mutation disrupted hydrophobic interactions between W6.48 and Y7.43 in the fentanyl–Y7.43A system but not in the morphine–Y7.43A system. Our results have disclosed novel mechanisms of Y7.43 mutation affecting MOR signaling pathways. Y7.43 mutation reduced the activation of the Gi/o protein pathway and blocked the ß-arrestin2 recruitment, increased the H6 outward movement of MOR, and disrupted hydrophobic interactions. This may be responsible for the enhanced fentanyl analgesia. These findings are conducive to designing new drugs from the perspective of ligand and receptor binding, and Y7.43 is also expected to be a key site to structure optimization of synthesized compounds.
Affecting children’s knowledge about rational use of medicines using read-along videos of pictorial storybooks
Authors: Bakaruddin Syafi’ah , Mohd Noordin Zakiah , Karuppannan Mahmathi
Published: September 2022

Although efforts have been taken to educate the public about medication from a very young age, there are very limited availability and accessibility of education material for children. The aim of this study is to assess the impact of read-along videos of pictorial storybooks on children’s knowledge about rational use of medicines. This study compared pre and post knowledge scores in a nonrandomized, one-group pre-test-post-test experimental design. Pre-recorded read-along storytelling videos were used as intervention covering two topics on rational use of medicine -medicine storage and antibiotic resistance. The questionnaire and intervention videos were distributed using Google Forms to children aged six and seven in Malaysia via online social media platforms. 521 children completed the study. The mean baseline knowledge score for medication storage was 4.89 (SD = 1.12) pre-test and 5.44 (SD = 0.78) post-test while for antibiotic resistance the mean was 3.616 (SD = 1.340) pre-test and 4.820 (SD = 1.134) post-test. A Wilcoxon signed-rank test showed statistically significant changes on medication storage (Z = −10.21, p < 0.001) and antibiotic resistance (Z = −14.869, p < 0.001) related knowledge among children. Pictorial storybook read-along video interventions were shown to be effective in improving children’s knowledge on rational use of medicine. Education and awareness on the use of antibiotics should be prioritized.
Intrapallidal injection of cannabidiol or a selective GPR55 antagonist decreases motor asymmetry and improves fine motor skills in hemiparkinsonian rats
Authors: Patricio Felipe , Morales Dávila Eliud , Patricio-Martínez Aleidy , Arana Del Carmen Nayeli , Martínez Isabel , Aguilera José , Perez-Aguilar Jose Manuel , Limón Ilhuicamina Daniel
Published: September 2022

Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets. Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson’s disease (PD). The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated. The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA. The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.
Efficacy and safety of Chinese herbal medicine for pneumonia convalescence in children: A systematic review and meta-analysis
Authors: Guo Jian-Ning , Bai Xue , Zhang Hong-Xian , Zhang Ning , Liang Jun-Ming , Guo Zi-Yi , Cui Xia
Published: September 2022

Background: Chinese herbal medicine (CHM) has advantages in treating sequela symptoms of pediatric pneumonia convalescence. Hence, this study aims to evaluate the efficacy and safety of CHM using a meta-analysis approach.

Methods: The randomized controlled trials (RCTs) that met the search strategy were selected from seven databases from the inception date to December 17, 2021. Based on the Cochrane handbook, the quality of the selected studies was assessed using the risk of bias. Data were expressed as relative risk (RR) or mean difference (MD) and with 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were performed. The Grading Recommendation Assessment, Development, and Evaluation (GRADE) method was used to assess the evidence certainty.

Result: Twenty RCTs with 2,241 participants were identified using the search criteria. CHMs included Danshen injection, Liujunzi decoction, Qingfei Tongluo decoction, Yiqi Huoxue decoction, Yupingfeng granule, XiaoErFeiKe granule, Sha-Sheng-Mai-Dong decoction, and so on. Results indicated that CHM combined with Western medicine (WM) or CHM alone improved the total clinical effective rate (RR = 1.22; 95% CI: 1.15–1.29), reduced cough relief time (MD = −2.16; 95% CI: −2.46 to −1.85), lung rales disappearance time (MD = −1.82; 95% CI: −2.17 to −1.47), and length of hospital stay (MD = −2.01, 95% CI: −3.81 to −0.22) in the treatment of pneumonia convalescence in children. However, there was no significant statistical difference regarding the incidence of adverse reactions (RR = 0.57; 95% CI: 0.23–1.43).

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/; Identifier CRD42022298936
Effects of the peripheral CB1 receptor antagonist JD5037 in mono— and polytherapy with the AMPK activator metformin in a monocrotaline-induced rat model of pulmonary hypertension
Authors: Remiszewski Patryk , Pędzińska-Betiuk Anna , Mińczuk Krzysztof , Schlicker Eberhard , Klimek Justyna , Dzięcioł Janusz , Malinowska Barbara
Published: September 2022

Pulmonary hypertension (PH) is a disease leading to increased pressure in the pulmonary artery and right heart failure. The adenosine monophosphate-activated protein kinase (AMPK) activator, metformin, has a protective effect against PH. CB1 receptor blockade reduces the number of pathological alterations in experimental lung fibrosis. The current study evaluates the effect of the peripheral cannabinoid CB1 receptor antagonist JD5037 in mono- and polytherapy with metformin in rat monocrotaline-induced mild PH. Animals received metformin (100 mg/kg), JD5037 (3 mg/kg), or a combination of both once daily for 21 days. Monocrotaline (60 mg/kg) increased right ventricular (RV) systolic pressure (RVSP), led to RV and lung hypertrophy and remodeling, and decreased oxygen saturation. Metformin partially restored the monocrotaline-induced effects, i.e., decreased RVSP, increased oxygen saturation, and counteracted cardiac fibrotic, hypertrophic, and inflammatory changes. JD5037 modified parameters related to inflammation and/or fibrosis. Only polytherapy with metformin and JD5037 improved Fulton’s index and coronary artery hypertrophy and tended to be more effective than monotherapy against alterations in RVSP, oxygen saturation and coronary artery tunica media vacuolization. In conclusion, monotherapy with JD5037 does not markedly influence the PH-related changes. However, polytherapy with metformin tends to be more efficient than any of these compounds alone.
Protective effect of quercetin on kidney diseases: From chemistry to herbal medicines
Authors: Chen Yi-Qin , Chen Hao-Yin , Tang Qin-Qi , Li Yi-Fan , Liu Xu-Sheng , Lu Fu-Hua , Gu Yue-Yu
Published: September 2022

Kidney injuries may trigger renal fibrosis and lead to chronic kidney disease (CKD), but effective therapeutic strategies are still limited. Quercetin is a natural flavonoid widely distributed in herbal medicines. A large number of studies have demonstrated that quercetin may protect kidneys by alleviating renal toxicity, apoptosis, fibrosis and inflammation in a variety of kidney diseases. Therefore, quercetin could be one of the promising drugs in the treatment of renal disorders. In the present study, we review the latest progress and highlight the beneficial role of quercetin in kidney diseases and its underlying mechanisms. The pharmacokinetics and bioavailability of quercetin and its proportion in herbal medicine will also be discussed.
β1-Integrin plays a major role in resveratrol-mediated anti-invasion effects in the CRC microenvironment
Authors: Brockmueller Aranka , Mueller Anna-Lena , Shayan Parviz , Shakibaei Mehdi
Published: September 2022

Background: Tumor microenvironment (TME) is one of the most important factors in tumor aggressiveness, with an active exchange between tumor and other TME-associated cells that promotes metastasis. The tumor-inhibitory effect of resveratrol on colorectal cancer (CRC) cells has been frequently reported. However, whether resveratrol can specifically suppress TME-induced CRC invasion via β1-integrin receptors has not been fully elucidated yet.

Methods: Two CRC cell lines (HCT116, RKO) were cultured in multicellular, pro-inflammatory 3D-alginate TME cultures (containing fibroblasts, T-lymphocytes) to investigate the role of β1-integrin receptors in the anti-invasive and anti-metastatic effect of resveratrol by antisense oligonucleotides (ASO).

Results: Our results show that resveratrol dose-dependently suppressed the migration-promoting adhesion adapter protein paxillin and simultaneously enhanced the expression of E-cadherin associated with the phenotype change of CRC cells, and their invasion. Moreover, resveratrol blocked TME-induced phosphorylation and nuclear translocation of p65-NF-κB, which was associated with changes in the expression pattern of epithelial-mesenchymal-transition-related biomarkers (slug, vimentin, E-cadherin), metastasis-related factors (CXCR4, MMP-9, FAK), and apoptosis (caspase-3). Finally, transient transfection of β1-integrin, in contrast to knockdown of NF-κB, abrogated most anti-invasive, anti-metastatic effects as well as downstream signaling of resveratrol, resulting in a concomitant increase in CRC cell invasion, indicating a central role of β1-integrin receptors in the anti-invasive function of resveratrol.

Conclusion: These results demonstrate for the first time that silencing β1-integrins may suppress, at least in part the inhibitory effects of resveratrol on invasion and migration of CRC cells, underscoring the crucial homeostatic role of β1-integrin receptors.
Therapeutic potential of WKYMVm in diseases
Authors: Ma Huan , Guo Xiaoming , Wang Zhiguo , Han Mei , Liu Hui
Published: September 2022

The synthetic hexapeptide WKYMVm, screened from a synthetic peptide library, has been identified as an agonist of FPRs with the strongest activating effect on FPR2. WKYMVm plays an anti-inflammatory role in most inflammatory diseases by increasing the chemotaxis of phagocytes and regulating the secretion of inflammatory factors. WKYMVm can inhibit or promote the progression of different types of tumors, which depends on the regulation of WKYMVm on various components such as immune cells, inflammatory factors, chemokines, and tumor epithelial cells. Another major function of WKYMVm is to promote angiogenesis, which is reflected in its therapeutic value in ischemic diseases, wound healing and bone repair. In addition to the above functions, this paper also reviews the effects of WKYMVm on fibrosis, insulin resistance, osteolytic diseases and neurodegenerative diseases. By summarizing related studies, this review can increase people’s comprehensive understanding of WKYMVm, promote its broad and in-depth research, and help to exert its therapeutic value as soon as possible.
Cardiac output monitoring with pulmonary versus trans-cardiopulmonary thermodilution in left ventricular assist devices: Interchangeable methods?
Authors: Quintana-Villamandos Begoña , Barranco Mónica , Fernández Ignacio , Ruiz Manuel , Del Cañizo Juan Francisco
Published: September 2022

Cardiac output (CO) measurement is mandatory in patients with left ventricular assist devices (LVADs). Thermodilution with pulmonary artery catheter (PAC) remains the clinical gold standard to measure CO in these patients, however it is associated with several complications. Therefore, the agreement between PAC and new, minimally invasive monitoring methods in LVAD needs to be further investigated. The aim of this study was to assess the accuracy and reliability of transpulmonary thermodilution with a PiCCO2 monitor compared with pulmonary artery thermodilution with PAC in a LVAD. Continuous-flow LVADs were implanted in six mini-pigs to assist the left ventricle. We studied two methods of measuring CO—intermittent transpulmonary thermodilution (COTPTD) by PiCCO2 and intermittent pulmonary artery thermodilution by CAP, standard technique (COPTD)—obtained in four consecutive moments of the study: before starting the LVAD (basal moment), and with the LVAD started in normovolemia, hypervolemia (fluid overloading) and hypovolemia (shock hemorrhage). A total of 72 paired measurements were analysed. At the basal moment, COTPTD and COPTD were closely correlated (r2 = 0.89), with a mean bias of −0.085 ± 0.245 L/min and percentage error of 16%. After 15 min of partial support LVAD, COTPTD and COPTD were closely correlated (r2 = 0.79), with a mean bias of −0.040 ± 0.417 L/min and percentage error of 26%. After inducing hypervolemia, COTPTD and COPTD were closely correlated (r2 = 0.78), with a mean bias of −0.093 ± 0.339 L/min and percentage error of 13%. After inducing hypovolemia, COTPTD and COPTD were closely correlated (r2 = 0.76), with a mean bias of −0.045 ± 0.281 L/min and percentage error of 28%. This study demonstrates a good agreement between transpulmonary thermodilution by PiCCO monitor and pulmonary thermodilution by PAC in the intermittent measurement of CO in a porcine model with a continuous-flow LVAD.
Opportunities and challenges of pain-related myocardial ischemia-reperfusion injury
Authors: Jiang Wenhua , Yin Yue , Gu Xiaoming , Zhang Zihui , Ma Heng
Published: September 2022

Pain is one of the most serious problems plaguing human health today. Pain is not an independent pathophysiological condition and is associated with a high impact on elevated disability and organ dysfunction. Several lines of evidence suggested the associations of pain with cardiovascular diseases, especially myocardial ischemia-reperfusion (I/R) injury, while the role of pain in I/R injury and related mechanisms are not yet comprehensively assessed. In this review, we attempted to explore the role of pain in myocardial I/R injury, and we concluded that acute pain protects myocardial ischemia-reperfusion injury and chronic pain aggravates cardiac ischemia-reperfusion injury. In addition, the construction of different pain models and animal models commonly used to study the role of pain in myocardial I/R injury were discussed in detail, and the potential mechanism of pain-related myocardial I/R injury was summarized. Finally, the future research direction was prospected. That is, the remote regulation of pain to cardiac function requires peripheral pain signals to be transmitted from the peripheral to the cardiac autonomic nervous system, which then affects autonomic innervation during cardiac ischemia-reperfusion injury and finally affects the cardiac function.
Ticking and talking in the brainstem satiety centre: Circadian timekeeping and interactions in the diet-sensitive clock of the dorsal vagal complex
Authors: Chrobok Lukasz , Ahern Jake , Piggins Hugh D.
Published: September 2022

The dorsal vagal complex (DVC) is a key hub for integrating blood-borne, central, and vagal ascending signals that convey important information on metabolic and homeostatic state. Research implicates the DVC in the termination of food intake and the transition to satiety, and consequently it is considered a brainstem satiety centre. In natural and laboratory settings, animals have distinct times of the day or circadian phases at which they prefer to eat, but if and how circadian signals affect DVC activity is not well understood. Here, we evaluate how intrinsic circadian signals regulate molecular and cellular activity in the area postrema (AP), nucleus of the solitary tract (NTS), and dorsal motor nucleus of the vagus (DMV) of the DVC. The hierarchy and potential interactions among these oscillators and their response to changes in diet are considered a simple framework in which to model these oscillators and their interactions is suggested. We propose possible functions of the DVC in the circadian control of feeding behaviour and speculate on future research directions including the translational value of knowledge of intrinsic circadian timekeeping the brainstem.
The impact of submaximal fatiguing exercises on the ability to generate and sustain the maximal voluntary contraction
Authors: Lebesque Loïc , Scaglioni Gil , Martin Alain
Published: September 2022

Neuromuscular fatigability is a failure to produce or maintain a required torque, and commonly quantified with the decrease of maximal torque production during a few seconds-long maximal voluntary contraction (MVC). The literature shows that the MVC reduction after exercises with different torque-time integral (TTI), is often similar. However, it was shown that after a fatiguing exercise, the decline in the capacity to sustain the maximal voluntary contraction for 1 min (MVC1-MIN) differs from the decrease in the capacity to perform a brief-MVC, suggesting that this latter can only partially assess neuromuscular fatigability. This study aims to highlight the relevance of using a sustained MVC to further explore the neuromuscular alterations induced by fatiguing exercises with different TTI. We used two contraction intensities (i.e., 20% and 40% MVC) to modulate the TTI, and two exercise modalities [i.e., voluntary (VOL) and electrical induced (NMES)], since the letter are known to be more fatiguing for a given TTI. Thirteen subjects performed a plantar-flexors MVC1-MIN before and after the fatiguing exercises. A similar MVC loss was obtained for the two exercise intensities despite a greater TTI at 40% MVC, regardless of the contraction modality. On the other hand, the torque loss during MVC1-MIN was significantly greater after the 40% compared to 20% MVC exercise. These findings are crucial because they demonstrate that maximal torque production and sustainability are two complementary features of neuromuscular fatigability. Hence, MVC1-MIN assessing simultaneously both capacities is essential to provide a more detailed description of neuromuscular fatigability.
Increased sulfur-containing amino acid content and altered conformational characteristics of soybean proteins by rebalancing 11S and 7S compositions
Authors: Wang Biao , Teng Da , Yu Cunhao , Yao Luming , Ma Xiaohong , Wu Tianlong
Published: September 2022

Soybean proteins are limited by their low contents of methionine and cysteine. Herein, 7S globulin accumulation was reduced using RNA interference to silence CG-β-1 expression, and the content of the A2B1a subunit was largely increased under the soybean seed-specific oleosin8 promoter. The results showed that the sulfur-containing amino acid content in soybean seeds drastically improved, reaching 79.194 nmol/mg, and the 11S/7S ratio had a 1.89-fold increase compared to the wild-type acceptor. The secondary structures of 11S globulin were also altered, and the β-sheet content increased with decreasing β-turn content, which was confirmed by Fourier transform infrared spectroscopy, Raman spectroscopy and circular dichroism analysis. Our findings suggested that raising the accumulation of 11S glycinin at the expense of reducing the content of 7S globulin is an attractive and precise engineering strategy to increase the amount of sulfur-containing amino acids, and soybean proteins with A2B1a subunits of 11S isolates improved, and β-subunits of 7S fractions reduced simultaneously might be an effective new material for food production.