Curcumol Enhances the Antitumor Effect of Lenvatinib on Hepatocellular Carcinoma Cells.

BACKGROUND: Lenvatinib is an important molecular target drug for the treatment of advanced hepatocellular carcinoma (HCC). However, the application of molecular targeted therapies for HCC also faces some challenges. Cumulative evidence has also shown that curcumol is a potential anti-HCC drug. Curcumol can be used as a chemosensitizer to enhance the antitumor effect of chemotherapeutic drugs. The purpose of our study is to explore the effect of curcumol combined with lenvatinib on HCC. METHODS: The antitumor effects of curcumol or/and lenvatinib on Huh 7 cells of the HCC cell line were examined using the cell counting kit-8 (CCK-8) assay, colony formation assay, and transwell assay. For in vivo investigation, the effect on subcutaneous growth was also determined in nude mice. Changes in autophagy were determined by transmission electron microscope (TEM). Protein levels of apoptotic-related factors, epithelial mesenchymal transition (EMT)-related factors, autophagy factors, and N-cadherin and janus tyrosine kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) were examined by Western blot. RESULTS: In this study, we found that curcumol or lenvatinib could promote HCC cell apoptosis in vitro and inhibit the growth of HCC tumors in vivo (curcumol or lenvatinib group compared with control group, p < 0.05). While combination with curcumol treatment could improve the effect of lenvatinib on promoting cell apoptosis of HCC in vitro and inhibiting the growth of HCC tumors in vivo (combination group compared with lenvatinib group, p < 0.05). Curcumol combined with lenvatinib could induce more autolysosome formation detected by TEM. Mechanically, curcumol or lenvatinib could increase the expression of Bcl-2-associated X protein (Bax), E-cadherin, UNC-51-like kinase 1 (ULK), and microtubule-associated protein 1 light chain 3 (LC3B) II/I, whereas it reduced the expression of B-cell lymphoma-2 (Bcl-2), JAK2/STAT3 (curcumol or lenvatinib group compared with control group, p < 0.05). Furthermore, combined with curcumol treatment could increase the expression of Bax, E-cadherin, ULK, and LC3B II/I, whereas it reduced the expression of Bcl-2, N-cadherin, and JAK2/STAT3 (combination group compared with lenvatinib group, p < 0.05). These findings suggest that curcumol enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells. CONCLUSION: Curcumol enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells.

6-Shogaol Inhibits the Cell Migration of Colon Cancer by Suppressing the EMT Process Through the IKKß/NF-κB/Snail Pathway.

6-Shogaol from ginger has anti-inflammatory, anti-oxidation and anti-cancer effects. Aim of the Study: To study the effects and possible mechanisms of 6-Shogaol on inhibiting the migration of colon cancer cells Caco2 and HCT116 and prove the effects on proliferation and apoptosis. Materials and methods: The cells were treated with 6-Shogaol at the concentrations of 20, 40, 60, 80, and 100 µM, the cytotoxicity was tested by Colony formation assays and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the Western blot was used to evaluate IKKß/NF-κB/Snail pathway and EMT-related proteins. In addition, in order to eliminate the interference of proliferation inhibition on the experiment, Caco2 cells were treated with 6-Shogaol at the concentrations of 0, 40, and 80 µM, HCT116 cells were treated with 6-Shogaol at the concentrations of 0, 20, and 40 µM, apoptosis was measured by Annex V/PI staining, and migration was measured by Wound healing assays and Transwell test. Results: 6-Shogaol significantly inhibited the growth of cells. The maximum inhibitory concentration of half of them was 86.63 µM in Caco2 cells and 45.25 µM in HCT116 cells. At 80 µM and 40 µM concentrations, 6-Shogaol significantly promoted apoptosis of colon cancer Caco2 cells and HCT116 cells, and also significantly inhibited cell migration (P < .05). In addition, Western blot analysis showed that at 80 µM dose of 6-Shogaol significantly reduced MMP-2, N-cadherin, IKKß, P-NF-κB and Snail expression in Caco2 cells (P < .05). 40 µM dose of 6-Shogaol significantly reduced VEGF, IKKß, and P-NF-κB expression, and MMP-2, N-cadherin and Snail was significantly decreased at 60 µM of 6-Shogaol in HCT116 cells(P < .05). However, there was no significant change in E-cadherin in Caco2 cells, and the expression of E-cadherin protein in HCT116 cells decreased. Conclusion: This study proposes and confirms that 6-Shogaol can significantly inhibit the migration of colon cancer cells Caco2 and HCT116, and its mechanism may be produced by inhibiting EMT through IKKß/NF-κB/Snail signaling pathway. It was also confirmed that 6-Shogaol inhibited the proliferation and promoted apoptosis of Caco2 and HCT116 cells.

Targeted delivery of budesonide in acetic acid induced colitis: impact on miR-21 and E-cadherin expression.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation along the gastrointestinal tract. For IBD effective treatment, developing an orally administered stable drug delivery system capable of targeting inflammation sites is a key challenge. Herein, we report pH responsive hyaluronic (HA) coated Eudragit S100 (ES) nanoparticles (NPs) for the targeted delivery of budesonide (BUD) (HA-BUD-ES-NPs). HA-BUD-ES-NPs showed good colloidal properties (274.8 ± 2.9 nm and - 24.6 ± 2.8 mV) with high entrapment efficiency (98.3 ± 3.41%) and pH-dependent release profile. The negative potential following incubation in simulated gastrointestinal fluids reflected the stability of HA coat. In vitro studies on Caco-2 cells showed HA-BUD-ES-NPs biocompatibility and enhanced cellular uptake and anti-inflammatory effects as shown by the significant reduction in IL-8 and TNF-α. The oral administration of HA-BUD-ES-NPs in an acetic acid induced colitis rat model significantly mitigated the symptoms of IBD, and improved BUD therapeutic efficacy compared to drug suspension. This was proved via the improvement in disease activity index and ulcer score in addition to refined histopathological findings. Also, the assessment of inflammatory markers, epithelial cadherin, and mi-R21 all reflected the higher efficiency of HA-BUD-ES-NPs compared to free drug and uncoated formulation. We thus suggest that HA-BUD-ES-NPs provide a promising drug delivery platform for the management and site specific treatment of IBD.

Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia.

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.

The correlation of EMT and p53 immunohistochemical markers with cisplatin resistance in muscle invasive bladder cancer patients: A single-centred study.

INTRODUCTION: Although epithelial-mesenchymal transition (EMT) and p53 have been established to play a pivotal role in the aggressiveness of muscle-invasive bladder cancer (MIBC), its pathological correlation to cisplatin treatment in the Malaysian patient cohort is lacking. This study aimed to evaluate the association of EMT markers, e-cadherin, vimentin and actin, as well as tumour suppressor gene, p53, in cisplatin-receiving MIBC patients. MATERIALS AND METHODS: Formalin-fixed paraffinembedded (FFPE) blocks of muscle-invasive bladder cancer patients receiving cisplatin-based chemotherapy between January 2010 to December 2020 were traced. Immunohistochemistry staining was performed on traced blocks using antibodies to e-cadherin, vimentin and actin, and p53. RESULTS: p53 and e-cadherin were stained positive in most cases (p=0.515 and 0.242 respectively), although e-cadherin showed stronger positive expression in pre-cisplatin receiving MIBC cases. All the cases stained negative for actin and vimentin except for faint staining observed in one pre-cisplatin case. CONCLUSION: Although this study does not show a significant correlation between EMT markers and p53 with cisplatin-responsiveness in MIBC patients, the results serve as preliminary findings on the heterogeneous outcomes of molecular staining in the Malaysian MIBC patient cohort.

Novel Histone Deacetylase 6 Inhibitor Confers Anti-inflammatory Effects and Enhances Gut Barrier Function.

Background/Aims: The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 inhibitor, on human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function. Methods: Lipopolysaccharide-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor (TNF)-α expression was measured using an enzyme-linked immunosorbent assay. The proliferation of CD4+ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, based on examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription polymerase chain reaction, immunofluorescence, and a fluorescein isothiocyanate-dextran permeability assay. Results: Secretion of TNF-α, a pivotal pro-inflammatory mediator in IBD, by lipopolysaccharide-triggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction in barrier permeability in a dose-dependent manner. Conclusions: The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4 T cells and improves gut barrier function, suggesting its potential as a small-molecule therapeutic option for IBD.

[Lutein inhibits the adhesion, invasiveness and metastasis of human prostate cancer PC-3M cells].

OBJECTIVE: To explore the effects of lutein on the adhesion, invasiveness and metastasis of human prostate cancer PC-3M cells and its action mechanism. METHODS: We divided human prostate cancer PC-3M cells into a control, a low-dose lutein, a medium-dose lutein and a high-dose lutein group, and treated them with 0, 10, 20 and 40 µmol/L lutein, respectively. Then we examined the adhesion of the cells to matrix by cell adhesion assay and the changes in cell pseudopodia by Phalloidin staining, detected the expressions of paxillin, matrix metalloproteinase 2 (MMP-2), MMP-9, recombinant tissue inhibitors of metalloproteinase 1 (TIMP-1), E-cadherin, N-cadherin and vimentin by Western blot, determined the invasiveness and migration of the cells by scratch and Transwell assays, and observed their dynamic movement by high-intension imaging. RESULTS: Compared with the control, the lutein intervention groups showed significant reduction in the number of the cells adhered to matrix, the number of cell pseudopodia, the expressions of paxillin, MMP-2, MMP-9, N-cadherin and vimentin, the rates of migration, invasion and metastasis, and the distances of displacement and movement of the cells. However, the expressions of TIMP-1 and epithelial-mesenchymal transition-related E-cadherin were upregulated significantly. CONCLUSION: Lutein can inhibit cell adhesion, reduce the expressions of MMPs, and suppress cell invasion and migration by inhibiting the process of epithelial-mesenchymal transition.

Amelioration of bleomycin induced pulmonary fibrosis by administration of Salvianolic acid B in mice.

Pulmonary fibrosis is the end­stage manifestation of wide range of respiratory diseases and during pulmonary fibrosis, pulmonary inflammation and epithelial­mesenchymal transition (EMT) play important roles. Salvianolic acid B (SAB) from the herb Salviae miltiorrhiza has been reported to possess an excellent anti­inflammatory, antifibrotic and antioxidant activity. The present study aimed to investigate the ameliorative effect of SAB on bleomycin induced pulmonary fibrosis in mice. Adult albino mice were divided as SHAM/control group (saline alone), BLM group (bleomycin @ 1mg/kg intratracheally once) and SAB groups (BLM challenged once and SAB administration in three dosages @ 5, 10 and 15 mg/kg intraperitoneally daily for 30 days). Lungs wet/dry ratio and protein concentration in bronchoalveolar lavage fluid, MPO activity, oxidative stress markers, hydroxyproline assay, levels of inflammatory cytokines (TNF­α, IL­6 and TGF­ß1), NF­κB activity, histopathology, immunostaining (E­cadherin, vimentin and alpha ­smooth muscle actin) and ultrastructural changes were studied. SAB showed anti­inflammatory and anti­fibrotic effects through inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition and the expression of several fibrogenic cytokines. SAB also up­regulate E­cadherin and down­regulated vimentin and alpha­smooth muscle actin expression. In conclusion, Salvianolic acid B is effective in alleviating the BLM induced lung fibrosis through suppression of oxidative stress, inflammation, histological, ultrastructural changes and EMT.

Nanotechnological approaches for diagnosis and treatment of ovarian cancer: a review of recent trends.

Formulations from nanotechnology platform promote therapeutic drug delivery and offer various advantages such as biocompatibility, non-inflammatory effects, high therapeutic output, biodegradability, non-toxicity, and biocompatibility in comparison with free drug delivery. Due to inherent shortcomings of conventional drug delivery to cancerous tissues, alternative nanotechnological-based approaches have been developed for such ailments. Ovarian cancer is the leading gynecological cancer with higher mortality rates due to its reoccurrence and late diagnosis. In recent years, the field of medical nanotechnology has witnessed significant progress in addressing existing problems and improving the diagnosis and therapy of various diseases including cancer. Nevertheless, the literature and current reviews on nanotechnology are mainly focused on its applications in other cancers or diseases. In this review, we focused on the nanoscale drug delivery systems for ovarian cancer targeted therapy and diagnosis, and different nanocarriers systems including dendrimers, nanoparticles, liposomes, nanocapsules, and nanomicelles for ovarian cancer have been discussed. In comparison to non-functionalized counterparts of nanoformulations, the therapeutic potential and preferential targeting of ovarian cancer through ligand functionalized nanoformulations' development has been reviewed. Furthermore, numerous biomarkers such as prostatic, mucin 1, CA-125, apoptosis repeat baculoviral inhibitor-5, human epididymis protein-4, and e-cadherin have been identified and elucidated in this review for the assessment of ovarian cancer. Nanomaterial biosensor-based tumor markers and their various types for ovarian cancer diagnosis are explained in this article. In association, different nanocarrier approaches for the ovarian cancer therapy have also been underpinned. To ensure ovarian cancer control and efficient detection, there is an urgent need for faster and less costly medical tools in the arena of oncology.

Simiao pill inhibits epithelial mesenchymal transition in a mouse model of chronic hyperuricemic nephropathy by inhibiting NLRP3 inflammasome activation.

BACKGROUND: Simiao pill module (SMM), a traditional Chinese medicine formula, has been widely used to treat gout and gouty arthritis. The goal of this study was to investigate the effects of SMM on epithelial-mesenchymal transition (EMT) and activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome in a mouse model of potassium oxonate (PO)-induced chronic hyperuricemic nephropathy (HN). METHODS: Mice were randomly divided into the following four groups: control, HN model (PO), febuxostat (FEB)-treated (PO + FEB), and SMM-treated (PO + SMM) groups. Following 6 weeks of treatment, blood samples were collected and mice were sacrificed to collect kidney samples to study the biochemical parameters associated with renal function and histopathological changes associated with HN, respectively. The samples were analyzed for the expression of markers of EMT (collagen type 3, α-smooth muscle actin [α-SMA], fibronectin, vimentin and E-cadherin) and activation of NLRP3 inflammasome (NLRP3, apoptosis-associated speck-like protein [ASC], caspase-1, interleukin [IL]-1ß, and IL-18). RESULTS: Our results showed that hyperuricemia, impaired kidney function, and renal pathological characteristics induced by PO treatment were improved following treatment with SMM and FEB. Additionally, treatment with SMM and FEB decreased the expression of vimentin, collagen 3, fibronectin, and α-SMA, and increased the expression of E-cadherin. Moreover, NLRP3 inflammasome activation, as assessed by the increased expression of NLRP3, ASC, and caspase-1, and secretion of IL-1ß and IL-18, was inhibited by treatment with SMM and FEB. CONCLUSION: These results suggest that SMM inhibited EMT and NLRP3 inflammasome activation in chronic HN mice, and the beneficial effect of SMM was compared with a standard drug, FEB.

IL-27 attenuates airway inflammation and epithelial-mesenchymal transition in allergic asthmatic mice possibly via the RhoA/ROCK signalling pathway

Background: Asthma is an airway disease characterized by airflow limitation and various additional clinical manifestations. Repeated inflammatory stimulation of the airways leads to epithelial-mesenchymal transition (EMT) which aggravates subepithelial fibrosis during the process of airway remodelling and enhances resistance to corticosteroids and bronchodilators in refractory asthma. There is growing evidence that IL-27 modulates airway remodelling, however, the molecular mechanisms involving IL-27 and EMT are poorly understood. The objective of this study was to investigate the effects of IL-27 on ovalbumin (OVA)-challenged asthmatic mice in vivo and TGF-ß1-induced EMT in 16HBE cells in vitro. Methods: Airway inflammation, mucus secretion, and collagen deposition were analysed by conventional pathological techniques. The ratio of Th17 and Th9 cells in the spleen of mice was measured using flow cytometry, ELISA was performed for cytokine analysis to identify EMT-related molecules and signalling pathways, and other molecular and cellular techniques were used to explore the functional mechanism involving IL-27 and EMT. Results: Airway inflammation in asthmatic mice was significantly alleviated by IL-27, with downregulation of RhoA and ROCK, upregulation of E-cadherin, and a decrease of vimentin and α-SMA expression, compared to asthmatic mice. Moreover, the frequency of Th17 and Th9 cells in the spleen of asthmatic mice decreased following treatment with IL-27. In TGF-ß1-induced 16HBE cells, the addition of IL-27 was shown to inhibit EMT, based on the expression of E-cadherin, vimentin, and α-SMA. Conclusion: Intranasal administration of IL-27 attenuates airway inflammation and EMT in a murine model of allergic asthma possibly by downregulating the RhoA/ROCK signalling pathway.

Antitumor activity of irinotecan with ellagic acid in C6 glioma cells.

OBJECTIVE: Irinotecan-based combination chemotherapies in malignant gliomas need to be examined. The aim of this study was to investigate the synergetic effect of ellagic acid, a natural polyphenolic antioxidant compound, with irinotecan, an inhibitor of topoisomerase I enzyme, on the growth, cadherin switch, and angiogenic processes of a glioma cell line. METHODS: A combination of 100 µM ellagic acid and 100 µM irinotecan was applied to rat C6 glioma cells for 24th, 48th, and 72nd h. The cell proliferation was evaluated by 5-bromo-2'-deoxyuridine immunocytochemistry. The expression levels of vascular endothelial growth factor, E-cadherin, and N-cadherin were measured using real-time polymerase chain reaction and their immunoreactivities using immunocytochemistry. RESULTS: The treatment of irinotecan with combining ellagic acid enhanced antitumor activity and the synergistic effect of these reduced the cell proliferation of C6 glioma by inhibiting the cadherin switch and promoting the antiangiogenic processes. CONCLUSIONS: Further research is required to prove a negative relationship between C6 glial cell proliferation and irinotecan with ellagic acid application. Our preliminary data suggest that even with the extremely short-term application, irinotecan with ellagic acid may affect glioma cells at the level of gene and protein expression.

Knockdown of circ_0025908 inhibits proliferation, migration, invasion, and inflammation while stimulates apoptosis in fibroblast-like synoviocytes by regulating miR-650-dependent SCUBE2.

BACKGROUND: Circular RNAs (circRNAs) are demonstrated to play vital roles in human diseases, including rheumatoid arthritis (RA). Therefore, this research aimed to explore the effects of hsa_circRNA_0025908 (circ_0025908) on RA. METHODS: RNA expression of circ_0025908, microRNA-650 (miR-650), and Signal peptide-CUBepidermal growth factor-like containing protein 2 (SCUBE2) were assessed by real-time quantitative polymerase chain reaction; protein expression of SCUBE2, apoptosis- and invasion-related proteins was evaluated by western blot assay. Functional assays were performed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide, 5-ethynyl-2'-deoxyuridine, transwell, flow cytometry, and enzyme linked immunosorbent assay assays. Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays confirmed the interaction relationship among circ_0025908, miR-650, and SCUBE2. RESULTS: Circ_0025908 was overexpressed in synovial tissues and fibroblast-like synoviocytes (FLS) from RA patients. Inhibition of circ_0025908 repressed proliferation, migration, invasion, inflammation, and cell cycle progression, while induced apoptosis in the FLS isolated from RA patients (FLS-RA), accompanied with increased Bax, cleaved caspase-3 and E-cadherin, but declined Bcl-2, N-cadherin and Vimentin. MiR-650 was a target of circ_0025908, and SCUBE2 was a target for miR-650. Silencing of miR-650 could overturned above effects of circ_0025908 knockdown in FLS-RA, whereas its overexpression could mimic those effects by downregulating SCUBE2. Additionally, SCUBE2 expression could be positively regulated by circ_0025908 and inversely regulated by miR-650. Notably, Pearson's correlation analysis confirmed the linear correlation among circ_0025908, miR-650 and SCUBE2 in these RA tissues. CONCLUSION: Circ_0025908 inhibition can suppress FLS-RA dysfunctions through targeting miR-650/SCUBE2 axis, suggesting a new potential therapeutic clue for RA patients.

Sustained effect of LACTIN-V (Lactobacillus crispatus CTV-05) on genital immunology following standard bacterial vaginosis treatment: results from a randomised, placebo-controlled trial.

BACKGROUND: Bacterial vaginosis might increase HIV risk by eliciting genital inflammation and epithelial barrier disruption, whereas vaginal Lactobacillus crispatus is associated with immune quiescence and HIV protection. We investigated the effect of a live biotherapeutic containing L crispatus CTV-05 (LACTIN-V) on genital immunology and key vaginal bacteria. METHODS: This substudy included women aged 18-45 years who participated in the randomised, placebo-controlled, phase 2b trial of LACTIN-V to reduce bacterial vaginosis recurrence, conducted at four universities and hospitals in the USA. Women with negative results for sexually transmitted infection, pregnancy, and urinary tract infection were provided a 5-day course of vaginal metronidazole 0·75% gel. Those who met at least three of four clinical Amsel criteria for bacterial vaginosis and had a Nugent score of 4-10 from Gram staining were eligible. Participants in the LACTIN-V trial were randomly assigned (2:1) to receive either LACTIN-V or placebo, applied vaginally once per day for 5 days during the first week and then twice per week for 10 more weeks. Follow-up visits occurred 4, 8, 12, and 24 weeks after enrolment. Soluble immune factors and the absolute abundance of bacterial taxa were assayed by mutliplex ELISA and quantitative PCR. The primary outcomes were vaginal levels of IL-1α and soluble E-cadherin at 24 weeks (ie, 13 weeks after treatment cessation). FINDINGS: Between Feb 21, 2020 and March 18, 2021, we characterised genital immune parameters and the vaginal microbiota in a subset of 66 highly adherent participants who were randomly selected, with no exclusion criteria, from those who had attended all study follow-up visits (n=166) in the larger LACTIN-V clinical trial (n=288). 32 (48%) participants received LACTIN-V and 34 (52%) received placebo. LACTIN-V treatment was significantly associated with lower concentrations of the proinflammatory cytokine IL-1α (ß coefficient 0·310, SE 0·149; p=0·042) and soluble E-cadherin (0·429, 0·199; p=0·035), a biomarker of epithelial barrier disruption. INTERPRETATION: Vaginal administration of LACTIN-V following standard bacterial vaginosis therapy resulted in a sustained reduction in genital inflammation and a biomarker of epithelial integrity. The potential of LACTIN-V to reduce HIV susceptibility merits further investigation. FUNDING: Canadian Institutes of Health Research and the National Institutes of Health National Institute of Allergy and Infectious Diseases.

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST.

Rheumatoid arthritis-associated bone erosions: evolving insights and promising therapeutic strategies.

The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work properly, it can mistakenly attack the body's own tissues and induce autoimmune diseases. Rheumatoid arthritis (RA) is such an autoimmune disease in which the synovial joints are predominately attacked by the immune system. Moreover, RA is associated with bone destruction and joint deformity. Although biologic agents have propelled RA treatment forward dramatically over the past 30 years, a considerable number of patients with RA still experience progressive bone damage and joint disability. That is to be expected since current RA therapies are all intended to halt inflammation but not to alleviate bone destruction. A better understanding of bone erosions is crucial to developing a novel strategy to treat RA-associated erosions. This review provides insights into RA-associated bone destruction and perspectives for future clinical interventions.

The role of CD29-ILK-Akt signaling-mediated epithelial-mesenchymal transition of liver epithelial cells and chemoresistance and radioresistance in hepatocellular carcinoma cells.

Hepatocellular carcinomas (HCC) are aggressive cancers, and the prognosis of HCC patients is poor. This study investigated the roles of CD29 in epithelial-mesenchymal transition (EMT) and chemoresistance and radioresistance in HCC tumors. CD29 expression in HCC and peritumoral tissues was measured by immunohistochemistry. CD29 overexpression was established by an adenovirus-carrying CD29 gene expression cassette, while silencing of CD29 expression was established by an adenovirus-carrying shRNA. Western blot was used to measure protein expression, and MTT was used to analyze cell viability. Xenograft HCC mouse model was established by inoculating isolated CD29(+) and CD29(-) HCC tumor cells. Significantly higher percentage of positive CD29 expression was observed in HCC tissues compared to peritumoral tissues. Xenograft CD29(+) tumors grew more quickly than CD29(-) tumors. CD29(+) tumors were more resistant to radiotherapy and cisplatin therapy than CD29(-) tumors. Overexpression of CD29 significantly increased the resistance of CD29(-) tumors to radiation and cisplatin treatment. In contrast, silencing of CD29 expression significantly sensitized CD29(+) tumors to irradiation and cisplatin treatment. Overexpression of CD29 decreased E-cadherin, but increased fibronectin, vimentin, ILK activity, Akt Ser(473) phosphorylation, and mTORC1 protein expression in Hep G2 and THLE-3 cells. Moreover, overexpression of CD29 significantly increased the resistance of Hep G2 and THLE-3 cells to starvation, radiation, and cisplatin treatments. This study suggests that CD29 plays a crucial role in the resistance of HCC to chemo/radiotherapy and EMT of liver epithelial cells.

GRP78 signaling hub a receptor for targeted tumor therapy.

Glucose-regulated protein 78 (GRP78) is a potential receptor for targeting therapy in cancer and chronic vascular disease due to its overexpression at the cell surface in tumor cells and in atherosclerotic lesions. Presence of the GRP78 autoantibody in cancer patient sera is generally associated with poor prognosis since it signals a prosurvival mechanism in response to cellular stress. Association of GRP78 with various binding partners involves coordination of multiple signaling pathways that result in either cell survival or cell death. Binding of activated alpha2-macroglobulin to cell-surface GRP78 activates Akt to suppress apoptotic pathways through multiple downstream effectors, and concomitantly upregulates NF-kappaBeta and induces the unfolded protein response (UPR) so that cell proliferation prevails. Interaction of GRP78 with cell-surface T-cadherin promotes endothelial cell survival. Association of oncogenic Cripto with GRP78 nullifies TGF-beta superfamily-dependent signaling through Smad2/3 to promote cell proliferation. In contrast, association of GRP78 with the plasminogen kringle 5 domain or extracellular Par-4 promotes apoptosis. Interaction of GRP78 with microplasminogen induces the UPR while association with tissue factor inhibits procoagulant activity. The diverse and multiple binding proteins of GRP78 and their equally diverse functional outcomes reflect the regulatory cellular functions that GRP78 orchestrates. Several GRP78 targeting peptides have been isolated from different tumors and they show remarkable tumor specificity. Conjugation of GRP78-targeting peptides to an apoptosis-inducing peptide suppresses tumor growth in tumor xenografts, thereby demonstrating that GRP78 is a viable target by which clinical cancer therapies can be successfully developed as well as its potential utility in treating vascular disease.

Adhesion molecules and gene transfer.

Cell adhesion molecules are a large group of molecules involved in a variety of cell-to-cell and cell-to-extra-cellular matrix (ECM) interactions. Apart from their cellular function these molecules are exploited by a number of pathogenic micro-organisms as receptors for cell entry. Discovery of the use of adhesion molecules for binding and internalisation by naturally occurring pathogens has fuelled much research, in recent years, into the utilisation of these molecules for the targeting and uptake of both gene and drug delivery systems. This review describes the development of such systems and their potential advantages over other receptor-targeted delivery systems.