Publications by authors named "Ziwei Huang"

112 Publications

Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis.

Front Oncol 2021 16;11:562315. Epub 2021 Apr 16.

Department of Medical Oncology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.

Background: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens.

Methods: Published articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata.

Results: A total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09-24.03), a median TTR of 2.05 months (m) (95%CI: 1.85-2.26), and a median DOR of 10.65 m (95%CI: 7.78-13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02-57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47-21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56-22.94]), while I+C (8.09 m [95%CI: 6.86-9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60-17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations.

Conclusions: PD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.
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http://dx.doi.org/10.3389/fonc.2021.562315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085334PMC
April 2021

Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors.

Transl Lung Cancer Res 2021 Mar;10(3):1397-1407

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Background: Advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS) are likely to receive programmed cell death 1 (PD-1) inhibitors, despite limited evidence. The aim of the present study was to report the clinical outcomes and potential prognostic biomarkers in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.

Methods: We conducted a retrospective study enrolling 101 advanced NSCLC patients from our hospital. Data of patients with poor PS 2-4 receiving PD-1 inhibitors were retrieved from medical records. Patients were stratified based on dichotomized baseline neutrophil-to-lymphocyte ratio (NLR), change in NLR (ΔNLR; 6 weeks post-treatment NLR minus baseline NLR), and their combination. The receiver-operating characteristic curve was used to assess the best cutoff for NLR. Multivariate Cox analysis was used to evaluate the prognostic value of NLR and ΔNLR for patients' survival.

Results: The optimal cutoff for NLR was 4.5. The median follow-up was 25.7 months, baseline NLR ≥4.5, and ΔNLR ≥0, which were independently and significantly associated with shorter overall survival (both P=0.002) and progression-free survival (P=0.004 for NLR and P<0.001 for ΔNLR). Furthermore, simultaneous elevation of the 2 factors was associated with worsened prognosis; patients with both NLR ≥4.5 and ΔNLR ≥0 had significantly increased risk of death [hazards ratio (HR): 10.79, 95% confidence interval (CI): 4.30-27.10] and disease progression (HR: 10.49, 95% CI: 4.39-25.09), compared with both low NLR and ΔNLR patients. Patients with either NLR ≥4.5 or ΔNLR ≥0 showed an intermediate risk for death (HR: 3.12, 95% CI: 1.35-7.21) and progression (HR: 3.45, 95% CI: 1.62-7.36).

Conclusions: High baseline NLR and increased post-treatment NLR might aid in the stratification of high progression and death risk groups in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.
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http://dx.doi.org/10.21037/tlcr-21-43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044483PMC
March 2021

Reducing bias to source samples for unsupervised domain adaptation.

Neural Netw 2021 Mar 26;141:61-71. Epub 2021 Mar 26.

School of Computer Science and Engineering, University of Electronic Science and Technology of China, China.

Unsupervised Domain Adaptation (UDA) makes predictions for the target domain data while labels are only available in the source domain. Lots of works in UDA focus on finding a common representation of the two domains via domain alignment, assuming that a classifier trained in the source domain can be generalized well to the target domain. Thus, most existing UDA methods only consider minimizing the domain discrepancy without enforcing any constraint on the classifier. However, due to the uniqueness of each domain, it is difficult to achieve a perfect common representation, especially when there is low similarity between the source domain and the target domain. As a consequence, the classifier is biased to the source domain features and makes incorrect predictions on the target domain. To address this issue, we propose a novel approach named reducing bias to source samples for unsupervised domain adaptation (RBDA) by jointly matching the distribution of the two domains and reducing the classifier's bias to source samples. Specifically, RBDA first conditions the adversarial networks with the cross-covariance of learned features and classifier predictions to match the distribution of two domains. Then to reduce the classifier's bias to source samples, RBDA is designed with three effective mechanisms: a mean teacher model to guide the training of the original model, a regularization term to regularize the model and an improved cross-entropy loss for better supervised information learning. Comprehensive experiments on several open benchmarks demonstrate that RBDA achieves state-of-the-art results, which show its effectiveness for unsupervised domain adaptation scenarios.
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http://dx.doi.org/10.1016/j.neunet.2021.03.021DOI Listing
March 2021

Gut Microbiota-Mediated Transformation of Coptisine Into a Novel Metabolite 8-Oxocoptisine: Insight Into Its Superior Anti-Colitis Effect.

Front Pharmacol 2021 30;12:639020. Epub 2021 Mar 30.

School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.

Coptisine (COP) is a bioactive isoquinoline alkaloid derived from Franch, which is traditionally applied for the management of colitis. However, the blood concentration of COP was extremely low, and its gut microbiota-mediated metabolites were thought to contribute to its prominent bioactivities. To comparatively elucidate the protective effect and underlying mechanism of COP and its novel gut microbiota metabolite (8-oxocoptisine, OCOP) against colitis, we used dextran sulfate sodium (DSS) to induce colitis in mice. Clinical symptoms, microscopic alternation, immune-inflammatory parameters for colitis were estimated. The results indicated that OCOP dramatically ameliorated disease activity index (DAI), the shortening of colon length and colonic histopathological deteriorations. OCOP treatment also suppressed the mRNA expression and release of inflammatory mediators (TGF-β, TNF-α, IL-6, IL-18, IL-1β and IFN-γ) and elevated the transcriptional and translational levels of anti-inflammatory cytokine (IL-10) as well as the mRNA expression levels of adhesion molecules ( and ). Besides, the activation of NF-κB pathway and NLRP3 inflammasome was markedly inhibited by OCOP. Furthermore, OCOP displayed superior anti-colitis effect to COP, and was similar to MSZ with much smaller dosage. Taken together, the protective effect of OCOP against DSS-induced colitis might be intimately related to inhibition of NF-κB pathway and NLRP3 inflammasome. And the findings indicated that OCOP might have greater potential than COP to be further exploited as a promising candidate in the treatment of colitis.
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http://dx.doi.org/10.3389/fphar.2021.639020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042337PMC
March 2021

Efficacy and safety of crizotinib plus bevacizumab in positive non-small cell lung cancer: an open-label, single-arm, prospective observational study.

Am J Transl Res 2021 15;13(3):1526-1534. Epub 2021 Mar 15.

School of Medicine, Nankai University Weijin Road 94#, Nankai District, Tianjin 300071, China.

Background: Crizotinib is a tyrosine kinase inhibitor (TKI) effective in positive non-small cell lung cancer (NSCLC) patients. Bevacizumab is an antiangiogenic monoclonal antibody, and improves clinical benefit of NSCLC in combination with EGFR-TKIs or chemotherapy. However, the efficacy and safety of crizotinib plus bevacizumab in treating naive positive NSCLC patients have not been studied.

Methods: In this open-label, single-arm, prospective observational study, locally advanced or metastatic rearrangement/ fusion/ amplification NSCLC patients were treated with crizotinib (250 mg orally twice daily) and bevacizumab (7.5 mg/kg intravenous every three weeks) until disease progression or intolerant toxicity or death. Primary end point was progressive free survival (PFS), secondary end points were duration of response (DOR), overall response rate (ORR), disease control rate (DCR) and safety. Patients receiving ≥1 cycle of treatment were evaluated.

Findings: Fourteen patients were eligible for analyzing between June 2016 and October 2017. There were 12 patients with rearrangement, 1 patient with fusion, and 1 patient with amplification. The median follow-up time was 42.8 months. The median PFS and DOR of the patients with rearrangement were 13.9 and 14.8 months respectively. Of the 12 patients, 7 gained partial response, 5 gained stable disease. The ORR and DCR were 58.3% and 100%. The PFS were 12.9 months and 1.9 months for patient with fusion or amplification. The most two common treatment-related adverse events were fatigue (28.6%) and rash (21.4%). 3 patients discontinued therapy because of liver damage or hemoptysis.

Interpretation: This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in positive NSCLC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014364PMC
March 2021

Development of a four-gene prognostic model for clear cell renal cell carcinoma based on transcriptome analysis.

Genomics 2021 Apr 7;113(4):1816-1827. Epub 2021 Apr 7.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address:

This study aimed to develop a prognostic model for clear cell renal cell carcinoma (ccRCC) based on transcriptome analysis. We screened Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database for gene expression data and clinical characteristics of ccRCC. After differentially expression analysis, we identified 533 key genes of the development of ccRCC. Next, a weighted gene co-expression network analysis (WGCNA) was executed to investigate the association between differentially expressed genes and clinical characteristics. Then, based on protein-protein interaction (PPI) network, least absolute shrinkage and selection operator (LASSO) regression and Cox regression, a four-gene (COL4A5, ABCB1, NR3C2 and PLG) prognostic model has been constructed in TCGA training cohort. Finally, we examined the predictive power of this model with survival analysis and receiver operating characteristic (ROC) curve both in training cohort and in validation cohorts. And we found this model was significantly correlated with infiltrating immune cells. The four-gene prognosis model could be a potential prediction tool with high accuracy and reliability for ccRCC patients.
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http://dx.doi.org/10.1016/j.ygeno.2021.04.005DOI Listing
April 2021

Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting.

Cancer Immunol Immunother 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, 100853, China.

Background: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited.

Method: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).

Results: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0-42.0%), with a DCR of 85.0% (95% CI, 73.4-96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events.

Conclusion: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.
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http://dx.doi.org/10.1007/s00262-021-02852-4DOI Listing
March 2021

The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors.

Clin Med Insights Oncol 2021 25;15:1179554921996288. Epub 2021 Feb 25.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.
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http://dx.doi.org/10.1177/1179554921996288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934064PMC
February 2021

Trends in application of advancing computational approaches in GPCR ligand discovery.

Exp Biol Med (Maywood) 2021 May 27;246(9):1011-1024. Epub 2021 Feb 27.

Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

G protein-coupled receptors (GPCRs) comprise the most important superfamily of protein targets in current ligand discovery and drug development. GPCRs are integral membrane proteins that play key roles in various cellular signaling processes. Therefore, GPCR signaling pathways are closely associated with numerous diseases, including cancer and several neurological, immunological, and hematological disorders. Computer-aided drug design (CADD) can expedite the process of GPCR drug discovery and potentially reduce the actual cost of research and development. Increasing knowledge of biological structures, as well as improvements on computer power and algorithms, have led to unprecedented use of CADD for the discovery of novel GPCR modulators. Similarly, machine learning approaches are now widely applied in various fields of drug target research. This review briefly summarizes the application of rising CADD methodologies, as well as novel machine learning techniques, in GPCR structural studies and bioligand discovery in the past few years. Recent novel computational strategies and feasible workflows are updated, and representative cases addressing challenging issues on olfactory receptors, biased agonism, and drug-induced cardiotoxic effects are highlighted to provide insights into future GPCR drug discovery.
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http://dx.doi.org/10.1177/1535370221993422DOI Listing
May 2021

A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities.

Eur J Med Chem 2021 Apr 10;215:113267. Epub 2021 Feb 10.

Nobel Institute of Biomedicine, Zhuhai, 519000, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, 518172, China. Electronic address:

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.
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http://dx.doi.org/10.1016/j.ejmech.2021.113267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873610PMC
April 2021

Coptisine ameliorates DSS-induced ulcerative colitis via improving intestinal barrier dysfunction and suppressing inflammatory response.

Eur J Pharmacol 2021 Apr 27;896:173912. Epub 2021 Jan 27.

Department of Pharmacology, Zunyi Medical University, Zhuhai Campus, Zhuhai, 519041, PR China. Electronic address:

Ulcerative colitis (UC), as an autoimmune disease, has been troubling human health for many years. Up to now, the available treatments remain unsatisfactory. Rhizoma Coptidis has been widely applied to treat gastrointestinal diseases in China for a long time, and coptisine (COP) is identified as one of its major active components. This study aimed to evaluate the bioactivity of COP on dextran sulfate sodium (DSS)-induced mice colitis and clarify the potential mechanism of action. The results revealed that COP treatment markedly alleviated DSS-induced clinical symptoms by relieving body weight loss and the disease activity index (DAI) score. Specifically, the colon length in the COP (50 and 100 mg/kg) groups were obviously longer than that in the DSS group (7.21 ± 0.34, 8.59 ± 0.45 cm vs. 6.71 ± 0.59 cm, P < 0.01). HE staining analysis revealed that COP treatment significantly protected the integrity of intestinal barrier and alleviated inflammatory cells infiltration. Western blot assay confirmed that COP notably improved the intestinal epithelial barrier function by enhancing the expressions of colonic tight junction proteins and inhibited the expressions of apoptosis-related proteins. In addition, COP treatment remarkably suppressed the levels of colonic myeloperoxidase (MPO), adhesion molecules and pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6 and IL-17), while enhanced IL-10 and TGF-β. The mechanism anti-inflammatory of COP might be related to inhibiting the phosphorylation of IκBα, and the translocation of NF-κB p65 from cytoplasm to nucleus. In summary, the study indicated that COP ameliorated DSS-induced colitis, at least partly through maintaining the integrity of intestinal epithelial barrier, inhibiting apoptosis and inflammatory response.
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http://dx.doi.org/10.1016/j.ejphar.2021.173912DOI Listing
April 2021

Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy.

Ann Transl Med 2020 Dec;8(24):1681

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Background: The molecular mechanisms underlying denervated skeletal muscle atrophy with concomitant muscle mass loss have not been fully elucidated. Therefore, this study aimed to attain a deeper understanding of the molecular mechanisms underlying denervated skeletal muscle atrophy as a critical step to developing targeted therapy and retarding the concomitant loss of skeletal muscle mass.

Methods: We employed microarray analysis to reveal the potential molecular mechanisms underlying denervated skeletal muscle atrophy. We used and atrophy models to explore the roles of the interleukin 6 (IL-6), Janus kinase (JAK), and signal transducers and activators of transcription 3 (STAT3) in muscle atrophy.

Results: In this study, microarray analysis of the differentially expressed genes demonstrated that inflammation-related cytokines were markedly triggered and IL-6/JAK/STAT3 signaling pathway was strongly activated during denervated skeletal muscle atrophy. The high level of IL-6 enhanced C2C12 myotube atrophy through the activation of JAK/STAT3, while inhibiting JAK/STAT3 pathway by ruxolitinib (a JAK1/2 inhibitor) or C188-9 (a STAT3 inhibitor) significantly attenuated C2C12 myotube atrophy induced by IL-6. Pharmacological blocking of IL-6 by tocilizumab (antibody against IL-6 receptor) and pharmacological/genetic inhibition of JAK/STAT3 pathway by ruxolitinib/C188-9 (JAK/STAT3 inhibitor) and STAT3 short hairpin RNA (shRNA) lentivirus in tibialis anterior muscles could suppress muscle atrophy and inhibit mitophagy, and was accompanied by the decreased expression of atrophic genes ( and ) and autophagy-related genes (, , , , and ).

Conclusions: Taken together, the results suggest that IL-6/JAK/STAT3 pathway may be a principal mediator in denervated skeletal muscle atrophy, meaning targeted therapy against IL-6/JAK/STAT3 pathway might have potential as a therapeutic strategy for prevention of skeletal muscle atrophy.
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http://dx.doi.org/10.21037/atm-20-7269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812230PMC
December 2020

BRD4 inhibition alleviates mechanical stress-induced TMJ OA-like pathological changes and attenuates TREM1-mediated inflammatory response.

Clin Epigenetics 2021 Jan 15;13(1):10. Epub 2021 Jan 15.

Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Central Road, Nanjing, 210008, China.

The aim of this paper was to investigate the protective effects of bromodomain containing 4 (BRD4) inhibition on the temporomandibular joint osteoarthritis (TMJ OA) induced by compressive mechanical stress and to explore the underlying mechanism. In vivo, a rat model of TMJ compressive loading device was used and BRD4 inhibitor was injected into the TMJ region. HE staining and micro-CT analysis were used for histological and radiographic assessment. Immunohistochemistry and qPCR were performed to detect inflammatory cytokines expressions. High-throughput ChIP-sequencing screening was performed to compare the BRD4 and H3K27ac binding patterns between condylar cartilage from control and mechanical force groups. In vitro, the mandibular condylar chondrocytes were treated with IL-1β. Small Interference RNA (siRNA) infection was used to silencing BRD4 or TREM1. qPCR was performed to detect inflammatory cytokines expressions. Our study showed that BRD4 inhibition can alleviate the thinning of condylar cartilage and subchondral bone resorption, as well as decrease the inflammatory factors expression both in vivo and in vitro. ChIP-seq analysis showed that BRD4 was more enriched in the promoter region of genes related to the stress and inflammatory pathways under mechanical stress in vivo. Trem1, a pro-inflammatory gene, was screened out from the overlapped BRD4 and H3K27ac increased binding sites, and Trem1 mRNA was found to be regulated by BRD4 inhibition both in vivo and in vitro. TREM1 inhibition reduced the expression of inflammatory factors induced by IL-1β in vitro. In summary, we concluded that BRD4 inhibition can protect TMJ OA-like pathological changes induced by mechanical stress and attenuate TREM1-mediated inflammatory response.
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http://dx.doi.org/10.1186/s13148-021-01008-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809762PMC
January 2021

A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys.

Stem Cell Res Ther 2021 Jan 7;12(1):17. Epub 2021 Jan 7.

School of Life Sciences, Tsinghua University, Beijing, China.

Background: Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB.

Methods: C3H/HEJ, DBA/2, CD45.1, and CD45.2 mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/noncompetitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays.

Results: In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte colony-stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration.

Conclusions: These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies.
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http://dx.doi.org/10.1186/s13287-020-02073-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791974PMC
January 2021

Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling.

Ann Transl Med 2020 Nov;8(22):1524

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Background: Our prior studies have shown that inflammation may play an important triggering role during the process of denervated muscle atrophy. The nonsteroidal anti-inflammatory drug aspirin exhibits the effect of anti-inflammatory factors. This study will investigate the protective effect of aspirin on denervated muscle atrophy and the underlying mechanism.

Methods: Mouse models of denervated muscle atrophy were established. The protective effect of aspirin (20 mg/kg/d, i.p.) on denervated muscle atrophy was analyzed using the wet weight ratio of tibialis anterior (TA) muscle and muscle fiber cross-sectional area (CSA). The levels of inflammatory factors were detected using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor γ Co-Activator 1α (PGC-1α) and Signal transducer and activator of transcription 3 (STAT3) signaling pathway and the muscle fiber type related proteins in TA muscle after denervation were analyzed by western blot assay.

Results: Intraperitoneal injection of aspirin (20 mg/kg/d) effectively alleviated denervation-induced muscle atrophy. This mainly manifested as follows: The wet weight ratio of TA muscle and muscle fiber CSA of mice treated with aspirin were significantly greater compared with mice treated with normal saline. The level of myosin heavy chain (MHC) increased, and the levels of muscle specific E3 ubiquitin ligase Muscle-specific RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx) were decreased. Mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy related proteins PINK1, BNIP3, LC3B and Atg7 in mice treated with aspirin compared with mice treated with saline. In addition, aspirin treatment inhibited the slow-to-fast twitch muscle fiber conversion, which were related with triggering the expression of Sirt1 and PGC-1α. Moreover, aspirin reduced the levels of inflammatory factors interleukin-6, interleukin-1β and tumor necrosis factor-α and decreased the activation of STAT3 signaling pathway.

Conclusions: This is the first study to find that aspirin can alleviate denervation-induced muscle atrophy and inhibit the type I-to-type II muscle fiber conversion and mitophagy possibly through regulating the STAT3 inflammatory signaling pathway and Sirt1/PGC-1α signal axis. This study expands our knowledge regarding the pharmacological function of aspirin and provides a novel strategy for prevention and treatment of denervated muscle atrophy.
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http://dx.doi.org/10.21037/atm-20-5460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729378PMC
November 2020

Risk of Death in Colorectal Cancer Patients with Multi-morbidities of Metabolic Syndrome: A Retrospective Multicohort Analysis.

Cancer Res Treat 2020 Dec 2. Epub 2020 Dec 2.

Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China.

Purpose: The prevalence of multi-morbidities with colorectal cancer (CRC) is known to be increasing. Particularly prognosis of CRC patients co-diagnosed with metabolic syndrome (MetSyn) was largely unknown. We aimed to examine the death risk of CRC patients according to the multiple MetSyn morbidities.

Materials And Methods: We identified CRC patients with MetSyn from the electronic medical records (EMR) systems in five independent hospitals during 2006-2011. Information on deaths was jointly retrieved from EMR, cause of death registry and chronic disease surveillance as well as study-specific questionnaire. Cox proportional hazards regression was used to calculate the overall and CRC-specific hazards ratios (HR) comparing MetSyn CRC cohort with reference CRC cohort.

Results: A total of 682 CRC patients in MetSyn CRC cohort were identified from 24 months before CRC diagnosis to 1 month after. During a median follow-up of 92 months, we totally observed 584 deaths from CRC, 245 being in MetSyn cohort and 339 in reference cohort. Overall, MetSyn CRC cohort had an elevated risk of CRC-specific mortality (HR, 1.49; 95% confidence interval [CI], 1.07 to 1.90) and overall mortality (HR, 1.43; 95% CI, 1.09 to 1.84) compared to reference cohort after multiple adjustment. Stratified analyses showed higher mortality risk among women (HR, 1.87; 95% CI, 1.04 to 2.27) and specific components of MetSyn. Notably, the number of MetSyn components was observed to be significantly related to CRC prognosis.

Conclusion: Our findings supported that multi-morbidities of MetSyn associated with elevated death risk after CRC. MetSyn should be considered as an integrated medical condition more than its components in CRC prognostic management.
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http://dx.doi.org/10.4143/crt.2020.481DOI Listing
December 2020

Author Correction: Pretreatment-Integration for Milk Protein Removal and Device-Facilitated Immunochromatographic Assay for 17 Items.

Sci Rep 2020 Dec 4;10(1):21602. Epub 2020 Dec 4.

Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-78536-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718914PMC
December 2020

Chemical mutagenesis of a GPCR ligand: Detoxifying "inflammo-attraction" to direct therapeutic stem cell migration.

Proc Natl Acad Sci U S A 2020 12 20;117(49):31177-31188. Epub 2020 Nov 20.

Center for Stem Cells and Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;

A transplanted stem cell's engagement with a pathologic niche is the first step in its restoring homeostasis to that site. Inflammatory chemokines are constitutively produced in such a niche; their binding to receptors on the stem cell helps direct that cell's "pathotropism." Neural stem cells (NSCs), which express CXCR4, migrate to sites of CNS injury or degeneration in part because astrocytes and vasculature produce the inflammatory chemokine CXCL12. Binding of CXCL12 to CXCR4 (a G protein-coupled receptor, GPCR) triggers repair processes within the NSC. Although a tool directing NSCs to where needed has been long-sought, one would not inject this chemokine in vivo because undesirable inflammation also follows CXCL12-CXCR4 coupling. Alternatively, we chemically "mutated" CXCL12, creating a CXCR4 agonist that contained a strong pure binding motif linked to a signaling motif devoid of sequences responsible for synthetic functions. This synthetic dual-moity CXCR4 agonist not only elicited more extensive and persistent human NSC migration and distribution than did native CXCL 12, but induced no host inflammation (or other adverse effects); rather, there was predominantly reparative gene expression. When co-administered with transplanted human induced pluripotent stem cell-derived hNSCs in a mouse model of a prototypical neurodegenerative disease, the agonist enhanced migration, dissemination, and integration of donor-derived cells into the diseased cerebral cortex (including as electrophysiologically-active cortical neurons) where their secreted cross-corrective enzyme mediated a therapeutic impact unachieved by cells alone. Such a "designer" cytokine receptor-agonist peptide illustrates that treatments can be controlled and optimized by exploiting fundamental stem cell properties (e.g., "inflammo-attraction").
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http://dx.doi.org/10.1073/pnas.1911444117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733796PMC
December 2020

Association of the Pretreatment Lung Immune Prognostic Index with Survival Outcomes in Advanced Hepatocellular Carcinoma Patients Treated with PD-1 Inhibitors.

J Hepatocell Carcinoma 2020 2;7:289-299. Epub 2020 Nov 2.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China.

Purpose: At present, there are no validated biomarkers that can predict whether patients with advanced hepatocellular carcinoma (aHCC) are likely to benefit from anti-PD-1 therapy. We aimed to determine whether lung immune prognostic index (LIPI) is associated with outcomes in patients with aHCC treated with PD-1 inhibitors.

Patients And Methods: Patients undergoing initial treatment with PD-1 inhibitors for aHCC at a single center from January 1, 2015 to August 31, 2019 were included. The patients were stratified according to pretreatment LIPI based on a derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) ≥ 3 and a lactate dehydrogenase (LDH) level ≥ the upper limit of normal (ULN). Kaplan-Meier analysis and the Log rank test were used to calculate and compare survival between good LIPI and intermediate/poor LIPI scores. The prognostic values of LIPI for survival and disease control rate were evaluated using Cox proportional hazard and logistic regression models, respectively.

Results: Of the 108 study patients, 53 (49%) had a good LIPI (dNLR < 3 and LDH normal) and 55 (51%) had intermediate/poor LIPI (dNLR ≥ 3 or/and LDH ≥ ULN). With a median follow-up of 12.4 months, intermediate/poor LIPI was independently associated with shorter overall survival (OS) (hazard ratio [HR] 4.00; 95% CI, 2.00-8.03) and progression-free survival (PFS) (HR 2.65; 95% CI, 1.61-4.37). The median OS for good and intermediate/poor LIPI was not reached and was 13.7 (95% CI, 8.2-19.1) months, respectively, and the median PFS was 10.9 (95% CI, 8.9-12.9) and 4.0 (95% CI, 2.2-5.8) months (both P < 0.001), respectively.

Conclusion: Pretreatment LIPI combined with a dNLR ≥ 3 and/or LDH ≥ ULN is associated with poor outcomes in patients with aHCC treated with PD-1 inhibitors. Further validation in large, prospective studies are warranted.
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http://dx.doi.org/10.2147/JHC.S277453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646485PMC
November 2020

Controlling the Poly(ε-caprolactone) Degradation to Maintain the Stemness and Function of Adipose-Derived Mesenchymal Stem Cells in Vascular Regeneration Application.

Macromol Biosci 2021 01 22;21(1):e2000226. Epub 2020 Oct 22.

S. Yang, Dr. X. Jiang, X. Xiao, C. Niu, Y. Xu, Z. Huang, Prof. Y. J. Kang, Prof. L. Feng, Regenerative Medicine Research Center, Sichuan University West China Hospital, No. 4 Keyuan Road, Wuhou District, Chengdu, 610041, China.

Biodegradable poly(ε-caprolactone) (PCL) scaffolds with adipose-derived mesenchymal stem cells (ADSCs) have been used in vascular regeneration studies. An evaluation method of the effect of PCL degradation products (DP) on the viability, stemness, and differentiation capacities of ADSCs is established. ADSCs are cultured in medium containing different concentrations of PCL DP before evaluating the effect of PCL DP on the cell apoptosis and proliferation, cell surface antigens, adipogenic and osteogenic differentiation capacities, and capacities to differentiate into endothelial cells and smooth muscle cells. The results demonstrate that PCL DP exceed 0.05 mg mL may change the stemness and differentiation capacities of ADSCs. Therefore, to control the proper concentration of PCL DP is essential for ADSCs in vascular regeneration application.
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http://dx.doi.org/10.1002/mabi.202000226DOI Listing
January 2021

Anterior chest wall in SAPHO syndrome: magnetic resonance imaging findings.

Arthritis Res Ther 2020 09 14;22(1):216. Epub 2020 Sep 14.

Department of Radiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Mei Shu Guan Hou Street, Beijing, 100010, China.

Background: The anterior chest wall (ACW) involvement is characteristic of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, yet little research has focused on its magnetic resonance imaging (MRI) findings.

Purpose: To characterize the MRI features of the ACW in patients with SAPHO syndrome.

Methods: Seventy-one patients with SAPHO syndrome and ACW involvement evidenced by bone scintigraphy were recruited in this cross-sectional study. The ACW region was scanned using sagittal, axial, and oblique coronal Dixon T2-weighted sequences and axial Dixon T1-weighted sequences. The characteristics of both active inflammatory and chronic structural lesions were evaluated.

Results: The ACW lesions exhibited an asymmetrical distribution and a predilection for the sternocostoclavicular region (93.0%). Notably, 91.5% of the patients had lesions in the area of the anterior first ribs. Bone marrow edema (BME) was observed in 63 (88.7%) patients, which mainly affected the sternocostal joints (87.3%) and the manubrium sterni (84.5%). All of the BMEs were distributed under the articular surface or the bone cortex, consistent with the distribution of the ligaments and joint capsules. Synovitis was detected in 64 (90.1%) patients, with a predilection for the sternoclavicular joints (76.1%). A soft tissue mass or infiltration was found in all the patients who had bone marrow edema. Thirteen (18.3%) patients showed venous stenosis. Structural changes included bone bridge formation (80.3%), hyperostosis (43.7%), and fat infiltration (39.4%). Four common patterns of involvement were observed: the first rib area, the sternoclavicular area, the sternal angle area, and the areas of the second to sixth sternocostal joints.

Conclusion: The ACW lesions of SAPHO syndrome demonstrated a triad of enthesitis, synovitis, and osteitis, suggesting complex interactions among the ligaments, synovium, and bones in the region. The inflammatory changes in the first rib area were highlighted in SAPHO syndrome.
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http://dx.doi.org/10.1186/s13075-020-02309-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491189PMC
September 2020

Post-treatment neutrophil-to-lymphocyte ratio (NLR) predicts response to anti-PD-1/PD-L1 antibody in SCLC patients at early phase.

Cancer Immunol Immunother 2021 Mar 10;70(3):713-720. Epub 2020 Sep 10.

Department of Oncology, General Hospital of Chinese PLA, Fuxing Road 28#, Haidian District, Beijing, 100853, China.

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) have been identified as predictors of treatment response in a variety of cancers. We conducted a retrospective analysis to investigate the usefulness of NLR, PLR and SII at baseline and at 6 weeks post-treatment as predictors of response to anti-PD-1/PD-L1 antibody treatment in small cell lung cancer (SCLC). Data of 41 SCLC patients receiving immunotherapy as second- or later-line treatment were analyzed. The overall median progression-free survival (PFS) was 5.1 months (95% CI 3.2-6.2). The median PFS was significantly longer in patients with NLR < 5 than in patients with NLR ≥ 5 at 6 weeks post treatment (HR = 0.29, 95%CI 0.09-0.96, P = 0.04). However, median PFS was comparable between patients with NLR < 5 and patients with NLR ≥ 5 at baseline (HR = 0.75, 95% CI 0.24-2.26, P = 0.56). The median PFS was similar between patients with PLR < 169 and those with PLR ≥ 169 at baseline (HR = 0.67, 95% CI 0.25-1.80, P = 0.43) and at 6 weeks post treatment (HR = 0.69, 95% CI 0.25-1.86, P = 0.46). No statistically different PFS was found between patients with SII < 730 and those with SII ≥ 730 at baseline (HR = 0.70, 95% CI 0.26-1.89, P = 0.48) and at 6 weeks post treatment (HR = 0.38, 95% CI 0.013-1.09, P = 0.07). In conclusion, NLR at 6 weeks after start of treatment appears to be a biomarker of response in the early phase in SCLC patients treated with anti-PD-1/PD-L1 antibodies as second- or later-line treatment.
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http://dx.doi.org/10.1007/s00262-020-02706-5DOI Listing
March 2021

Anti-PD-1/L1 plus anti-angiogenesis therapy as second-line or later treatment in advanced lung adenocarcinoma.

J Cancer Res Clin Oncol 2021 Mar 9;147(3):881-891. Epub 2020 Sep 9.

School of Medicine, Nankai University, 94 Weijin Road, Nankai, Tianjin, 300071, People's Republic of China.

Purpose: Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting.

Methods: Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models.

Results: Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337-0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305-0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298-0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group.

Conclusion: Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.
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http://dx.doi.org/10.1007/s00432-020-03380-xDOI Listing
March 2021

Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation.

Front Physiol 2020 12;11:988. Epub 2020 Aug 12.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Although denervated muscle atrophy is common, the underlying molecular mechanism remains unelucidated. We have previously found that oxidative stress and inflammatory response may be early events that trigger denervated muscle atrophy. Isoquercitrin is a biologically active flavonoid with antioxidative and anti-inflammatory properties. The present study investigated the effect of isoquercitrin on denervated soleus muscle atrophy and its possible molecular mechanisms. We found that isoquercitrin was effective in alleviating soleus muscle mass loss following denervation in a dose-dependent manner. Isoquercitrin demonstrated the optimal protective effect at 20 mg/kg/d, which was the dose used in subsequent experiments. To further explore the protective effect of isoquercitrin on denervated soleus muscle atrophy, we analyzed muscle proteolysis the ubiquitin-proteasome pathway, mitophagy, and muscle fiber type conversion. Isoquercitrin significantly inhibited the denervation-induced overexpression of two muscle-specific ubiquitin ligases-muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), and reduced the degradation of myosin heavy chains (MyHCs) in the target muscle. Following isoquercitrin treatment, mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy-related proteins (ATG7, BNIP3, LC3B, and PINK1); slow-to-fast fiber type conversion in the target muscle was delayed triggering expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α); and the production of reactive oxygen species (ROS) in the target muscle was reduced, which might be associated with the upregulation of antioxidant factors (SOD1, SOD2, NRF2, NQO1, and HO1) and the downregulation of ROS production-related factors (Nox2, Nox4, and DUOX1). Furthermore, isoquercitrin treatment reduced the levels of inflammatory factors-interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)-in the target muscle and inactivated the JAK/STAT3 signaling pathway. Overall, isoquercitrin may alleviate soleus muscle atrophy and mitophagy and reverse the slow-to-fast fiber type conversion following denervation inhibition of oxidative stress and inflammatory response. Our study findings enrich the knowledge regarding the molecular regulatory mechanisms of denervated muscle atrophy and provide a scientific basis for isoquercitrin as a protective drug for the prevention and treatment of denervated muscle atrophy.
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http://dx.doi.org/10.3389/fphys.2020.00988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435639PMC
August 2020

Comparative effectiveness of pembrolizumab vs. nivolumab in patients with recurrent or advanced NSCLC.

Sci Rep 2020 08 4;10(1):13160. Epub 2020 Aug 4.

Department of Graduate Administration, Chinese PLA General Hospital, Beijing, China.

The efficacies of pembrolizumab and nivolumab have never been directly compared in a real-world study. Therefore, we sought to retrospectively evaluate the objective response rate (ORR) and the progression-free survival (PFS) of patients with recurrent or advanced non-small cell lung cancer (NSCLC) in a real-world setting. This study included patients with recurrent or advanced NSCLC diagnosed between September 1, 2015 and August 31, 2019, who were treated with programmed cell death 1 (PD-1) inhibitors at the Cancer Center of the Chinese People's Liberation Army. PFS was estimated for each treatment group using Kaplan-Meier curves and log-rank tests. The multivariate analysis of PFS was performed with Cox proportional hazards regression models. A total of 255 patients with advanced or recurrent NSCLC treated with PD-1 inhibitors were identified. The ORR was significantly higher in the pembrolizumab group than in the nivolumab group, while PFS was not significantly different between the two groups. Subgroup analysis showed that the ORR was significantly higher for pembrolizumab than for nivolumab in patients in the first-line therapy subgroup and in those in the combination therapy as first-line therapy subgroup. Survival analysis of patients receiving combination therapy as second- or further-line therapy showed that nivolumab had better efficacy than pembrolizumab. However, the multivariate analysis revealed no significant difference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup. In our study, no significant difference in PFS was noted between patients treated with pembrolizumab and those treated with nivolumab in various clinical settings. This supports the current practice of choosing either pembrolizumab or nivolumab based on patient preferences.
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http://dx.doi.org/10.1038/s41598-020-70207-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403144PMC
August 2020

Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma.

Cell Death Dis 2020 07 8;11(7):515. Epub 2020 Jul 8.

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China.

Renal cell carcinoma (RCC) is one of the most frequently observed malignant tumours in the urinary system and targeted drug resistance is quite common in RCC. Long noncoding RNA SNHG12 (lncRNA SNHG12) has emerged as a key molecule in numerous human cancers, but its functions in renal cell carcinoma (RCC) sunitinib resistance remain unclear. In this study, we found SNHG12 was highly expressed in RCC tissues and in sunitinib-resistant RCC cells and was associated with a poor clinical prognosis. SNHG12 promoted RCC proliferation, migration, invasion and sunitinib resistance via CDCA3 in vitro. Mechanically, SNHG12 bound to SP1 and prevented the ubiquitylation-dependent proteolysis of SP1. Stabilised SP1 bound to a specific region in the promoter of CDCA3 and increased CDCA3 expression. Furthermore, in vivo experiments showed that SNHG12 increased tumour growth and that knocking down SNHG12 could reverse RCC sunitinib resistance. Our study revealed that the lncRNA SNHG12/SP1/CDCA3 axis promoted RCC progression and sunitinib resistance, which could provide a new therapeutic target for sunitinib-resistant RCC.
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http://dx.doi.org/10.1038/s41419-020-2713-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343829PMC
July 2020

Design, synthesis, and biological characterization of a new class of symmetrical polyamine-based small molecule CXCR4 antagonists.

Eur J Med Chem 2020 Aug 16;200:112410. Epub 2020 May 16.

Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. Electronic address:

CXCR4, a well-studied coreceptor of human immunodeficiency virus type 1 (HIV-1) entry, recognizes its cognate ligand SDF-1α (also named CXCL12) which plays many important roles, including regulating immune cells, controlling hematopoietic stem cells, and directing cancer cells migration. These pleiotropic roles make CXCR4 an attractive target to mitigate human disorders. Here a new class of symmetrical polyamines was designed and synthesized as potential small molecule CXCR4 antagonists. Among them, a representative compound 21 (namely HF50731) showed strong CXCR4 binding affinity (mean IC = 19.8 nM) in the CXCR4 competitive binding assay. Furthermore, compound 21 significantly inhibited SDF-1α-induced calcium mobilization and cell migration, and blocked HIV-1 infection via antagonizing CXCR4 coreceptor function. The structure-activity relationship analysis, site-directed mutagenesis, and molecular docking were conducted to further elucidate the binding mode of compound 21, suggesting that compound 21 could primarily occupy the minor subpocket of CXCR4 and partially bind in the major subpocket by interacting with residues W94, D97, D171, and E288. Our studies provide not only new insights for the fragment-based design of small molecule CXCR4 antagonists for clinical applications, but also a new and effective molecular probe for CXCR4-targeting biological studies.
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http://dx.doi.org/10.1016/j.ejmech.2020.112410DOI Listing
August 2020

Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

Ther Adv Med Oncol 2020 9;12:1758835920922033. Epub 2020 May 9.

Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, China.

Background: Cutaneous adverse events (AEs) have been positively associated with immune checkpoint inhibitor (ICI) efficacy in patients with melanoma, but little is known regarding the association between checkpoint inhibitor pneumonitis (CIP) and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor efficacy in non-small cell lung cancer (NSCLC).

Methods: A single-institution, retrospective medical record review of patients with advanced or recurrent NSCLC who were treated with PD-1/PD-L1 inhibitors between 1 September 2015 and 1 June 2019 was conducted. A total of 276 NSCLC patients with or without immune-related pneumonitis who received at least one dose of ICIs and had at least one follow-up visit were identified. Kaplan-Meier curves of the progression-free survival (PFS) of patients stratified according to immune-related pneumonitis development were evaluated with the log-rank test as a preplanned primary objective. Multivariate analysis of PFS was performed with Cox proportional hazard regression models.

Results: In the cohort of 276 patients, 42 patients developed CIP attributed to PD-1/PD-L1 inhibitors. Survival analysis showed that the overall response rate was significantly higher in patients with CIP than in those without CIP (61.90% 29.91%, respectively, < 0.01), and that CIP development was significantly associated with increased PFS (45.80 weeks 21.15 weeks, respectively, < 0.01). Additionally, 16-week landmark analysis produced the same results. Similarly, subgroup analysis of PD-1 inhibitor-treated, nivolumab-treated, and pembrolizumab-treated groups also revealed that CIP increased survival in NSCLC patients. Additionally, grade 1-2 pneumonitis showed an association with increased ICI efficacy in NSCLC; however, grade 3-4 pneumonitis did not. In addition, only two of the four pneumonitis radiological subtypes showed associations with increased ICI efficacy in NSCLC.

Conclusion: CIP is associated with enhanced PD-1/PD-L1 inhibitor efficacy in NSCLC patients. Grade 1-2 pneumonitis and the radiological features of hypersensitivity and cryptogenic organizing pneumonia (COP) may be signs of enhanced ICI efficacy. However, further studies with larger numbers of patients and longer follow-up times are needed to validate our findings.
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http://dx.doi.org/10.1177/1758835920922033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222233PMC
May 2020

Type-specific dendritic integration in mouse retinal ganglion cells.

Nat Commun 2020 04 30;11(1):2101. Epub 2020 Apr 30.

Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.

Neural computation relies on the integration of synaptic inputs across a neuron's dendritic arbour. However, it is far from understood how different cell types tune this process to establish cell-type specific computations. Here, using two-photon imaging of dendritic Ca signals, electrical recordings of somatic voltage and biophysical modelling, we demonstrate that four morphologically distinct types of mouse retinal ganglion cells with overlapping excitatory synaptic input (transient Off alpha, transient Off mini, sustained Off, and F-mini Off) exhibit type-specific dendritic integration profiles: in contrast to the other types, dendrites of transient Off alpha cells were spatially independent, with little receptive field overlap. The temporal correlation of dendritic signals varied also extensively, with the highest and lowest correlation in transient Off mini and transient Off alpha cells, respectively. We show that differences between cell types can likely be explained by differences in backpropagation efficiency, arising from the specific combinations of dendritic morphology and ion channel densities.
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http://dx.doi.org/10.1038/s41467-020-15867-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193577PMC
April 2020

Immune and Stroma Related Genes in Breast Cancer: A Comprehensive Analysis of Tumor Microenvironment Based on the Cancer Genome Atlas (TCGA) Database.

Front Med (Lausanne) 2020 5;7:64. Epub 2020 Mar 5.

Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Tumor microenvironment is essential for breast cancer progression and metastasis. Our study sets out to examine the genes affecting stromal and immune infiltration in breast cancer progression and prognosis. This work provides an approach for quantifying stromal and immune scores by using ESTIMATE algorithm based on gene expression matrix of breast cancer patients in TCGA database. We found differentially expressed genes (DEGs) through limma R package. Functional enrichments were accessed through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Besides, we constructed a protein-protein network, identified several hub genes in Cytoscape, and discovered functionally similar genes in GeneMANIA. Hub genes were validated with prognostic data by Kaplan-Meier analysis both in The Cancer Genome Atlas (TCGA) database and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database and a meta-analysis of hub genes prognosis data was utilized in multiple databases. Furthermore, their relationship with infiltrating immune cells was evaluated by Tumor IMmune Estimation Resource (TIMER) web tool. Cox regression was utilized for overall survival (OS) and recurrence-free survival (RFS) in TCGA database and OS in METABRIC database in order to evaluate the impact of stromal and immune scores on patients prognosis. One thousand and eighty-five breast cancer patients were investigated and 480 differentiated expressed genes (DEGs) were found based on the analysis of mRNA expression profiles. Functional analysis of DEGs revealed their potential functions in immune response and extracellular interaction. Protein-protein interaction network gave evidence of 10 hub genes. Some of the hub genes could be used as predictive markers for patients prognosis. In this study, we found that tumor purity and specific immune cells infiltration varied in response to hub genes expression. The multivariate cox regression highlighted the fact that immune score played a detrimental role in overall survival (HR = 0.45, 95% CI: 0.27-0.74, = 0.002) and recurrence-free survival (HR = 0.41, 95% CI: 0.22-0.77, = 0.006) in TCGA database. These result was confirmed in METABRIC database that immune score was a protector of OS (HR = 0.88, 95% CI: 0.77-0.99, = 0.039). Our findings promote a better understanding of the potential genes behind the regulation of tumor microenvironment and cells infiltration. Immune score should be considered as a prognostic factor for patients' survival.
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http://dx.doi.org/10.3389/fmed.2020.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066229PMC
March 2020