bluuebunny/crossref_metadata_2025 huggingface dataset:
Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report
Authors: Yang James Chih-Hsin , Schuler Martin , Popat Sanjay , Miura Satoru , Park Keunchil , Passaro Antonio , De Marinis Filippo , Solca Flavio , Märten Angela , Kim Edward S.
Published: April 2022

Introduction

Previously, we developed a database of 693 patients with NSCLC and uncommon EGFR mutations treated with afatinib. Here, we provide an update of >1000 patients, with more data on specific mutations.

Methods

Patients were identified from a prospective database developed by Boehringer Ingelheim and via literature review. Mutations were categorized as T790M-positive, exon 20 insertions, major uncommon (G719X, L861Q, S768I) and ‘others’. Patients with compound mutations (≥2 EGFR mutations) were analyzed separately. Key endpoints were time to treatment failure (TTF) and objective response rate (ORR).

Results

Of 1023 patients included, 587 patients were EGFR TKI-naïve and 425 were EGFR TKI-pretreated. The distribution of mutation categories was: major uncommon (41.4%); exon 20 insertions (22.3%); T790M (20.3%); and ‘others’ (15.9%); 38.6% had compound mutations. Overall, median TTF (TKI naïve/pretreated) was 10.7 and 4.5 months. ORR was 49.8% and 26.8%, respectively. In TKI-naïve patients, afatinib demonstrated activity against major uncommon mutations (median TTF: 12.6 months; ORR: 59.0%), ‘other’ mutations (median TTF: 10.7 months; ORR: 63.9%) including strong activity against E709X (11.4 months; 84.6%) and L747X (14.7 months; 80.0%), and compound mutations (11.5 months; 63.9%). Although sample sizes were small, notable activity was observed against specific exon 20 insertions at residues A763, M766, N771, and V769, and against osimertinib resistance mutations (G724S, L718X, C797S).

Conclusion

Afatinib should be considered as a first-line treatment option for NSCLC patients with major uncommon, compound, ‘other’ (including E709X and L747X) and some specific exon 20 insertion mutations. Moderate activity was seen against osimertinib resistance EGFR mutations.
Human Epidermal Growth Factor Receptor 2 Overexpression and Amplification in Patients With Colorectal Cancer: A Large-Scale Retrospective Study in Chinese Population
Authors: Ni Shujuan , Wang Xin , Chang Jinjia , Sun Hui , Weng Weiwei , Wang Xu , Tan Cong , Zhang Meng , Wang Lei , Huang Zhaohui , Huang Dan , Xu Midie , Sheng Weiqi
Published: April 2022

Background

Cumulative evidence in colorectal cancer (CRC) suggests that patients with human epidermal growth factor receptor 2 (HER2) overexpression or amplification can benefit from anti-HER2 therapy. The purpose of our study was to evaluate HER2 status and its correlation with clinicopathological characteristics and survival according to currently utilized HER2 diagnostic criteria in a large cohort of Chinese CRC patients.

Methods

HER2 protein expression was tested by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded (FFPE) samples from 4,836 CRC patients in our institution. Breast cancer (BC) and gastroesophageal adenocarcinoma (GEA) criteria, as well as the HERACLES criteria, were used for the determination of HER2 status. Dual-color silver-enhanced in situ hybridization (DSISH) was performed in all IHC 2+~3+ cases determined by BC/GEA criteria.

Results

The HER2 expression rate of IHC (1+~3+) was 7.01% (339/4,836) and 6.02% (291/4,836) in CRCs based on the BC/GEA criteria and the HERACLES criteria, respectively, while combined DSISH results in the HER2 amplification/overexpression ratio of 3.39% (164/4,836) in our cohort. HER2 expression detected by IHC was positively correlated with the female gender, whereas the HER2 overexpression/amplification showed no correlation with any clinicopathological parameter. In addition, no significant correlation was found between HER2 statuses and either disease-free survival or overall survival regardless of the evaluation criterion used. However, patients with HER2 1+ CRC showed a tendency of having the shortest overall survival as compared with any other group of patients according to the HERACLES criteria, and this trend has always existed in the rectal location, T3 stage, and TNM stage II, medium differentiation, and perineural invasion stratified group. Furthermore, the HER2 protein expression was significantly negatively correlated with RAS/BRAF mutations according to the HERACLES criteria.

Conclusion

To our knowledge, this is the largest study of HER2 status in Asian patients with CRC. Our findings suggest that the current most commonly used HERACLES criteria might be too strict for patients with CRC. Future studies are needed to explore the most suitable criteria for screening CRC patients who could benefit from anti-HER2 therapy as much as possible.
Circular RNAs and Their Role in Exosomes
Authors: Han Zeping , Chen Huafang , Guo Zhonghui , Shen Jian , Luo Wenfeng , Xie Fangmei , Wan Yu , Wang Shengbo , Li Jianhao , He Jinhua
Published: April 2022

As a novel class of endogenous non-coding RNAs discovered in recent years, circular RNAs (circRNAs) are highly conserved and stable covalently closed ring structures with no 5′-end cap or 3′-end poly(A) tail. CircRNAs are formed by reverse splicing, mainly by means of a noose structure or intron complementary pairing. Exosomes are tiny discoid vesicles with a diameter of 40-100 nm that are secreted by cells under physiological and pathological conditions. Exosomes play an important role in cell-cell communication by carrying DNA, microRNAs, mRNAs, proteins and circRNAs. In this review, we summarize the biological functions of circRNAs and exosomes, and further reveal the potential roles of exosomal circRNAs in different diseases, providing a scientific basis for the diagnosis, treatment, and prognosis of a wide variety of diseases.
FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
Authors: Huo Xueyun , Zhang Wenjing , Zhao Guannan , Chen Zhenwen , Dong Peixin , Watari Hidemichi , Narayanan Ramesh , Tillmanns Todd D. , Pfeffer Lawrence M. , Yue Junming
Published: April 2022

Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent pathway. To effectively target FAK, it is required to block both FAK kinase-dependent and FAK-independent pathways. Thus, we tested a new generation drug FAK PROTAC for ovarian cancer therapy, which blocks both kinase and scaffold activity. We tested the efficacy of FAK PROTAC and its parent kinase inhibitor (VS-6063) in ovarian cancer cell lines in vitro by performing cell functional assays including cell proliferation, migration, invasion. We also tested in vivo activity in orthotopic ovarian cancer mouse models. In addition, we assessed whether FAK PROTAC disrupts kinase-dependent and kinase-independent pathways. We demonstrated that FAK PROTAC is highly effective as compared to its parent FAK kinase inhibitor VS-6063 in inhibiting cell proliferation, survival, migration, and invasion. FAK PROTAC not only inhibits the FAK kinase activity but also FAK scaffold function by disrupting the interaction between FAK and its interaction protein ASAP1. We further showed that FAK PROTAC effectively inhibits ovarian tumor growth and metastasis. Taken together, FAK PROTAC inhibits both FAK kinase activity and its scaffold protein activity by disrupting the interaction between FAK and ASAP1 and is highly effective in inhibiting ovarian tumor growth and metastasis.
Association Between Diabetes Risk Reduction Diet and Lung Cancer Risk in 98,159 Participants: Results From a Prospective Study
Authors: Zhang Yin , Zhong Guochao , Zhu Min , Chen Ling , Wan Huajing , Luo Fengming
Published: April 2022

Purpose

To evaluate the association between diabetes risk reduction diet (DRRD) score and the risk of lung cancer in a large population.

Methods

Data of participants in this study were collected from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in the Cox proportional hazards regression model for the association of DRRD score and lung cancer incidence in all included participants. Prespecified subgroup analyses were performed to evaluate whether the observed association was modified by age, sex, BMI, race/ethnicity, family history of lung cancer, smoking status and history of diabetes.

Results

A total of 98,159 participants were included in this study. The mean (SD) age of the study participants cohort at baseline was 65.5 (5.73) years old. The mean (SD) follow-up time was 8.83 (1.96) years. The mean (SD) score of DRRD was 26.82 (5.19), and ranged from 20.47 (2.3) to 33.65 (2.42) from the lowest quartile to the highest quartile of the DRRD score, inferring the possibility of highest through the lowest risk of type 2 diabetes. The calculated HRs showed there was a trend that higher quartile indicated lower risk of lung cancer after adjusted for covariates (HRQ4vsQ1: 0.85; 95% CI:0.73,0.98; p for trend =0.036). The inverse trend between higher DRRD score and the risk of squamous cell carcinoma was more evident (HRQ4vsQ1: 0.50; 95% CI:0.34,0.73; p for trend =0.002). The inverse association between DRRD score and the incidence of lung cancer was more pronounced in participants who had a clear family history of lung cancer (p for interaction=0.016).

Conclusion

A protective association between DRRD score and risk of lung cancer is obtained. People are encouraged to adhere to higher DRRD score in their daily diet. Further studies should be conducted to confirm the result and explore the mechanism.
METTL3-Mediated ADAMTS9 Suppression Facilitates Angiogenesis and Carcinogenesis in Gastric Cancer
Authors: Wang Nuofan , Huo Xinying , Zhang Baoguo , Chen Xiaoxiang , Zhao Shuli , Shi Xuesong , Xu Hao , Wei Xiaowei
Published: April 2022

The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration.
Case Report: Short-Term Response to First-Line Crizotinib Monotherapy in a Metastatic Lung Adenocarcinoma Patient Harboring a Novel TPR-ROS1 Fusion
Authors: Wei Shuli , Hu Mangsha , Yang Yan , Huang Xiaojie , Li Baizhou , Ding Liren , Wang Pingli
Published: April 2022

ROS1-rearranged patients account for 1-2% of non-small cell lung cancer (NSCLC) cases. Approximately 10 fusion partners have been discovered, while clinical practice is actively generating knowledge of new ones and their therapeutic responses. Herein, we report a patient with stage IV NSCLC that harbored a novel TPR-ROS1 fusion, which demonstrated a rapid but short partial response to first line crizotinib and primary resistance to subsequent ceritinib. Computed tomography detected a pulmonary nodule in a 53-year-old woman who presented with persistent cough. Histopathologic and molecular examination of the tissue biopsy indicated a poorly differentiated adenocarcinoma staining negative for PD-L1 but harbored a novel translocated promoter region (TPR)-ROS1 (T4:R35) gene fusion. Frontline crizotinib monotherapy elicited a rapid partial response after 1 month, although the disease progressed another 2 months later. After another 3 months of continued crizotinib treatment, the patient manifested newly emerged and enlarged lung and brain lesions. Genomic profiling still identified TPR-ROS1 as the only aberration, while a lymph node biopsy indicated PD-L1 immunopositivity. The patient was then treated with ceritinib and progressed within 1 month. She was started on chemotherapy with pemetrexed plus carboplatin and has achieved rapid partial response as of the latest follow-up. In summary, we provided clinical evidence of a novel TPR-ROS1 fusion and its roles as an oncogenic driver in metastatic NSCLC. To the best of our knowledge, ours is the first case to report this fusion in NSCLC. This case was characterized by a rapid yet short-term response to first line crizotinib and primary resistance to subsequent ceritinib, while no known genetic resistance mechanism was identified and other mechanisms including histologic transformation were unlikely. Future research is needed to unveil the resistance mechanism and formulate effective treatment strategies.
Organoids as a Systems Platform for SCLC Brain Metastasis
Authors: Quaranta Vito , Linkous Amanda
Published: April 2022

Small Cell Lung Cancer (SCLC) is a highly aggressive, neuroendocrine tumor. Traditional reductionist approaches have proven ineffective to ameliorate the uniformly dismal outcomes for SCLC – survival at 5 years remains less than 5%. A major obstacle to improving treatment is that SCLC tumor cells disseminate early, with a strong propensity for metastasizing to the brain. Accumulating evidence indicates that, contrary to previous textbook knowledge, virtually every SCLC tumor is comprised of multiple subtypes. Important questions persist regarding the role that this intra-tumor subtype heterogeneity may play in supporting the invasive properties of SCLC. A recurrent hypothesis in the field is that subtype interactions and/or transition dynamics are major determinants of SCLC metastatic seeding and progression. Here, we review the advantages of cerebral organoids as an experimentally accessible platform for SCLC brain metastasis, amenable to genetic manipulations, drug perturbations, and assessment of subtype interactions when coupled, e.g., to temporal longitudinal monitoring by high-content imaging or high-throughput omics data generation. We then consider systems approaches that can produce mathematical and computational models useful to generalize lessons learned from ex vivo organoid cultures, and integrate them with in vivo observations. In summary, systems approaches combined with ex vivo SCLC cultures in brain organoids may effectively capture both tumor-tumor and host-tumor interactions that underlie general principles of brain metastasis.
Development and Validation of a Prognostic Model for Post-Operative Recurrence of Pituitary Adenomas
Authors: Lu Liang , Wan Xueyan , Xu Yu , Chen Juan , Shu Kai , Lei Ting
Published: April 2022

Background

We aimed to assess clinical factors associated with tumor recurrence and build a nomogram based on identified risk factors to predict postoperative recurrence in patients with pituitary adenomas (PAs) who underwent gross-total resection (GTR).

Methods

A total of 829 patients with PAs who achieved GTR at Tongji Hospital between January 2013 and December 2018 were included in this retrospective study. The median follow-up time was 66.7 months (range: 15.6–106.3 months). Patients were randomly divided into training (n = 553) or validation (n = 276) cohorts. A range of clinical characteristics, radiological findings, and laboratory data were collected. Uni- and multivariate Cox regression analyses were applied to determine the potential risk factors for PA recurrence. A nomogram model was built from the identified factors to predict recurrence. Concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) were used to determine the predictive accuracy of the nomogram. Decision curve analysis (DCA) was performed to evaluate the clinical efficacy of the nomogram.

Results

Pseudocapsule-based extracapsular resection (ER), cavernous sinus invasion (CSI), and tumor size were included in the nomogram. C-indices of the nomogram were 0.776 (95% confidence interval [CI]: 0.747–0.806) and 0.714 (95% CI: 0.681–0.747) for the training and validation cohorts, respectively. The area under the curve (AUC) of the nomogram was 0.770, 0.774, and 0.818 for 4-, 6-, 8-year progression-free survival (PFS) probabilities in the training cohort, respectively, and 0.739, 0.715 and 0.740 for 4-, 6-, 8-year PFS probabilities in the validation cohort, respectively. Calibration curves were well-fitted in both training and validation cohorts. DCA revealed that the nomogram model improved the prediction of PFS in both cohorts.

Conclusions

Pseudocapsule-based ER, CSI, and tumor size were identified as independent predictors of PA recurrence. In the present study, we developed a novel and valid nomogram with potential utility as a tool for predicting postoperative PA recurrence. The use of the nonogram model can facilitate the tailoring of counseling to meet the individual needs of patients.
Microsatellite Instability and Metastatic Colorectal Cancer – A Clinical Perspective
Authors: Buchler Tomas
Published: April 2022

Approximately 4-5% of patients with metastatic colorectal cancer (mCRC) have mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumours. These tumours present challenges in the clinical practice due to variant response to fluoropyrimidine-based chemotherapy and, perhaps, also non-immunologic targeted therapies. Recently, a breakthrough in the treatment of dMMR/MSI-H mCRC has been achieved with several clinical trials showing dramatic long-term benefit of immunotherapy using checkpoint inhibitors. Nevertheless, several questions remain regarding the optimisation of immunotherapy regimens and the use of biomarkers to identify populations set to derive the greatest benefit from immunotherapy. Combination regimens and/or the use of immunotherapy as a maintenance after induction non-immunologic systemic therapy may be the way forward to improve outcomes.
Noninvasive Pediatric Liver Fibrosis Measurement: Two-Dimensional Shear Wave Elastography Compared With Transient Elastography
Authors: Tran Léa Chantal , Ley Delphine , Bourdon Gurvan , Coopman Stéphanie , Lerisson Héloïse , Tillaux Céline , Béhal Hélène , Gottrand Frédéric , Aumar Madeleine
Published: April 2022

Objectives

Although transient elastography (TE) is the primary noninvasive method for assessing liver fibrosis, its use remains to be validated in children. This study aims to evaluate the agreement between two-dimensional ultrasound shear wave elastography (2D-SWE) and TE to assess pediatric liver stiffness method.

Methods

During the 18-month study, we prospectively included 101 consecutive children (median age: 8.5 years, range: 1 month to 17 years) who required TE for medical reasons, and in whom 2D-SWE measurement was performed within a 3-month follow-up during a routine ultrasound. Liver elasticity values were classified according to the Metavir score using published pediatric norms for TE and according to the manufacturer's reference values for 2D-SWE. The Spearman's correlation coefficient was used to assess the relationship between the elasticity measured by the two techniques. Concordance was described by the Bland–Altman method.

Results

A strong correlation (rho = 0.70, p < 0.001) was found between 2D-SWE and TE for the elasticity measures. The strength of correlation was higher among patients older than 6 years (rho = 0.79, p < 0.001). Concordance between liver fibrosis stages assessed by these techniques was moderate [weighted kappa = 0.46, (95% CI: 0.35–0.57)]. When considering stages over F2, 2D-SWE diagnostic performances showed a sensitivity of 85% (95% CI: 74–92) and a specificity of 57% (95% CI: 42–70) compared with TE.

Conclusion

Measurements of the liver stiffness using 2D-SWE and TE are strongly correlated. The moderate concordance between these techniques for assessing the liver fibrosis stage provides evidence against alternating between these methods during follow-up of patients with the chronic liver diseases.
Prevalence and Risk Factors for Rapid Eye Movement-Related Obstructive Sleep Apnea in Children
Authors: Chamnanpet Surisa , Tovichien Prakarn , Tanphaichitr Archwin , Chotinaiwattarakul Wattanachai
Published: April 2022

Objectives

Different pathophysiological mechanisms and the distribution of respiratory events among rapid eye movement (REM) and non-rapid eye movement (NREM) sleep modulate the effect of obstructive sleep apnea (OSA). We aimed to study the prevalence and risk factors for REM-related OSA in children.

Study Design

Retrospective, cross-sectional study.

Methods

We recruited 366 children with OSA confirmed by polysomnography (PSG) over a 5-year period. REM-related OSA is defined by an obstructive apnea-hypopnea index (OAHI) in the REM sleep ≥2× than during NREM sleep.

Results

The prevalence of REM-related OSA in children was 50.3%. Children with REM-related OSA were more likely to be female (P = 0.042), and had lower prevalence of adenotonsillar hypertrophy (P = 0.043) compared with children with other OSA subtypes. Children with REM-related OSA slept longer in the supine position (P = 0.003), had shorter duration of NREM1 sleep (P = 0.018), lower nadir SpO2 (P = 0.005), and a higher oxygen desaturation index 3% (ODI3%) (P = 0.014), and lower arousal index (P = 0.034) compared with other OSA subtypes. Female gender and supine sleep was the independent risk factors for REM-related OSA.

Conclusion

The prevalence of REM-related OSA was 50.3%. OAHIREM should be considered as an important parameter in future clinical research studies done in children with OSA.
Effects of Early Motor Interventions on Gross Motor and Locomotor Development for Infants at-Risk of Motor Delay: A Systematic Review
Authors: Dumuids-Vernet Marie-Victorine , Provasi Joëlle , Anderson David Ian , Barbu-Roth Marianne
Published: April 2022

Aim

To systematically examine the effect of early motor interventions on motor and locomotor development in infants <1 year of age with motor developmental disability or at risk of motor delay.

Methods

Pertinent literature from January 2000 to September 2021 was identified by searching the PubMed, Embase, Cochrane, Pedro and Web of Science databases. Selection criteria included interventions starting before 12 months corrected age. Methodological quality was assessed with AACPDM criteria, Mallen score and Cochrane risk of bias methodology. Evaluation procedure was performed using PRISMA protocol (PICO approach) and AMSTAR-2. This review was preregistered in PROSPERO (CRD42021286445).

Results

Ten articles met the inclusion criteria; seven had moderate to strong methodological quality. The interventions included treadmill training (n = 3), crawling training (n = 1), “tummy time” (n = 1), physical therapy with neonatal developmental program (n = 1) or Bobath approach (n = 1), treadmill training combined with active leg movements (n = 2) or Bobath physiotherapy (n = 1). The three key characteristics of effective interventions that emerged from the review were: (1) the infants' disability or risk of delay was well-defined; (2) the protocol was standardized and easy to replicate; (3) infants were required to make active movements.

Conclusion

There is an urgent need for additional high-quality studies on the effects of early motor interventions on the gross motor and locomotor development of infants with a range of disabilities or risks for delay. Suggestions for future research are outlined.
Xanthine Derivative KMUP-1 Attenuates Experimental Periodontitis by Reducing Osteoclast Differentiation and Inflammation
Authors: Kuo Cheng-Hsiang , Zhang Ban-Hua , Huang Shang-En , Hsu Jong-Hau , Wang Yan-Hsiung , Nguyen Thi Tuyet Ngan , Lai Chao-Han , Yeh Jwu-Lai
Published: April 2022

Periodontitis is an inflammatory disease of gum that may predispose to serious systemic complications such as diabetes and cardiovascular diseases. Activation of macrophages and osteoclasts around periodontal tissue can accelerate gum inflammation. In addition, alteration of cyclic nucleotide levels is associated with the severity of periodontitis. Our previous study has shown that KMUP-1, a xanthine derivative exhibiting phosphodiesterase inhibition and soluble guanylyl cyclase activation, can inhibit lipopolysaccharide (LPS)-induced inflammation and receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. This study was aimed to investigate whether KMUP-1 could attenuate periodontitis both in vitro and in vivo. In vitro, the protective effect of KMUP-1 on inflammation and osteoclastogenesis was investigated in RANKL-primed RAW264.7 cells treated by Porphyromonas gingivalis LPS (PgLPS). The results showed that KMUP-1 attenuated PgLPS-induced osteoclast differentiation as demonstrated by decreased TRAP-positive multinuclear cells and TRAP activity. This reduction of osteoclast differentiation by KMUP-1 was reversed by KT5823, a protein kinase G inhibitor. Similarly, pro-inflammatory cytokine levels induced by PgLPS were inhibited by KMUP-1 in a dose-dependent manner whereas reversed by KT5823. Mechanistically, suppression of MAPKs, PI3K/Akt, and NF-κB signaling pathways and decrease of c-Fos and NFATc1 expression in osteoclast precursors by KMUP-1 may mediate its protective effect. In vivo, two models of periodontitis in rats were induced by gingival injections of PgLPS and ligature placement around molar teeth, respectively. Our results showed that KMUP-1 inhibited alveolar bone loss in both rat models, and this effect mediated at least partly by reduced osteoclastogenesis. In conclusion, our study demonstrated the therapeutic potential of KMUP-1 on periodontitis through suppression of inflammation and osteoclast differentiation.
Di’ao Xinxuekang Capsule Improves the Anti-Atherosclerotic Effect of Atorvastatin by Downregulating the SREBP2/PCSK9 Signalling Pathway
Authors: Liang Jiyi , Li Wei , Liu Honglin , Li Xiaofen , Yuan Chuqiao , Zou Wenjun , Qu Liping
Published: April 2022

Statins are the first choice for lowering low-density lipoprotein cholesterol (LDL-C) and preventing atherosclerotic cardiovascular disease (ASCVD). However, statins can also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn might limits the cholesterol-lowering effect of statins through the degradation of LDL receptors (LDLR). Di’ao Xinxuekang (DXXK) capsule, as a well-known traditional Chinese herbal medicine for the prevention and treatment of coronary heart disease, can alleviate lipid disorders and ameliorate atherosclerosis in atherosclerosis model mice and downregulate the expression of PCSK9. In this study, we further explored whether DXXK has a synergistic effect with atorvastatin (ATO) and its underlying molecular mechanism. The results showed that both ATO monotherapy (1.3 mg/kg) and ATO combined with DXXK therapy significantly lowered serum lipid levels and reduced the formation of atherosclerotic plaques and the liver lipid accumulation. Moreover, compared with ATO monotherapy, the addition of DXXK (160 mg/kg) to the combination therapy further lowered LDL-C by 15.55% and further reduced the atherosclerotic plaque area by 25.98%. In addition, the expression of SREBP2, PCSK9 and IDOL showed a significant increase in the model group, and the expression of LDLR was significantly reduced; however, there were no significant differences between the ATO (1.3 mg/kg) and the model groups. When ATO was combined with DXXK, the expression of LDLR was significantly increased and was higher than that of the model group and the expression of SREBP2 and PCSK9 in the liver was also significantly inhibited. Moreover, it can be seen that the expression of SREBP2 and PCSK9 in the combination treatment group was significantly lower than that in the ATO monotherapy group (1.3 mg/kg). Besides, the expression of IDOL mRNA in each treatment group was not significantly different from that of the model group. Our study suggests that DXXK might have a synergistic effect on the LDL-C lowering and antiatherosclerosis effects of ATO through the SREBP2/PCSK9 pathway. This indicates that a combination of DXXK and ATO may be a new treatment for atherosclerosis.
Effect of Combined Mycophenolate and Rapamycin Treatment on Kidney Fibrosis in Murine Lupus Nephritis
Authors: Zhang Chenzhu , Tam Tsz Wai , Chau Mel KM , García Córdoba Cristina Alexandra , Yung Susan , Chan Tak Mao
Published: April 2022

Background: A significant proportion of lupus nephritis patients develop chronic kidney disease (CKD) and progressive kidney fibrosis, for which there is no specific treatment. We previously reported that mycophenolate or rapamycin monotherapy showed comparable efficacy in suppressing kidney fibrosis in a murine model of lupus nephritis through their direct action on mesangial cells. We extended our study to investigate the effect of combined mycophenolate and rapamycin treatment (MR) on kidney fibrosis in NZBWF1/J mice.

Methods: Female NZBWF1/J mice with active nephritis were randomized to receive vehicle or treatment with mycophenolate (50 mg/kg/day) and rapamycin (1.5 mg/kg/day) (MR) for up to 12 weeks, and the effect of treatment on clinical parameters, kidney histology, and fibrotic processes was investigated.

Results: Progression of nephritis in untreated mice was accompanied by mesangial proliferation, glomerulosclerosis, tubular atrophy, protein cast formation, increased mTOR and ERK phosphorylation, and induction of TGF-β1, IL-6, α-smooth muscle actin, fibronectin, and collagen expression. Combined MR treatment prolonged survival, improved kidney function, decreased anti-dsDNA antibody level, and ameliorated histopathological changes. The effect of combined MR treatment on kidney histology and function was comparable to that of mycophenolate or rapamycin monotherapy. In vitro studies in human mesangial cells showed that exogenous TGF-β1 and IL-6 both induced mTOR and ERK phosphorylation and downstream fibrotic processes. Both mycophenolic acid and rapamycin inhibited inflammatory and fibrotic processes induced by TGF-β1 or IL-6 by downregulating mTOR and ERK phosphorylation.

Conclusions: Our findings indicate that combined mycophenolate and rapamycin, at reduced dose, improves kidney fibrosis in murine lupus nephritis through their distinct effect on mTOR and ERK signaling in mesangial cells.
Cannabinoid Use for Pain Reduction in Spinal Cord Injuries: A Meta-Analysis of Randomized Controlled Trials
Authors: Tsai Sung Huang Laurent , Lin Chun-Ru , Shao Shih-Chieh , Fang Chao-Hua , Fu Tsai-Sheng , Lin Tung-Yi , Hung Yu-Chiang
Published: April 2022

Background: Spinal cord injury (SCI) often involves multimodal pain control. This study aims to evaluate the efficacy and safety of cannabinoid use for the reduction of pain in SCI patients.

Methods and Findings: This study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. We searched PubMed, EMBASE, Scopus, Cochrane, Web of Science, and ClinicalTrials.gov for relevant randomized controlled trials (RCTs) reporting the efficacy (e.g., pain relief) or safety (e.g., adverse events) of cannabinoids in patients with SCI, from inception to 25 December 2021. The study quality and the quality of evidence were evaluated by Cochrane ROB 2.0 and the Grading of Recommendations, Assessment, Development, and Evaluations system (GRADE), respectively. We used the random-effects model to perform the meta-analysis. From a total of 9,500 records, we included five RCTs with 417 SCI patients in the systematic review and meta-analysis. We judged all five of the included RCTs as being at high risk of bias. This meta-analysis indicated no significant difference in pain relief between the cannabinoids and placebo in SCI patients (mean difference of mean differences of pain scores: −5.68; 95% CI: −13.09, 1.73; p = 0.13; quality of evidence: very low), but higher odds of adverse events were found in SCI patients receiving cannabinoids (odds ratio: 3.76; 95% CI: 1.98, 7.13; p < 0.0001; quality of evidence: moderate).

Conclusion: The current best evidence suggests that cannabinoids may not be beneficial for pain relief in SCI patients, but they do increase the risks of adverse events, including dizziness, somnolence, and dysgeusia, compared to the placebo. Cannabinoids should not be regularly suggested for pain reduction in SCI patients. Updating the systematic reviews and meta-analyses by integrating future RCTs is necessary to confirm these findings.
Network Pharmacology and Bioinformatics Analyses Identify Intersection Genes of Vitamin D3 and COVID-19 as Potential Therapeutic Targets
Authors: Wang Shanglin , Gao Huayu , Wang Xiaoru , Ma Xiaoli , Zhang Lulu , Xing Yuanxin , Jia Yanfei , Wang Yunshan
Published: April 2022

Purpose: The persistent pandemic of coronavirus disease 2019 (COVID-19), the discovery of gastrointestinal transmission routes and the possible susceptibility of cancer patients to COVID-19 have forced us to search for effective pathways against stomach adenocarcinoma (STAD)/COVID-19. Vitamin D3 (VD3) is a steroid hormone with antiviral, anti-inflammatory and immunomodulatory properties. This study aimed to evaluate the possible functional role and potential mechanisms of action of VD3 as an anti-COVID-19 and anti- STAD.

Methods: Clinicopathological analysis, enrichment analysis and protein interaction analysis using bioinformatics and network pharmacology methods. Validate the binding activity of VD3 to core pharmacological targets and viral crystal structures using molecular docking.

Results: We revealed the clinical characteristics of STAD/COVID-19 patients. We also demonstrated that VD3 may be anti- STAD/COVID-19 through antiviral, anti-inflammatory, and immunomodulatory pathways. Molecular docking results showed that VD3 binds well to the relevant targets of COVID-19, including the spike RBD/ACE2 complex and main protease (Mpro, also known as 3CLpro). We also identified five core pharmacological targets of VD3 in anti-STAD/COVID-19 and validated the binding activity of VD3 to PAI1 by molecular docking.

Conclusion: This study reveals for the first time that VD3 may act on disease target gene SERPINE1 through inflammatory and viral related signaling pathways and biological functions for the therapy of STAD/COVID-19. This may provide a new idea for the use of VD3 in the treatment of STAD/COVID-19.
Shenling Baizhu Powder Alleviates TNBS-Induced Colitis in Rats by Improving Intestinal Epithelial Permeability and Inhibiting Inflammation Through the TLR5/MyD88/NF-κB Pathway
Authors: Rao Kehan , Qin Shumin , Yang Yuanming , Zhan Kai , Wu Haomeng , Zheng Huan , Huang Shaogang
Published: April 2022

Aim of the study: To evaluate the protective effect and mechanism of shenling baizhu powder (SBP) on TNBS-induced colitis.

Methods: Rats were given TNBS to establish the model of colitis and subsequently treated with different doses of SBP or mesalamine (MES). In addition, the expression of the TLR5/MyD88/NF-κB signaling pathway and critical targets of the intestinal mucosal barrier was detected by immunochemical analysis techniques.

Results: SBP significantly ameliorated the symptoms of TNBS-induced colitis in rats and reduced the secretion of pro-inflammatory cytokines. SBP could effectively strengthen epithelial barrier integrity in TNBS-induced colitis by increasing the secretion of mucin and tight junction and inhibiting apoptosis. Furthermore, we identified the crucial role of the TLR5/MyD88/NF-κB signaling pathway in exerting the therapeutic effect of SBP.

Conclusion: The results of our study suggest that SBP has therapeutic effects on TNBS-induced colitis and potential value in treating and maintaining remission of colitis.
Recent Advances in Chitosan and its Derivatives in Cancer Treatment
Authors: Ding Jingxian , Guo Yonghong
Published: April 2022

Cancer has become a main public health issue globally. The conventional treatment measures for cancer include surgery, radiotherapy and chemotherapy. Among the various available treatment measures, chemotherapy is still one of the most important treatments for most cancer patients. However, chemotherapy for most cancers still faces many problems associated with a lot of adverse effects, which limit its therapeutic potency, low survival quality and discount cancer prognosis. In order to decrease these side effects and improve treatment effectiveness and patient’s compliance, more targeted treatments are needed. Sustainable and controlled deliveries of drugs with controllable toxicities are expected to address these hurdles. Chitosan is the second most abundant natural polysaccharide, which has excellent biocompatibility and notable antitumor activity. Its biodegradability, biocompatibility, biodistribution, nontoxicity and immunogenicity free have made chitosan become a widely used polymer in the pharmacology, especially in oncotherapy. Here, we make a brief review of the main achievements in chitosan and its derivatives in pharmacology with a special focus on their agents delivery applications, immunomodulation, signal pathway modulation and antitumor activity to highlight their role in cancer treatment. Despite a large number of successful studies, the commercialization of chitosan copolymers is still a big challenge. The further development of polymerization technology may satisfy the unmet medical needs.
Efficacy and Safety of Qili Qiangxin Capsule on Dilated Cardiomyopathy: A Systematic Review and Meta-Analysis of 35 Randomized Controlled Trials
Authors: Wei Jingjing , Li Bin , Wang Xinlu , Li Xingyuan , Hu Yucai , Qiao Lijie , Zhou Cheng , Yu Peng , Sang Tianqing , Zhu Mingjun , Wang Yongxia
Published: April 2022

Objective: Qili Qiangxin Capsule (QQC), a Chinese patent medicine, is clinically effective in treating dilated cardiomyopathy (DCM). However, the meta-analysis of QCC combined with conventional western medicine (CWM) on DCM remains unexplored. This study aimed to systematically evaluate the efficacy and safety of QCC in the treatment of DCM.

Methods: Searched the studies of the combination of QQC and CWM in the treatment of DCM, from databases like PubMed, Cochrane Library, Web of Science, Wan Fang Databases, Chinese Biomedical Literature Database, China Science and Technology Journal Database, China National Knowledge Infrastructure, prior to 15 January 2022. Two reviewers respectively regulated research selection, data extraction, and risk of bias assessment. Review Manager Software 5.4 was used for meta-analysis. Furthermore, GRADE pro3.6.1 software was selected to grade the current evidence in our findings. This meta-analysis has been registered in PROSPERO (CRD42022297906).

Results: There were 35 studies pertaining to 3,334 patients included. The meta-analysis showed compared with CWM alone, the combination therapy had significant advantages in improving the clinical efficiency rate (RR = 1.24, 95% CI: 1.19 to 1.29, p < 0.00001), 6 min walking distance (6MWD) (MD = 41.93, 95%CI: 39.82 to 44.04, p < 0.00001), superior in ameliorating the left ventricular ejection fraction (LVEF) (MD = 5.73, 95%CI: 4.70 to 6.77, p < 0.00001), left ventricular end-diastolic dimension (LVEDD) (MD = −4.09, 95%CI: −4.91 to −3.27), p < 0.00001), left ventricular end-systolic diameter (LVESD) (MD = −4.73, 95%CI: −5.63 to −3.84), p < 0.00001) and BNP (MD = −101.09, 95%CI: -132.99 to −69.18), p < 0.00001), and also superior in reducing hypersensitive-C-Reactive Protein (hs-CRP) (MD = −3.78, 95%CI: −4.35 to −3.21), p < 0.00001), Interleukin- 6 (IL-6) (MD = −25.92, 95%CI: −31.35 to -20.50), p < 0.00001), tumor necrosis factor-α (TNF-α) (MD = -5.04, 95%CI: −6.13 to −3.95), p < 0.00001), high mobility group protein B1 (HMGB1) (MD = −4.34, 95%CI: −5.22 to −3.46), p < 0.00001), and adverse reactions (ARs) (RR = 0.70, 95%CI: 0.51–0.97), p = 0.03). The GRADE evidence quality rating presented with moderate or low quality of evidence for the available data.

Conclusion: Compared with the control group, QQC combined with CWM may be effective in treating DCM. However, the conclusion of this study must be interpreted carefully due to the inferior quality and ambiguity of bias in the included trials.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier [CRD42022297906].
Peripheral Immune Activation in Mice Elicits Unfolded Protein Responses Independent on MyD88 Pathway in the Liver but not the Hypothalamus and Hippocampus
Authors: Yamawaki Yosuke , Kimura Hitomi , Nagata Susumu , Ozawa Koichiro , Hosoi Toru
Published: April 2022

Neuroimmune interactions between the immune system and CNS as well as peripheral organs such as the liver play a key role in the pathophysiological state of diseases. Unfolded protein responses (UPRs), which are activated by cells in response to endoplasmic reticulum stress, have been linked to the occurrence of inflammation diseases, neurodegenerative diseases, and metabolic disorders such as type 2 diabetes. Peripheral injection of lipopolysaccharide (LPS) is known to induce a systemic inflammatory response, along with fever, anorexia, and depressive behaviors. LPS also elicits UPRs, although the underlying physiological mechanism remains unclear. In the present study, we investigated whether peripheral activation of the immune system can elicit UPRs in the CNS and liver. Peripheral injection of LPS is known to elevate pro-inflammatory cytokines in the liver, hypothalamus and hippocampus. We report that LPS-induced systemic inflammation elicits UPRs in the liver, but not the hypothalamus. Injection of LPS upregulated the expression levels of glucose-regulated protein 78 and pro-apoptotic transcription factor C/EBP homologous protein, along with increased splicing of X-box binding protein one mRNA in the liver, but not in the hypothalamus and hippocampus. Myeloid differentiation primary response 88 (MyD88), an adaptor protein, is known to play a key role in the signal transduction of LPS mediated by Toll-like receptor 4. Using MyD88 deficient mice, we found that LPS-induced UPRs occurred independently of MyD88 expression. In summary, peripheral activation of the immune system elicits UPRs in the liver, but not the hypothalamus and hippocampus, which may have implications for the pathophysiology of diseases.
Increased Serum Levels of Proinflammatory Cytokines Are Accompanied by Fatigue in Military T-6A Texan II Instructor Pilots
Authors: Damato Elizabeth G. , Fillioe Seth J. , Margevicius Seunghee P. , Mayes Ryan S. , Somogyi Jonathan E. , Vannix Ian S. , Abdollahifar Alireza , Turner Anthony M. , Ilcus Lidia S. , Decker Michael J.
Published: April 2022

Tactical aviation imposes unprecedented physical challenges including repetitive exposure to hypergravity, hyperoxia, increased work of breathing, and profound cognitive workloads. Each stressor evokes outcomes ranging from musculoskeletal duress and atelectasis to physical and cognitive fatigue, the latter among the foremost threats to aviators. Whereas sleep loss is traditionally considered the primary cause of fatigue in aviators, converging experimental, observational, and medical studies have identified biochemical mechanisms promoting onset of fatigue. Those mechanisms, which fundamentally differ from sleep loss, revolve around increased proinflammatory cytokines, produced and released in response to tissue injury, chronic inflammatory disorders, allergens, or physical duress. This study’s objective was to inform our understanding of potential relationships between serum levels of proinflammatory cytokines and onset of fatigue within a cohort of aviators who experience multiple high-performance sorties on a daily basis.

Methods:Active duty and reservist T-6A Texan II instructor pilots were studied on three separate days across their week-long flying schedule. Data collected included a physical assessment, subjective fatigue levels, venous blood samples for measures of chemistry and serum analytes, and urine samples for specific gravity.

Results:Twenty-three persons were studied, of which 22 fulfilled minimum study requirements of completing two sorties. The study cohort was comprised of primarily males, age 37.95 ± 4.73 years with a BMI of 26.63 ± 3.15 kg/m2. Of 37 measurable serum analytes, 20 differed significantly (p< 0.05) between baseline values with those measured at the study endpoint. Thirteen of the aviators reported increased fatigue scores across their flying schedule whereas nine did not. Eleven blood serum analytes were associated with increasing levels of fatigue.

Discussion:Fatigue in aviators has been attributed almost solely to sleep loss, nocturnal sorties, or disrupted circadian rhythmicity. In contrast, our study findings suggest an alternative mechanism that can promote onset of fatigue: increased blood levels of proinflammatory cytokines. Specific mechanisms triggering synthesis and release of those cytokines and other analytes are yet to be determined. However, their expression patterns suggest responses to both chronic and acute inflammation, hyperoxia, or bronchopulmonary responses to inspiration of dry gas, positive airway pressure, or perhaps atelectasis.
Basal Vascular Smooth Muscle Cell Tone in eNOS Knockout Mice Can Be Reversed by Cyclic Stretch and Is Independent of Age
Authors: De Moudt Sofie , Hendrickx Jhana O. , De Meyer Guido R. Y. , Martinet Wim , Fransen Paul
Published: April 2022

Introduction and Aims: Endothelial nitric oxide synthase (eNOS) knockout mice develop pronounced cardiovascular disease. In the present study, we describe the alterations in aortic physiology and biomechanics of eNOS knockout and C57Bl/6 control mice at 2–12 months of age, including a thorough physiological investigation of age and cyclic stretch-dependent VSMC contractility and aortic stiffness.

Methods and Results: Peripheral blood pressure and aortic pulse wave velocity were measured in vivo, and aortic biomechanical studies and isometric contractions were investigated ex vivo. Age-dependent progression of aortic stiffness, peripheral hypertension, and aortic contractility in eNOS knockout mice was absent, attenuated, or similar to C57Bl/6 control mice. Voltage-gated calcium channel (VGCC)-dependent calcium influx inversely affected isometric contraction and aortic stiffening by α1-adrenergic stimulation in eNOS knockout mice. Baseline aortic stiffness was selectively reduced in eNOS knockout mice after ex vivo cyclic stretch exposure in an amplitude-dependent manner, which prompted us to investigate cyclic stretch dependent regulation of aortic contractility and stiffness. Aortic stiffness, both in baseline conditions and after activation of vascular smooth muscle cell (VSMC) contraction, was reduced with increasing cyclic stretch amplitude. This cyclic stretch dependency was attenuated with age, although aged eNOS knockout mice displayed better preservation of cyclic stretch-dependency compared to C57Bl/6 control mice. Store operated calcium entry-medicated aortic stiffening as induced by inhibiting sarcoplasmic reticulum calcium ATPase pumps with 10 µM CPA was most pronounced in the aorta of aged mice and at low cyclic stretch amplitude, but independent of eNOS. Basal aortic tonus and VSMC depolarization were highly dependent on eNOS, and were most pronounced at low cyclic stretch, with attenuation at increasing cyclic stretch amplitude.

Conclusion: eNOS knockout mice display attenuated progression of arterial disease as compared to C57Bl/6 control mice. Basal VSMC tone in eNOS knockout mice could be reduced by ex vivo exposure to cyclic stretch through stretch-dependent regulation of cytosolic calcium. Both baseline and active aortic stiffness were highly dependent on cyclic stretch regulation, which was more pronounced in young versus aged mice. Other mediators of VSMC contraction and calcium handling were dependent on cyclic stretch mechanotransduction, but independent of eNOS.