Publications by authors named "Han Liang"

682 Publications

Rheumatic Manifestations and Diseases From Immune Checkpoint Inhibitors in Cancer Immunotherapy.

Front Med (Lausanne) 2021 4;8:762247. Epub 2021 Nov 4.

Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

Immune checkpoint inhibitors (ICIs), which can enhance antitumor immunity and inhibit cancer growth, have revolutionized the treatment of multiple cancers and dramatically decreased mortality. However, treatment with ICIs is directly associated with immune-related adverse events (irAEs) because of inflammation in off-target organs and autoimmunity resulting from non-specific immune activation. These irAEs can cause rheumatic diseases and manifestations such as inflammatory arthritis, polymyalgia rheumatica, myositis, vasculitis, Sicca and Sjogen's syndrome, and systemic lupus erythematosus. Early diagnosis and treatment of these adverse events will improve outcomes and quality of life for cancer patients. The treatment of rheumatic diseases induced by ICIs requires multidisciplinary cooperation among physicians. Furthermore, the underlying mechanisms are not fully understood and it is difficult to predict and evaluate these side effects precisely. In this review, we summarize available studies and findings about rheumatic irAEs, focusing mainly on the clinical manifestations, epidemiology, possible mechanisms, and guiding principles for treating these irAEs.
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http://dx.doi.org/10.3389/fmed.2021.762247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599930PMC
November 2021

Hierarchical Chiral Supramolecular Nanoarchitectonics with Molecular Detection: Helical Structure Controls upon Self-Assembly and Coassembly.

Macromol Rapid Commun 2021 Nov 7:e2100690. Epub 2021 Nov 7.

Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China.

The morphological transformation from microspheres to helical supramolecular nanofibers with controllable handedness is achieved by the introduction of molecular chirality based on amino acid derivatives (TDAP), and the chirality of the supramolecular architectures that are achieved is nullified through the coassembly of the equivalent TDAP enantiomers. The molecular detection of achiral melamine based on the R-TDAP-COOH supramolecular system is achieved by the appearance of helicity and inversion.
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http://dx.doi.org/10.1002/marc.202100690DOI Listing
November 2021

Honokiol Suppresses Perineural Invasion of Pancreatic Cancer by Inhibiting SMAD2/3 Signaling.

Front Oncol 2021 4;11:728583. Epub 2021 Oct 4.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Perineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.

Methods: In our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI .

Results: We found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. , we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.

Conclusion: Our results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.
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http://dx.doi.org/10.3389/fonc.2021.728583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521150PMC
October 2021

WTD Attenuating Rheumatoid Arthritis Suppressing Angiogenesis and Modulating the PI3K/AKT/mTOR/HIF-1α Pathway.

Front Pharmacol 2021 27;12:696802. Epub 2021 Sep 27.

Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Wutou Decoction (WTD), as a classic prescription, has been generally used to treat rheumatoid arthritis (RA) for two thousand years in China. However, the potential protective effects of WTD on rheumatoid arthritis and its possible mechanism have rarely been reported. The aim of this study was to explore the possible mechanism of WTD against RA and a promising alternative candidate for RA therapy. A model of collagen-induced arthritis (CIA) was constructed in rats to assess the therapeutic effects of WTD. Histopathological staining, immunofluorescence, and western blotting of synovial sections were conducted to detect the antiangiogenic effects of WTD. Then, cell viability assays, flow cytometry, scratch healing assays, and invasion assays were conducted to explore the effects of WTD on MH7A human fibroblast-like synoviocyte (FLS) cell proliferation, apoptosis, migration, and invasion . The ability of WTD to induce blood vessel formation after MH7A cell and human umbilical vein endothelial cell line (HUVEC) coculture with WTD intervention was detected by a tube formation assay. The mechanisms of WTD were screened by network pharmacology and confirmed by and experiments. WTD ameliorated the symptoms and synovial pannus hyperplasia of CIA rats. Treatment with WTD inhibited MH7A cell proliferation, migration, and invasion and promoted MH7A apoptosis. WTD could inhibit MH7A cell expression of proangiogenic factors, including VEGF and ANGI, to induce HUVEC tube formation. Furthermore, the PI3K-AKT-mTOR-HIF-1α pathway was enriched as a potential target of WTD for the treatment of RA through network pharmacology enrichment analysis. Finally, it was confirmed and that WTD inhibits angiogenesis in RA by interrupting the PI3K-AKT-mTOR-HIF-1α pathway. WTD can inhibit synovial hyperplasia and angiogenesis, presumably by inhibiting the migration and invasion of MH7A cells and blocking the production of proangiogenic effectors in MH7A cells. The possible underlying mechanism by which WTD ameliorates angiogenesis in RA is the PI3K-AKT-mTOR-HIF-1α pathway.
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http://dx.doi.org/10.3389/fphar.2021.696802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502817PMC
September 2021

Self-Aligned Emission of Distributed Feedback Lasers on Optical Fiber Sidewall.

Nanomaterials (Basel) 2021 Sep 13;11(9). Epub 2021 Sep 13.

Faculty of Science, College of Physics and Optoelectronics, Beijing University of Technology, Beijing 100124, China.

This article assembles a distributed feedback (DFB) cavity on the sidewalls of the optical fiber by using very simple fabrication techniques including two-beam interference lithography and dip-coating. The DFB laser structure comprises graduated gratings on the optical fiber sidewalls which are covered with a layer of colloidal quantum dots. Directional DFB lasing is observed from the fiber facet due to the coupling effect between the grating and the optical fiber. The directional lasing from the optical fiber facet exhibits a small solid divergence angle as compared to the conventional laser. It can be attributed to the two-dimensional light confinement in the fiber waveguide. An analytical approach based on the Bragg condition and the coupled-wave theory was developed to explain the characteristics of the laser device. The intensity of the output coupled laser is tuned by the coupling coefficient, which is determined by the angle between the grating vector and the fiber axis. These results afford opportunities to integrate different DFB lasers on the same optical fiber sidewall, achieving multi-wavelength self-aligned DFB lasers for a directional emission. The proposed technique may provide an alternative to integrating DFB lasers for applications in networking, optical sensing, and power delivery.
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http://dx.doi.org/10.3390/nano11092381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470634PMC
September 2021

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies.

Acta Pharm Sin B 2021 Aug 31;11(8):2306-2325. Epub 2020 Dec 31.

Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, China.

Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (.., intranasal treatment) for BBB bypassing are not included in this review.
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http://dx.doi.org/10.1016/j.apsb.2020.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424230PMC
August 2021

Convergent Usage of Amino Acids in Human Cancers as A Reversed Process of Tissue Development.

Authors:
Yikai Luo Han Liang

Genomics Proteomics Bioinformatics 2021 Sep 4. Epub 2021 Sep 4.

Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Genome- and transcriptome-wide amino acid usage preference across different species is a well-studied phenomenon in molecular evolution, but its characteristics and implication in cancer evolution and therapy remain largely unexplored. Here, we analyzed large-scale transcriptome/proteome profiles, such as The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and found that compared to normal tissues, different cancer types showed a convergent pattern toward using biosynthetically low-cost amino acids. Such a pattern can be accurately captured by a single index based on the average biosynthetic energy cost of amino acids, termed energy cost per amino acid (ECPA). With this index, we further compared the trends of amino acid usage and the contributing genes in cancer and tissue development, and revealed their reversed patterns. Finally, focusing on the liver, a tissue with a dramatic increase in ECPA during development, we found that EPCA represents a powerful biomarker that could distinguish liver tumors from normal liver samples consistently across 11 independent patient cohorts and outperforms any index based on single genes. Our study reveals an important principle underlying cancer evolution and suggests the global amino acid usage as a system-level biomarker for cancer diagnosis.
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http://dx.doi.org/10.1016/j.gpb.2021.08.004DOI Listing
September 2021

A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis.

Aging (Albany NY) 2021 08 25;13(16):20511-20533. Epub 2021 Aug 25.

Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.

Interferon (IFN) signaling pathways play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Prior studies have mainly studied mixed alterations in the IFN signaling pathway in RA, but these studies have not been sufficient to elucidate how imbalanced IFN signaling subtly influences immune cells. Single-cell RNA (scRNA) sequencing makes it possible to better understand the alternations in the interferon signaling pathways in RA. In the present study, we found that IFN signaling pathways were activated in natural killer (NK) cells, monocytes, T cells, B cells, and most immune cell subclasses in RA. We then explored and analyzed the connections between abnormal IFN signaling pathways and cellular functional changes in RA. Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis and gene regulatory network (GRN) construction were also performed to identify key transcription factors in RA. Finally, we also investigated altered IFN signaling pathways in multiple RA peripheral blood samples, which indicated that abnormal IFN signaling pathways were universally observed in RA. Our study contributes to a better understanding of the delicate and precise regulation of IFN signaling in the immune system in RA. Furthermore, common alternations in IFN signaling pathway-related transcription factors could help to identify novel therapeutic targets for RA treatment.
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http://dx.doi.org/10.18632/aging.203432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436925PMC
August 2021

Systematic functional interrogation of human pseudogenes using CRISPRi.

Genome Biol 2021 08 23;22(1):240. Epub 2021 Aug 23.

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Background: The human genome encodes over 14,000 pseudogenes that are evolutionary relics of protein-coding genes and commonly considered as nonfunctional. Emerging evidence suggests that some pseudogenes may exert important functions. However, to what extent human pseudogenes are functionally relevant remains unclear. There has been no large-scale characterization of pseudogene function because of technical challenges, including high sequence similarity between pseudogene and parent genes, and poor annotation of transcription start sites.

Results: To overcome these technical obstacles, we develop an integrated computational pipeline to design the first genome-wide library of CRISPR interference (CRISPRi) single-guide RNAs (sgRNAs) that target human pseudogene promoter-proximal regions. We perform the first pseudogene-focused CRISPRi screen in luminal A breast cancer cells and reveal approximately 70 pseudogenes that affect breast cancer cell fitness. Among the top hits, we identify a cancer-testis unitary pseudogene, MGAT4EP, that is predominantly localized in the nucleus and interacts with FOXA1, a key regulator in luminal A breast cancer. By enhancing the promoter binding of FOXA1, MGAT4EP upregulates the expression of oncogenic transcription factor FOXM1. Integrative analyses of multi-omic data from the Cancer Genome Atlas (TCGA) reveal many unitary pseudogenes whose expressions are significantly dysregulated and/or associated with overall/relapse-free survival of patients in diverse cancer types.

Conclusions: Our study represents the first large-scale study characterizing pseudogene function. Our findings suggest the importance of nuclear function of unitary pseudogenes and underscore their underappreciated roles in human diseases. The functional genomic resources developed here will greatly facilitate the study of human pseudogene function.
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http://dx.doi.org/10.1186/s13059-021-02464-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381491PMC
August 2021

Emodin Attenuates Acetaminophen-Induced Hepatotoxicity via the cGAS-STING Pathway.

Inflammation 2021 Aug 18. Epub 2021 Aug 18.

Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.

Emodin is a natural bioactive compound from traditional Chinese herbs that exerts anti-inflammatory, antioxidant, anticancer, hepatoprotective, and neuroprotective effects. However, the protective effects of emodin in acetaminophen (APAP)-induced hepatotoxicity are not clear. The present study examined the effects of emodin on APAP-induced hepatotoxicity and investigated the potential molecular mechanisms. C57BL/6 mice were pretreated with emodin (15 and 30 mg/kg) for 5 consecutive days and then given APAP (300 mg/kg) to establish an APAP-induced liver injury model. Mice were sacrificed to detect the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) and the liver tissue levels of glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Histological assessment, Western blotting, and ELISA were performed. Emodin pretreatment significantly reduced the levels of ALT, AST, and ALP; increased the levels of ALB; alleviated hepatocellular damage and apoptosis; attenuated the exhaustion of GSH and SOD and the accumulation of MDA; and increased the expression of antioxidative enzymes, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1). Emodin also inhibited the expression of NLRP3 and reduced the levels of pro-inflammatory factors, including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α). Emodin inhibited interferon (IFN)-α, cyclic GMP-AMP synthase (cGAS), and its downstream signaling effector stimulator of interferon genes (STING) expression to protect the liver against APAP-induced inflammatory responses and apoptosis. These results suggest that emodin protected hepatocytes from APAP-induced liver injury via the upregulation of the Nrf2-mediated antioxidative stress pathway, the inhibition of the NLRP3 inflammasome, and the downregulation of the cGAS-STING signaling pathway.
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http://dx.doi.org/10.1007/s10753-021-01529-5DOI Listing
August 2021

Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer.

Nat Commun 2021 08 6;12(1):4753. Epub 2021 Aug 6.

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.
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http://dx.doi.org/10.1038/s41467-021-25012-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346570PMC
August 2021

Immunogenomic pan-cancer landscape reveals immune escape mechanisms and immunoediting histories.

Sci Rep 2021 08 3;11(1):15713. Epub 2021 Aug 3.

Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Immune reactions in the tumor microenvironment are an important hallmark of cancer, and emerging immune therapies have been proven effective against several types of cancers. To investigate cancer genome-immune interactions and the role of immunoediting or immune escape mechanisms in cancer development, we analyzed 2834 whole genome and RNA sequencing datasets across 31 distinct tumor types with respect to key immunogenomic aspects and provided comprehensive immunogenomic profiles of pan-cancers. We found that selective copy number changes in immune-related genes may contribute to immune escape. Furthermore, we developed an index of the immunoediting history of each tumor sample based on the information of mutations in exonic regions and pseudogenes and evaluated the immunoediting history of each tumor. Our immuno-genomic analyses of pan-cancers have the potential to identify a subset of tumors with immunogenicity and diverse backgrounds or intrinsic pathways associated with their immune status and immunoediting history.
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http://dx.doi.org/10.1038/s41598-021-95287-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333422PMC
August 2021

Exploring the Clinical Characteristics of COVID-19 Clusters Identified Using Factor Analysis of Mixed Data-Based Cluster Analysis.

Front Med (Lausanne) 2021 16;8:644724. Epub 2021 Jul 16.

Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

The COVID-19 outbreak has brought great challenges to healthcare resources around the world. Patients with COVID-19 exhibit a broad spectrum of clinical characteristics. In this study, the Factor Analysis of Mixed Data (FAMD)-based cluster analysis was applied to demographic information, laboratory indicators at the time of admission, and symptoms presented before admission. Three COVID-19 clusters with distinct clinical features were identified by FAMD-based cluster analysis. The FAMD-based cluster analysis results indicated that the symptoms of COVID-19 were roughly consistent with the laboratory findings of COVID-19 patients. Furthermore, symptoms for mild patients were atypical. Different hospital stay durations and survival differences among the three clusters were also found, and the more severe the clinical characteristics were, the worse the prognosis. Our aims were to describe COVID-19 clusters with different clinical characteristics, and a classifier model according to the results of FAMD-based cluster analysis was constructed to help provide better individualized treatments for numerous COVID-19 patients in the future.
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http://dx.doi.org/10.3389/fmed.2021.644724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323882PMC
July 2021

17.6%-Efficient Quasiplanar Heterojunction Organic Solar Cells from a Chlorinated 3D Network Acceptor.

Adv Mater 2021 Sep 28;33(37):e2102778. Epub 2021 Jul 28.

Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China.

Bulk heterojunction (BHJ) organic solar cells (OSCs) have achieved great success because they overcome the shortcomings of short exciton diffusion distances. With the progress in material innovation and device technology, the efficiency of BHJ devices is continually being improved. For some special photovoltaic material systems, it is difficult to manipulate the miscibility and morphology of blend films, and this results in moderate, even poor device performance. Quasiplanar heterojunction (Q-PHJ) OSCs have been proposed to exploit the excellent photovoltaic properties of these materials. An OSC with BTIC-BO-4Cl has a 3D interpenetrating network structure with multiple channels that can facilitate the exciton diffusion and charge transport, and BTIC-BO-4Cl is therefore a good candidate for Q-PHJ OSCs. In this work, a D18:BTIC-BO-4Cl-based Q-PHJ device is fabricated. The exciton diffusion lengths of D18 and BTIC-BO-4Cl are in accord with the requirements of the Q-PHJ device and the efficiency of Q-PHJ device is as high as 17.60%. This study indicates that the Q-PHJ architecture can replace the BHJ architecture to produce excellent OSCs for certain unique donors and acceptors, providing an alternative approach to photovoltaic material design and device fabrication.
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http://dx.doi.org/10.1002/adma.202102778DOI Listing
September 2021

Intraperitoneal Chemotherapy Using Fluorouracil Implants Combined With Radical Resection and Postoperative Adjuvant Chemotherapy for Stage III Gastric Cancer: A Multi-Center, Randomized, Open-Label, Controlled Clinical Study.

Front Oncol 2021 8;11:670651. Epub 2021 Jul 8.

Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China.

Background: Reducing peritoneal recurrence after radical surgery is an important choice to improve the prognosis of patients with advanced gastric cancer. Intraoperative intraperitoneal chemotherapy has the potential to be a promising treatment strategy. In the present study, we conducted a multi-center, randomized, controlled clinical study to evaluate the efficacy and safety of intraoperative intraperitoneal chemotherapy using sustained-release fluorouracil implants plus radical gastrectomy and adjuvant chemotherapy for cTNM stage III gastric cancer.

Methods: The patients were randomized into intraperitoneal chemotherapy group (sustained-release fluorouracil implants administration after standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy) and control group (standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy). A total of 122 patients from three centers were enrolled from September 2015 to February 2017.

Results: One hundred and two eligible patients completed the treatment course. The median follow-up time was 41.7 months (36.1-52.9 months). The 3-year progression-free survival rate and overall survival of patients in the intraperitoneal chemotherapy group were 43.9% and 49.1%, respectively, which were significantly better than those of the control group, 31.0% and 38.4%. In the intraperitoneal chemotherapy group, the number of cases with peritoneal recurrence was significantly less than that of the control group, 9 cases (17.3%) 19 cases (44.2%). There were neither significant differences between the groups in the incidence of hematogenous metastasis, lymph node metastasis, nor local metastasis.

Conclusion: For cTNM stage III gastric cancer, intraoperative sustained-release fluorouracil implants after radical resection combined with postoperative adjuvant chemotherapy, could significantly reduce the risk of peritoneal recurrence and prolong PFS. https://clinicaltrials.gov/, identifier (NCT02269904).
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http://dx.doi.org/10.3389/fonc.2021.670651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298064PMC
July 2021

Hyperprogressive Disease in Cancers Treated With Immune Checkpoint Inhibitors.

Front Pharmacol 2021 5;12:678409. Epub 2021 Jul 5.

Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

Immunotherapy, which takes advantage of the immune system to eliminate cancer cells, has been widely studied and applied in oncology. Immune checkpoint inhibitors (ICIs) prevent the immune system from being turned off before cancer cells are eliminated. They have proven to be among the most promising and effective immunotherapies, with significant survival benefits and durable responses in diverse tumor types. However, an increasing number of retrospective studies have found that some patients treated with ICIs experience unusual responses, including accelerated proliferation of tumor cells and rapid progression of the disease, with poor outcomes. Such unexpected adverse events are termed hyperprogressive disease (HPD), and their occurrence suggests that ICIs are detrimental to a subset of cancer patients. HPD is common, with an incidence ranging between 4 and 29% in several cancer types. However, the mechanisms of HPD remain poorly understood, and no clinical predictive factors of HPD have been identified. In this review, we summarize current findings, including retrospective studies and case reports, and focus on several key issues including the defining characteristics, predictive biomarkers, potential mechanisms of HPD, and strategies for avoiding HPD after ICI treatment.
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http://dx.doi.org/10.3389/fphar.2021.678409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287409PMC
July 2021

Laboratory Study of Deformation Behaviour of Two New Reinforcing Polymeric TSLs and Their Potential Application in Deep Underground Coal Mine.

Polymers (Basel) 2021 Jul 3;13(13). Epub 2021 Jul 3.

College of Mining, Liaoning Technical University, Fuxin 123000, China.

Thin spray-on liner (TSL) is a surface protection technology used by spraying a polymer film, which is widely used for mine airtightness and waterproofing. A reinforcing TSL can replace steel mesh, which is a new method for roadway support. This paper reviews the development of a reinforcing TSL. Considering the deterioration of geological conditions in deep underground mining and the demand for reinforcing automation, two kinds of polymeric reinforcing TSL (RPTSL) materials are developed. The mechanical characteristics of the new TSL materials are studied experimentally. Results show that the average compressive strength, tensile strength, cohesion, and internal friction angle of the two TSL materials are 52 and 32 MPa, 12 and 8 MPa, 6.2 and 17.2 MPa, and 33.6° and 25.9°, respectively. The bonding strength between the two materials and coal is greater than the tensile strength of coal itself, and the mechanical properties of the material for comparison are lower than those of both materials. Based on the TSL support mechanism, we examine the application of the two TSL materials to the mining environment and compare the mechanical properties of polymer materials and cement-based materials. The advantages of polymer materials include versatile mechanical properties, good adhesion, and high early strength. This study provides a new support material to replace steel mesh for roadway surface support, which satisfies the needs of different surface support designs under complex geological conditions, and promotes the automation of roadway support.
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http://dx.doi.org/10.3390/polym13132205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271717PMC
July 2021

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

Lancet Oncol 2021 08 9;22(8):1081-1092. Epub 2021 Jul 9.

Department of General Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China.

Background: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.

Methods: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral capecitabine 1000 mg/m twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.

Findings: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.

Interpretation: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.

Funding: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00297-7DOI Listing
August 2021

Potential Implications of Quercetin in Autoimmune Diseases.

Front Immunol 2021 23;12:689044. Epub 2021 Jun 23.

Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

Autoimmune diseases are a worldwide health problem with growing rates of morbidity, and are characterized by breakdown and dysregulation of the immune system. Although their etiology and pathogenesis remain unclear, the application of dietary supplements is gradually increasing in patients with autoimmune diseases, mainly due to their positive effects, relatively safety, and low cost. Quercetin is a natural flavonoid that is widely present in fruits, herbs, and vegetables. It has been shown to have a wide range of beneficial effects and biological activities, including anti-inflammation, anti-oxidation, and neuroprotection. In several recent studies quercetin has reportedly attenuated rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus in humans or animal models. This review summarizes the evidence for the pharmacological application of quercetin for autoimmune diseases, which supports the view that quercetin may be useful for their prevention and treatment.
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http://dx.doi.org/10.3389/fimmu.2021.689044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260830PMC
November 2021

Low-Threshold Microlasers Based on Holographic Dual-Gratings.

Nanomaterials (Basel) 2021 Jun 9;11(6). Epub 2021 Jun 9.

Faculty of Science, College of Physics and Optoelectronics, Beijing University of Technology, Beijing 100124, China.

Among the efforts to improve the performances of microlasers, optimization of the gain properties and cavity parameters of these lasers has attracted significant attention recently. Distributed feedback lasers, as one of the most promising candidate technologies for electrically pumped microlasers, can be combined with dual-gratings. This combination provides additional freedom for the design of the laser cavity. Here, a holographic dual-grating is designed to improve the distributed feedback laser performance. The holographic dual-grating laser consists of a colloidal quantum dot film with two parallel gratings, comprising first-order (210 nm) and second-order (420 nm) gratings that can be fabricated easily using a combination of spin coating and interference lithography. The feedback and the output from the cavity are controlled using the first-order grating and the second-order grating, respectively. Through careful design and analysis of the dual-grating, a balance is achieved between the feedback and the cavity output such that the lasing threshold based on the dual-grating is nearly half the threshold of conventional distributed feedback lasers. Additionally, the holographic dual-grating laser shows a high level of stability because of the high stability of the colloidal quantum dots against photobleaching.
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http://dx.doi.org/10.3390/nano11061530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226637PMC
June 2021

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021.

Cancer Commun (Lond) 2021 08 1;41(8):747-795. Epub 2021 Jul 1.

Department of Gastrointestinal Medical Oncology, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, 150081, P. R. China.

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.
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http://dx.doi.org/10.1002/cac2.12193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360643PMC
August 2021

Novel method using DW-MRI and ADC images to guide stereotactic biopsy for the diagnosis small primary angiitis of the central nervous system: a case report.

Eur J Med Res 2021 Jun 23;26(1):58. Epub 2021 Jun 23.

Department of Neurosurgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, China.

Objective: To determine the role of diffusion-weighted magnetic resonance imaging (DW-MRI) and apparent diffusion coefficient (ADC) imaging to guide stereotactic biopsy for the diagnosis of intracranial angiitis.

Case Presentation: In a 28-year-old woman who had experienced inactive headache and right limbs numbness for 4 days, preoperative magnetic resonance (MR) scanning, enhanced scanning, diffusion tensor imaging, magnetic resonance spectroscopy, diffusion-weighted imaging (DWI), and ADC image scanning were performed. Stereotactic biopsy was performed in one target where the area of edema detected with MR FLAIR, and two targets where the area shown as a high-value and a lower value area in the DWI/ADC image. Pathological examinations together with computed tomographic and enhanced MRI scans were conducted after surgery. A preoperative enhanced MRI scan showed a uniform low-intensity lesion in the patient's left centrum semiovale, with a volume of 3.1 cm. The DWI and ADC images showed uneven high-intensity signals and different ADC values in the lesion area, respectively. During surgery, tissues around the lesion and the lesion center were sampled at the three selected targets. The postoperative pathological diagnosis was primary angiitis of the central nervous system, and the patient was given anti-inflammatory medication and hormone therapy. The 3-year follow-up confirmed that the patient had recovered well, with a Glasgow Outcome Scale score of five.

Conclusion: DW-MRI and ADC images can be reliably used to determine the location of small intracranial lesions, and guide stereotactic biopsy to facilitate the diagnosis of primary vasculitis of the central nervous system.
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http://dx.doi.org/10.1186/s40001-021-00529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220829PMC
June 2021

Current status of lymph node dissection in gastric cancer.

Authors:
Bin Ke Han Liang

Chin J Cancer Res 2021 Apr;33(2):193-202

Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin 300060, China.

Gastrectomy with lymph node (LN) dissection has been regarded as the standard surgery for gastric cancer (GC), however, the rational extent of lymphadenectomy remains controversial. Though gastrectomy with extended lymphadenectomy beyond D2 is classified as a non-standard gastrectomy, its clinical significance has been evaluated in many studies. Although hard evidence is lacking, D2 plus superior mesenteric vein (No. 14v) LN dissection is recommended when harbor metastasis to No. 6 nodes is suspected in the lower stomach, and dissection of splenic hilar (No. 10) LN can be performed for advanced GC invading the greater curvature of the upper stomach, and D2 plus posterior surface of the pancreatic head (No. 13) LN dissection may be an option in a potentially curative gastrectomy for cancer invading the duodenum. Prophylactic D2+ para-aortic nodal dissection (PAND) was not routinely recommended for advanced GC patients, but therapeutic D2 plus PAND may offer a chance of cure in selected patients, preoperative chemotherapy was considered as the standard treatment for GC with para-aortic node metastasis. There has been no consensus on the extent of lymphadenectomy for the adenocarcinoma of the esophagogastric junction (AEG) so far. The length of esophageal invasion can be used as a reference point for mediastinal LN metastases, and the distance from the esophagogastric junction to the distal end of the tumor is essential for determining the optimal extent of resection. The quality of lymphadenectomy may influence prognosis in GC patients. Both hospital volume and surgeon volume were important factors for the quality of radical gastrectomy. Centralization of GC surgery may be needed to improve prognosis.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.02.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181876PMC
April 2021

Nanographene-Osmapentalyne Complexes as a Cathode Interlayer in Organic Solar Cells Enhance Efficiency over 18.

Adv Mater 2021 Jul 12;33(30):e2101279. Epub 2021 Jun 12.

Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China.

Interface engineering is a critical method by which to efficiently enhance the photovoltaic performance of nonfullerene solar cells (NFSC). Herein, a series of metal-nanographene-containing large transition metal involving d -p conjugated systems by way of the addition reactions of osmapentalynes and p-diethynyl-hexabenzocoronenes is reported. Conjugated extensions are engineered to optimize the π-conjugation of these metal-nanographene molecules, which serve as alcohol-soluble cathode interlayer (CIL) materials. Upon extension of the π-conjugation, the power conversion efficiency (PCE) of PM6:BTP-eC9-based NFSCs increases from 16% to over 18%, giving the highest recorded PCE. It is deduced by X-ray crystallographic analysis, interfacial contact methods, morphology characterization, and carrier dynamics that modification of hexabenzocoronenes-styryl can effectively improve the short-circuit current density (J ) and fill factor of organic solar cells (OSCs), mainly due to the strong and ordered charge transfer, more matching energy level alignments, better interfacial contacts between the active layer and the electrodes, and regulated morphology. Consequently, the carrier transport is largely facilitated, and the carrier recombination is simultaneously impeded. These new CIL materials are broadly able to enhance the photovoltaic properties of OSCs in other systems, which provides a promising potential to serve as CILs for higher-quality OSCs.
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http://dx.doi.org/10.1002/adma.202101279DOI Listing
July 2021

Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance.

Nat Commun 2021 06 11;12(1):3579. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Yolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-021-23681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196104PMC
June 2021

Prodrug Delivery Using Dual-Targeting Nanoparticles To Treat Breast Cancer Brain Metastases.

Mol Pharm 2021 07 10;18(7):2694-2702. Epub 2021 Jun 10.

Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.

Brain metastases from breast cancer are the most frequent brain metastasis in women, which are often difficult to be surgically removed due to the multifocal and infiltrative intracranial growth patterns. Cytotoxic drugs have potent anti-breast cancer properties. However, owing to the toxic side effects and the blood-brain barrier (BBB), these drugs cannot be fully and aggressively exploited with systemic administration and hence have very limited application for brain metastases. In this study, hyaluronidase-activated prodrug hyaluronic-doxorubicin (DOX) was assembled by the BBB and metastatic breast cancer dual-targeting nanoparticles (NPs), which were constructed based on transcytosis-targeting peptide and hyaluronic acid co-modified poly(lactic-co-glycolic acid)-poly(-carbobenzoxy-l-lysine). DOX showed enzyme-recovered DNA insertion, selective cytotoxicity to metastatic breast cancer cells rather than astrocytes, and efficient loading into dual-targeting NPs. [email protected] displayed the ability of dually targeting the BBB and metastatic breast cancer and significantly extended the median survival time of mice with intracranial metastatic breast cancer. Based on these improvements, this prodrug delivery tactic may serve as an important direction for drug therapy against brain metastases.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00224DOI Listing
July 2021

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment.

Acta Pharm Sin B 2021 May 21;11(5):1341-1354. Epub 2020 Oct 21.

Jiangsu Key Laboratory of Neuropsychiatric Diseases Research and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.
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http://dx.doi.org/10.1016/j.apsb.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148067PMC
May 2021

Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma.

Carcinogenesis 2021 07;42(7):995-1007

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.

MicroRNAs, as a group of post-transcriptional regulators, regulate multiple pathological processes including metastasis during tumor development. Here, we demonstrated the metastasis-suppressive function of microRNA (miR)-338-5p in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-338-5p had inhibitory effect on invasive ability of ESCC cells and extracellular matrix degradation, whereas silencing miR-338-5p had opposite effects. Mechanistically, miR-338-5p directly targeted the 3' untranslated regions of hepatocellular growth factor receptor cMet (cMET) and epidermal growth factor receptor (EGFR). As a result, miR-338-5p inhibited the downstream signaling cascades of cMET and EGFR and repressed cMET- and EGFR-mediated ESCC cell invasion. Re-expression of cMET or EGFR in miR-338-5p overexpressing ESCC cells was sufficient to derepress ESCC cell invasion both in vitro and in vivo. We further showed that such manipulation downregulated the expression and secretion of matrix metalloproteinases 2 and 9, which resulted in impaired extracellular matrix degradation and cell invasion. Most importantly, systemic delivery of miR-338-5p mimic significantly inhibited metastasis of ESCC cells in nude mice. Taken together, our results uncovered a previously unknown mechanism through which miR-338-5p suppresses ESCC invasion and metastasis by regulating cMET/EGFR-matrix metalloproteinase 2/9 axis and highlighted the potential significance of miR-338-5p-based therapy in treating patients with metastatic ESCC.
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http://dx.doi.org/10.1093/carcin/bgab046DOI Listing
July 2021

Open total dislocation of ankle joint without fractures: A case report.

Medicine (Baltimore) 2021 Jun;100(22):e26247

Department of Orthopedics, Affiliated Hospital of Jining Medical University, Jining City, Shandong Province, China.

Rationale: Open total dislocation of ankle joint is rare and often caused by high-energy injury. The present study describes a patient with open total lateral dislocation of ankle joint without fractures and obtained a satisfactory clinical result following early debridement and irrigation, one-stage repairment of ligaments, and plaster external fixation.

Patient Concerns: The patient, a 45-year-old male, complained of right foot pain with bleeding and limited motion. Physical examination showed a 15-cm open wound at the medial ankle region, with soft tissues impaired and ankle bones exposed. The 3 dimensional reconstruction computed tomography (CT) examination showed an open total dislocation of ankle joint without concomitant fractures.

Diagnoses: open total lateral dislocation of ankle joint without fractures.

Interventions: Early modern wound care including thorough debridement and irrigation on the wound was performed to remove contaminated soft tissues. Subsequently, the dislocated ankle joint was reduced by hand and the medial and lateral collateral ligaments were repaired using wire anchors.

Outcomes: The medial wound healed at 2 weeks after surgery, and several common complications such as infection and skin necrosis did not occur. The last follow-up showed a good range of metatarsal flexion and extension of the injured foot, and obvious signs of traumatic arthritis were not observed. According to Kaikkonen ankle function score, the patient was assessed with 90 points.

Lessons: For open total dislocation of ankle joint, early treatment should focus on debridement and irrigation, reduction and fixation of the dislocated ankle, protection of the weak soft tissues, and stable external fixation to promote wound healing and reduce the incidence of related complications.
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http://dx.doi.org/10.1097/MD.0000000000026247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183828PMC
June 2021

Quercetin-mediated SIRT1 activation attenuates collagen-induced mice arthritis.

J Ethnopharmacol 2021 Oct 20;279:114213. Epub 2021 May 20.

Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, China. Electronic address:

Ethnopharmacological Relevance: Herba taxilli (HT, Sangjisheng in Chinese), which is composed of the dried stems and leaves of Taxillus chinensis (DC.) Danser, has been commonly used to treat inflammation and arthritis in traditional Chinese medicine (TCM). Quercetin (Que) is a major active flavonoid component isolated from HT and is one of the quality control indexes of HT. In the clinical practice of TCM, formulas containing HT are commonly used to treat rheumatoid arthritis (RA). Recent studies have shown that Que exerts antiarthritic effects. However, the mechanism by which Que treatment affects RA is not fully understood.

Aim Of The Study: This study aimed to explore the antiarthritic activity of Que in a collagen-induced arthritis (CIA) mouse model and investigate the underlying mechanisms.

Materials And Methods: The antiarthritic activity of Que was evaluated in a CIA mouse model by determining the paw clinical arthritis scores and left ankle thicknesses and by conducting micro-PET imaging and histopathological analysis of ankle joint tissues. The proinflammatory cytokine (IL-6, TNF-α, IL-1β, IL-8, IL-13, IL-17) levels in the serum and ankle joint tissues were measured by ELISA. Mitochondrial oxidative stress was assessed by biochemical methods. Mitochondrial biogenesis was analysed by RT-qPCR. The protein levels of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), p38, phospho-p38, extracellular signal-regulated kinases (ERK)-1/2, phospho-ERK1/2, p65, and phospho-p65 in ankle joint tissues were detected by Western blot analysis. A total of 30 RA patients were recruited to investigate the relationship between the disease activity score (DAS28) and the SIRT1, PGC-1α, NRF1, and HMGB1 plasma levels.

Results: Que treatment decreased the clinical score and left ankle thickness of CIA mice, attenuated the synovial inflammation and hyperplasia and bone/cartilage destruction in ankle joints, and decreased the secretion of IL-6, TNF-α, IL-1β, IL-8, IL-13, and IL-17. Mechanistically, Que treatment improved impaired mitochondrial biogenesis and mitochondrial function by regulating the SIRT1/PGC-1α/NRF1/TFAM pathway and inhibited inflammation via the HMGB1/TLR4/p38/ERK1/2/NF-κB p65 pathway. Notably, epidemiological data revealed correlations between abnormal circulating levels of SIRT1, PGC-1α, NRF1, HMGB1 and RA disease activity in patients.

Conclusions: Our data suggested a potential role of Que as a dietary therapeutic drug for RA treatment that may act through SIRT1 to target mitochondrial biogenesis. Additionally, the role of impaired mitochondrial biogenesis in RA was evaluated.
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http://dx.doi.org/10.1016/j.jep.2021.114213DOI Listing
October 2021
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