The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.

https://www.mdpi.com/1422-0067/19/11/3295/pdf

HGF/c-MET: A Promising Therapeutic Target in the Digestive System Cancers.

The autonomic nervous system, consisting of sympathetic and parasympathetic/vagal nerves, is known to control the functions of any organ, maintaining whole-body homeostasis under physiological conditions. Recently, there has been increasing evidence linking sympathetic and parasympathetic/vagal nerves to cancers. The present review aimed to summarize recent developments from studies addressing the relationship between sympathetic and parasympathetic/vagal nerves and cancer behavior. Literature review. Human and animal studies have revealed that sympathetic and parasympathetic/vagal nerves innervate the cancer microenvironment and alter cancer behavior. The sympathetic nerves have cancer-promoting effects on prostate cancer, breast cancer, and melanoma. On the other hand, while the parasympathetic/vagal nerves have cancer-promoting effects on prostate, gastric, and colorectal cancers, they have cancer-suppressing effects on breast and pancreatic cancers. These neural effects may be mediated by β-adrenergic or muscarinic receptors and can be explained by changes in cancer cell behavior, angiogenesis, tumor-associated macrophages, and adaptive antitumor immunity. Sympathetic nerves innervating the tumor microenvironment promote cancer progression and are related to stress-induced cancer behavior. The parasympathetic/vagal nerves have variable (promoting or suppressing) effects on different cancer types. Approaches directed toward the sympathetic and parasympathetic/vagal nerves can be developed as a new cancer therapy. In addition to existing pharmacological, surgical, and electrical approaches, a recently developed virus vector-based genetic local neuroengineering technology is a powerful approach that selectively manipulates specific types of nerve fibers innervating the cancer microenvironment and leads to the suppression of cancer progression. This technology will enable the creation of "cancer neural therapy" individually tailored to different cancer types.

Sympathetic and parasympathetic innervation in cancer: therapeutic implications.

A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut–brain interaction, inflammatory bowel diseases, and colorectal cancer.

/pdf/the-enteric-nervous-system-in-gastrointestinal-disease-30efhn4hy5.pdf

The enteric nervous system in gastrointestinal disease etiology

Background Breast cancer is the most common malignancy in women and the underlying mechanism of breast cancer cell metastasis is still far from uncover. Integrin subunit alpha 7 (ITGA7) is a functioning protein. It has been detected in many malignancies. But the function of ITGA7 in breast cancer is not clear. Our aim is to explore ITGA7 expression and its role in breast cancer. Methods Real-time PCR was performed to determine ITGA7 expression in BC tissues and normal adjacent tissues. The specific functions of ITGA7 in breast cancer cell lines (MDA-MB-231 and BT-549) transfected with small interfering RNA were determined through migration, invasion assays. Western blot assays were performed to determine the expression of c-met and vimentin. Results ITGA7 was down-regulated in breast cancer tissues compared to the adjacent normal tissues (T:N =7.68±27.38: 41.01± 31.47, P<0.001) and this observation was consistent with the TCGA cohort (T:N =4.51±0.45:5.40±0.61, P<0.0001). In vitro experiments showed that knocking down ITGA7 significantly inhibited the migration and invasion of the breast cancer cell lines (MDA-MB-231 and BT-549). Meanwhile, knockdown of ITGA7 promoted c-met and vimentin expression, which may induce invasion and migration. Conclusion ITGA7 plays an important tumorigenic function and acts as a suppress gene in breast cancer. Our findings indicate that ITGA7 was the gene associated with breast cancer.

/pdf/itga7-functions-as-a-tumor-suppressor-and-regulates-z7vz797pug.pdf

ITGA7 functions as a tumor suppressor and regulates migration and invasion in breast cancer.

Background Diabetes mellitus (DM) have become seriously threatens to human health and life quality worldwide. As a systemic metabolic disease, multiple studies have revealed that DM is related to metabolic bone diseases and always induces higher risk of fracture. In view of this, the links between bone metabolism (BM) and DM (BMDM) have gained much attention and numerous related papers have been published. Nevertheless, no prior studies have yet been performed to analyze the field of BMDM research through bibliometric approach. To fill this knowledge gap, we performed a comprehensive bibliometric analysis of the global scientific publications in this field. Methods Articles and reviews regarding BMDM published between 2000 and 2021 were obtained from the Web of Science after manually screening. VOSviewer 1.6.16, CiteSpace V 5.8.R3, Bibliometrix, and two online analysis platforms were used to conduct the bibliometric and visualization analyses. Results A total of 2,525 documents including 2,255 articles and 270 reviews were retrieved. Our analysis demonstrated a steady increasing trend in the number of publications over the past 22 years (R2 = 0.989). The United States has occupied the leading position with the largest outputs and highest H-index. University of California San Francisco contributed the most publications, and Schwartz AV was the most influential author. Collaboration among institutions from different countries was relatively few. The journals that published the most BMDM-related papers were Bone and Osteoporosis International. Osteoporosis and related fractures are the main bone metabolic diseases of greatest concern in this field. According to co-cited references result, “high glucose environment,” “glycation end-product” and “sodium-glucose co-transporter” have been recognized as the current research focus in this domain. The keywords co-occurrence analysis indicated that “diabetic osteoporosis,” “osteoarthritis,” “fracture risk,” “meta-analysis,” “osteogenic differentiation,” “bone regeneration,” “osteogenesis,” and “trabecular bone score” might remain the research hotspots and frontiers in the near future. Conclusion As a cross-discipline research field, the links between bone metabolism and diabetes mellitus are attracting increased attention. Osteoporosis and related fractures are the main bone metabolic diseases of greatest concern in this field. These insights may be helpful for clinicians to recognize diabetic osteopenia and provide more attention and support to such patients.

Mapping Knowledge Landscapes and Emerging Trends of the Links Between Bone Metabolism and Diabetes Mellitus: A Bibliometric Analysis From 2000 to 2021

A growing body of research has illuminated that photodynamic therapy (PDT) serves as an important therapeutic strategy in oncology and has become a hot topic in recent years. Although numerous papers related to cancer PDT (CPDT) have been published, no bibliometric studies have been conducted to summarize the research landscape, and highlight the research trends and hotspots in this field. This study collected 5,804 records on CPDT published between 2000 and 2021 from Web of Science Core Collection. Bibliometric analysis and visualization were conducted using VOSviewer, CiteSpace, and one online platform. The annual publication and citation results revealed significant increasing trends over the past 22 years. China and the United States, contributing 56.24% of the total publications, were the main driving force in this field. Chinese Academy of Sciences was the most prolific institution. Photodiagnosis and Photodynamic Therapy and Photochemistry and Photobiology were the most productive and most co-cited journals, respectively. All keywords were categorized into four clusters including studies on nanomaterial technology, clinical applications, mechanism, and photosensitizers. “nanotech-based PDT” and “enhanced PDT” were current research hotspots. In addition to several nano-related topics such as “nanosphere,” “nanoparticle,” “nanomaterial,” “nanoplatform,” “nanomedicine” and “gold nanoparticle,” the following topics including “photothermal therapy,” “metal organic framework,” “checkpoint blockade,” “tumor microenvironment,” “prodrug” also deserve further attention in the near future.

/pdf/bibliometric-analysis-of-global-research-on-cancer-g9s1wkdh.pdf

Bibliometric Analysis of Global Research on Cancer Photodynamic Therapy: Focus on Nano-Related Research

Osteonecrosis of the femoral head (ONFH) is a common disabling disease with considerable social and economic impacts. Although extensive studies related to ONFH have been conducted in recent years, a specific bibliometric analysis on this topic has not yet been performed. Our study attempted to summarize the comprehensive knowledge map, development landscape, and future directions of ONFH research with the bibliometric approach.All publications concerning ONFH published from 2001 to 2020 were identified from Web of Science Core Collection. Key bibliometric indicators were calculated and evaluated using CiteSpace, VOSviewer, and the online bibliometric analysis platform.A total of 2594 publications were included. Our analysis revealed a significant exponential growth trend in the annual number of publications over the past 20 years (R2 = 0.9663). China, the USA, and Japan were the major contributors both from the quality and quantity points of view. Correlation analysis indicated that there was a high positive correlation between the number of publications and gross domestic product (r = 0.774), and a moderate positive correlation between publications and demographic factor (r = 0.673). All keywords were categorized into four clusters including Cluster 1 (etiology and risk factors study); Cluster 2 (basic research and stem cell therapy); cluster 3 (hip-preserving study); and Cluster 4 (hip replacement study). Stem cell therapy-related research has been recognized as an important research hotspot in this field. Several topics including exosomes, autophagy, biomarkers, osteogenic differentiation, microRNAs, steroid-induced osteonecrosis, mesenchymal stem cells, double-blind, early-stage osteonecrosis, and asymptomatic osteonecrosis were considered as research focuses in the near future.Over the past two decades, increasing attention has been paid to global ONFH-related research. Our bibliometric findings provide valuable information for researchers to understand the basic knowledge structure, identify the current research hotspots, potential collaborators, and future research frontiers in this field. 

/pdf/knowledge-structure-and-emerging-trends-on-osteonecrosis-of-t8yd40ws.pdf

Knowledge structure and emerging trends on osteonecrosis of the femoral head: a bibliometric and visualized study

The present study evaluated the distribution of sympathetic and parasympathetic nerves and the expression of the α9 nicotinic acetylcholine receptor (α9nAChR) and investigated their potential association with colorectal cancer (CRC) development. The distribution of autonomic nerves and α9nAChR in CRC was detected by immunohistochemistry, which was then used to analyze their association with clinicopathological parameters and prognosis. Sympathetic fibers were primarily observed in the stroma adjacent to cancer cells, whereas parasympathetic fibers were primarily observed in the stroma away from cancer cells. Patients with samples positive for sympathetic nerve fibers had less lymph node invasion and a better prognosis compared with patients with samples negative for sympathetic nerve fibers. The expression of parasympathetic nerves in patients >60 years old was increased compared with patients ≤60 years old. The expression of parasympathetic nerves in patients with lymph node invasion was increased compared with patients without lymph node invasion. The detection of parasympathetic nerves gradually increased as CRC (T stage) advanced. Patients with parasympathetic negative samples had better prognoses compared with patients with parasympathetic positive samples. The expression of α9nAChR was principally localized in cellular membranes and the cytoplasm of CRC tissues and it was revealed to have a positive association with the number of parasympathetic nerves. Increased α9nAChR expression was observed in patients >60 years old compared with patients <60 years old. The detection rate of α9nAChR in tissues from patients with lymph node invasion was increased compared with patients without lymph node invasion. The detection of α9nAChR gradually increased as the CRC stage advanced. The prognoses for patients with α9nAChR negative tissue were improved compared with the prognoses for patients with α9nAChR positive tissue. Sympathetic nerves were primarily detected in the early phases of CRC and indicated a good prognosis. Parasympathetic nerves and α9nAChR were principally observed in the late phases of cancer and indicated a poor prognosis. The present study revealed that parasympathetic nerves may promote the progression of CRC through α9nAChR.

/pdf/expression-and-significance-of-autonomic-nerves-and-a9-2slml1l7ai.pdf

Expression and significance of autonomic nerves and α9 nicotinic acetylcholine receptor in colorectal cancer.

The aim of the present study was to investigate the effect of hepatocyte growth factor receptor (c-MET) inhibition on the viability of colon cancer cells and xenografts exposed to irradiation using short hairpin (sh)RNA or the c-MET inhibitor PHA665752. The underlying mechanisms were also investigated. Human colorectal adenocarcinoma HT-29 cells were infected with a lentivirus expressing shRNAs against c-MET and were irradiated at 0, 2, 4, 6 and 8 Gy. The viability of the cells was assessed by alamarBlue® assays. Mice bearing human colon carcinoma SW620 xenografts were randomly selected to receive 2.5% dimethyl sulfoxide (DMSO), 25 mg/kg PHA665752 intraperitoneally once every 2 days for 3 weeks, irradiation at 10 Gy, or 25 mg/kg PHA665752 intraperitoneally once every 2 days for 3 weeks followed 24 h later by irradiation at 10 Gy. The mean tumor volume (MTV) was measured. The apoptotic rate of cells was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays, and double stranded break marker antibody γ-H2AX and hypoxia inducible factor (HIF)-1α expression was examined by immunohistochemistry. alamarBlue assays revealed that c-MET downregulation by shRNA markedly accentuated the irradiation-induced reduction in the viability of HT-29 cells compared with HT-29 cells irradiated at the same doses (P<0.05). A combination of irradiation and PHA665752 caused an additional reduction in the MTV (382.8±42.4 mm3; P<0.01 vs. irradiation and PHA665752, 998.0±180.6 and 844.8±190.0 mm3, respectively). TUNEL assays revealed that irradiation and PHA665752 alone caused significant apoptosis of the SW620 cells in the tumor xenografts (P<0.01 vs. DMSO). The apoptotic index in the tumor xenografts of mice treated with a combination of irradiation and PHA665752 was significantly increased compared with mice treated with either agent alone (P<0.01). The combination of irradiation and PHA665752 was also associated with a marked increase in γ-H2AX levels and a significant decrease in HIF-1α expression in the xenografts (P<0.01). In conclusion, c-MET inhibition sensitizes colorectal cancer cells to irradiation by enhancing the formation of DNA double strand breaks and possibly alleviating tumor hypoxia.

/pdf/c-met-inhibition-enhances-the-response-of-the-colorectal-3oewpi14mw.pdf

Weiguang Yang

Papers

Mapping Knowledge Landscapes and Emerging Trends of the Links Between Bone Metabolism and Diabetes Mellitus: A Bibliometric Analysis From 2000 to 2021

Bibliometric Analysis of Global Research on Cancer Photodynamic Therapy: Focus on Nano-Related Research

Knowledge structure and emerging trends on osteonecrosis of the femoral head: a bibliometric and visualized study

Expression and significance of autonomic nerves and α9 nicotinic acetylcholine receptor in colorectal cancer.

c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo.