Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis

Imatinib is a selective tyrosine kinase inhibitor that can block activity of the platelet-derived growth factor receptor (PDGFR) and that has immunomodulatory effects on various cell types. Here we measured the protective effects of imatinib in Wistar-Kyoto rats with nephrotoxic serum nephritis, a kidney disease model where CD8+ T cells and macrophages play pathogenetic roles. Groups of animals were given imatinib from one day before up to 13 days following induction of nephritis and from day 7 to 20 following disease induction. Compared to control rats, at each time point imatinib treatment caused significantly less proteinuria, lowered serum blood urea nitrogen and creatinine, and decreased the number of glomeruli with necrosis, crescents, and fibrin deposits. Imatinib-treated rats had a significant reduction in glomerular macrophage accumulation and reduced renal cortical PDGFR-β and M-CSF receptor mRNA expression. Using colocalization we found that glomerular macrophages had reduced IL-1β and MCP-1 protein expression. Late imatinib treatment significantly reduced proteinuria, serum blood urea nitrogen, and creatinine, and reversed renal histopathological changes. We show that imatinib has renoprotective and therapeutic properties and provide pre-clinical work that will need to be confirmed in patients with crescentic glomerulonephritis

Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms

Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small-molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma of the head and neck. Although these therapies can significantly prolong progression-free survival, curative effects are not often achieved because of intrinsic and/or acquired resistance. The resistance mechanisms to EGFR-targeted therapies can be categorized as resistant gene mutations, activation of alternative pathways, phenotypic transformation, and resistance to apoptotic cell death. Analysis of the processes that modulate EGFR signal transduction by EGFR-targeted inhibitors, such as tyrosine kinase inhibitors and monoclonal antibodies, has revealed new therapeutic opportunities and has elucidated novel mechanisms contributing to the discovery of more effective anticancer treatments. In this review, we discuss the roles of EGFR in cancer development, therapeutic strategies for targeting EGFR, and resistance mechanisms to EGFR-targeted therapies, with a focus on cancer therapies for individual patients

Up-regulation of Syndecan-4 contributes to TGF-β1-induced epithelial to mesenchymal transition in lung adenocarcinoma A549 cells

Syndecan-4 (SDC4) is a cell-surface proteoglycan associated with cell adhesion, motility, and intracellular signaling. Here, we present that SDC4 functions as a positive regulator of the transforming growth factor (TGF)-β1-induced epithelial to mesenchymal transition (EMT) via Snail in lung adenocarcinoma, A549 cells. TGF-β1 up-regulated the expression of SDC4, accompanied by the induction of EMT. Wound-healing and transwell chemotaxis assay revealed that SDC4 promoted cell migration and invasion. SDC4 knockdown recovered the E-cadherin and decreased vimentin and Snail expression in EMT-induced A549 cells. However, depletion of SDC4 resulted in little change of the Slug protein expression and mesenchymal cell morphology induced by TGF-β1. The double knockdown of SDC-4 and Slug was required for reversal of epithelial morphology; it did not occur from the SDC4 single knockdown. These findings suggest that Snail is a transcriptional factor downstream of SDC4, and SDC4 regulates TGF-β1-induced EMT by cooperating with Slug. Our data provide a novel insight into cellular mechanisms, whereby the cell-surface proteoglycan modulated TGF-β1-induced EMT in lung adenocarcinoma, A549 cells

Receptor Tyrosine Kinase-Targeted Cancer Therapy

In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms

Comparative Efficacy and Safety of Anti-Interleukin-5 Therapies and Placebo in Patients with Uncontrolled Eosinophilic Asthma:A Systematic Review and Meta-analysis of Phase 3 Trials

The overall efficacy and safety of anti-interleukin （IL）-5 therapies at currently recommended dosages and administration remain to be fully characterized. The present study was a meta-analysis of Phase 3 trials of the efficacy and safety of anti-IL-5 therapies at the currently recommended dosages and administration compared with placebo in patients with uncontrolled eosinophilic asthma. This meta-analysis complied with the PRISMA guidelines. The primary efficacy outcome was asthma exacerbation rate, and the primary safety outcomes included the incidence rates of all adverse events, asthma worsening, and injection site reactions. A subgroup analysis was also performed according to the type of anti-IL-5 agent. Pooled estimates are presented as rate ratios or relative risks （RRs） with 95% confidence intervals （CIs）. Analyses included intention-to-treat cases. Six randomized controlled trials of anti-IL-5 therapies met the inclusion criteria. The overall rate ratio for asthma exacerbation was 0.54 （95% CI 0.47-0.61）. The RRs （95% CIs） for the incidence of all adverse events, asthma worsening, and injection site reactions compared with placebo were 0.93 （0.89-0.96）, 0.63 （0.56-0.72）, and 1.59 （0.95-2.65）, respectively. The subgroup analysis revealed that the incidence of injection site reactions was significantly higher among mepolizumab- than placebo-treated patients, with an RR of 2.56 （95% CI 1.15-5.68）. These results suggest that anti-IL-5 therapies at the currently recommended dosages and administration are effective and generally well tolerated in patients with uncontrolled eosinophilic asthma. However, the occurrence of injection site reactions warrants specific attention, especially concerning mepolizumab administration

Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC