Targeting hyaluronic acid and peritoneal dissemination in colorectal cancer

Peritoneal metastasis (PM) from colorectal cancer (CRC) carries a significant mortality rate for patients and treatment is challenging. The development of PM is a multistep process involving detachment, adhesion, invasion and colonisation of the peritoneal cavity. Cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy) for PM from CRC has some benefit but overall survival is poor and recurrence rates are high. Treatments to prevent the development of peritoneal metastasis could have the potential to improve CRC survival and disease-free outcomes. The ability of cancer cells to invade the peritoneum and become established as metastatic tumours is influenced by a multifactorial process. Hyaluronic acid (HA) has been shown to coat the mesothelial cells of the peritoneum and has been demonstrated to be utilised in various malignancies as part of the metastatic process in peritoneal dissemination. CD44, RHAMM (CD168) and ICAM-1 have all been shown to be binding partners for HA. Targeting HA-mediated binding may prevent adhesion to distant sites within the peritoneum through suppression of interaction of these molecules. Here we review the current literature and discuss key molecules involved with PM dissemination, with the potential to target these mechanisms in the delivery of future treatments

SIPA1 Is a modulator of HGF/MET induced tumour metastasis via the regulation of tight junction-based cell to cell barrier function

Background: Lung cancer is the leading cause of cancer death. SIPA1 is a mitogen induced GTPase activating protein (GAP) and may hamper cell cycle progression. SIPA1 has been shown to be involved in MET signaling and may contribute to tight junction (TJ) function and cancer metastasis. Methods: Human lung tumour cohorts were analyzed. In vitro cell function assays were performed after knock down of SIPA1 in lung cancer cells with/without treatment. Quantitative polymerase chain reaction (qPCR) and western blotting were performed to analyze expression of HGF (hepatocyte growth factor), MET, and their downstream markers. Immunohistochemistry (IHC) and immunofluorescence (IFC) staining were performed. Results: Higher expression of SIPA1 in lung tumours was associated with a poorer prognosis. Knockdown of SIPA1 decreased invasiveness and proliferation of in vitro cell lines, and the SIPA1 knockdown cells demonstrated leaky barriers. Knockdown of SIPA1 decreased tight junction-based barrier function by downregulating MET at the protein but not the transcript level, through silencing of Grb2, SOCS, and PKCμ (Protein kinase Cµ), reducing the internalization and recycling of MET. Elevated levels of SIPA1 protein are correlated with receptor tyrosine kinases (RTKs), especially HGF/MET and TJs. The regulation of HGF on barrier function and invasion required the presence of SIPA1. Conclusions: SIPA1 plays an essential role in lung tumourigenesis and metastasis. SIPA1 may be a diagnostic and prognostic predictive biomarker. SIPA1 may also be a potential therapeutic target for non-small cell lung cancer (NSCLC) patients with aberrant MET expression and drug resistance

Local bone metabolism balance regulation via double-adhesive hydrogel for fixing orthopedic implants

© 2021 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)The effective osteointegration of orthopedic implants is a key factor for the success of orthopedic surgery. However, local metabolic imbalance around implants under osteoporosis condition could jeopardize the fixation effect. Inspired by the bone structure and the composition around implants under osteoporosis condition, alendronate (A) was grafted onto methacryloyl hyaluronic acid (H) by activating the carboxyl group of methacryloyl hyaluronic acid to be bonded to inorganic calcium phosphate on trabecular bone, which is then integrated with aminated bioactive glass (AB) modified by oxidized dextran (O) for further adhesion to organic collagen on the trabecular bone. The hybrid hydrogel could be solidified on cancellous bone in situ under UV irradiation and exhibits dual adhesion to organic collagen and inorganic apatite, promoting osteointegration of orthopedic implants, resulting in firm stabilization of the implants in cancellous bone areas. In vitro, the hydrogel was evidenced to promote osteogenic differentiation of embryonic mouse osteoblast precursor cells (MC3T3-E1) as well as inhibit the receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteoclast differentiation of macrophages, leading to the upregulation of osteogenic-related gene and protein expression. In a rat osteoporosis model, the bone-implant contact (BIC) of the hybrid hydrogel group increased by 2.77, which is directly linked to improved mechanical stability of the orthopedic implants. Overall, this organic-inorganic, dual-adhesive hydrogel could be a promising candidate for enhancing the stability of orthopedic implants under osteoporotic conditions.This work was supported by the National Key R&D Program of China (2020YFA0908200), National Natural Science Foundation of China (82120108017), Six talent peaks project in Jiangsu Province (WSW-018). This work was financed by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” UID/BIM/04293/2019.info:eu-repo/semantics/publishedVersio

Evaluating active versus passive sources of human brucellosis in Jining City, China

Human brucellosis (HB) remains a serious public health concern owing to its resurgence across the globe and specifically in China. The timely detection of this disease is the key to its prevention and control. We sought to describe the differences in the demographics of high-risk populations with detected cases of HB contracted from active versus passive sources. We collected data from a large sample population from January to December 2018, in Jining City, China. We recruited patients that were at high-risk for brucellosis from three hospitals and Centers of Disease Control and Prevention (CDCs). These patients were classified into two groups: the active detection group was composed of individuals receiving brucellosis counseling at the CDCs; the passive detection group came from hospitals and high-risk HB groups. We tested a total of 2,247 subjects and 13.3% (299) presented as positive for HB. The positive rates for active and passive detection groups were 20.5% (256/1,249) and 4.3% (43/998), respectively (p < 0.001). The detection rate of confirmed HB cases varied among all groups but was higher in the active detection group than in the passive detection group when controlled for age, sex, ethnicity, education, career, and contact history with sheep or cattle (p < 0.05). Males, farmers, those with four types of contact history with sheep or cattle, and those presenting fever, hyperhidrosis and muscle pain were independent factors associated with confirmed HB cases in multivariate analysis of the active detection group. Active detection is the most common method used to detect brucellosis cases and should be applied to detect HB cases early and avoid misdiagnosis. We need to improve our understanding of brucellosis for high-risk populations. Passive HB detection can be supplemented with active detection when the cognitive changes resulting from brucellosis are low. It is important that healthcare providers understand and emphasis the timely diagnosis of HB

Tim-3 promotes cell aggressiveness and paclitaxel resistance through the NF-κB /STAT3 signalling pathway in breast cancer cells

Objective: Although T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3) has been recognized as a promising target for cancer immunotherapy, its exact role in breast cancer has not been fully elucidated. Methods: Tim-3 gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells. Results: In a pooled analysis of The Cancer Genome Atlas (TCGA) database, Tim-3 gene expression levels were significantly higher (P<0.001) in breast cancer tissue, compared with normal tissues. Tim-3 was a prognosis indicator in breast cancer patients [relapse-free survival (RFS), P=0.004; overall survival (OS), P=0.099]. Tim-3 overexpression in Tim-3low breast cancer cells promoted aggressiveness of breast cancer cells, as evidenced by enhanced proliferation, migration, invasion, tight junction deterioration and tumor-associated tubal formation. Tim-3 also enhanced cellular resistance to paclitaxel. Furthermore, Tim-3 exerted its function by activating the NF-κB/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (CCND1), C-Myc, matrix metalloproteinase-1(MMP1), TWIST, vascular endothelial growth factor (VEGF) upregulation, concomitant with E-cadherin downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression. Conclusions: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy

TfR1 binding with H-ferritin nanocarrier achieves prognostic diagnosis and enhances the therapeutic efficacy in clinical gastric cancer

H-ferritin (HFn) nanocarrier is emerging as a promising theranostic platform for tumor diagnosis and therapy, which can specifically target tumor cells via binding transferrin receptor 1 (TfR1). This led us to investigate the therapeutic function of TfR1 in GC. The clinical significance of TfR1 was assessed in 178 GC tissues by using a magneto-HFn nanoparticle-based immunohistochemistry method. The therapeutic effects of doxorubicin-loaded HFn nanocarriers (HFn-Dox) were evaluated on TfR1-positive GC patient-derived xenograft (GC-PDX) models. The biological function of TfR1 was investigated through in vitro and in vivo assays. TfR1 was upregulated (73.03%) in GC tissues, and reversely correlated with patient outcome. TfR1-negative sorted cells exhibited tumor-initiating features, which enhanced tumor formation and migration/invasion, whereas TfR1-positive sorted cells showed significant proliferation ability. Knockout of TfR1 in GC cells also enhanced cell invasion. TfR1-deficient cells displayed immune escape by upregulating PD-L1, CXCL9, and CXCL10, when disposed with IFN-γ. Western blot results demonstrated that TfR1-knockout GC cells upregulated Akt and STAT3 signaling. Moreover, in TfR1-positive GC-PDX models, the HFn-Dox group significantly inhibited tumor growth, and increased mouse survival, compared with that of free-Dox group. TfR1 could be a potential prognostic and therapeutic biomarker for GC: (i) TfR1 reversely correlated with patient outcome, and its negative cells possessed tumor-aggressive features; (ii) TfR1-positive cells can be killed by HFn drug nanocarrier. Given the heterogeneity of GC, HFn drug nanocarrier combined with other therapies toward TfR1-negative cells (such as small molecules or immunotherapy) will be a new option for GC treatment

Elongation of Fibers from Highly Viscous Dextran Solutions Enables Fabrication of Rapidly Dissolving Drug Carrying Fabrics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110570/1/adhm201400287-sup-0001-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110570/2/adhm201400287.pd

Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone

Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial–mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC