CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.

Cisplatin-based chemotherapy is the foundation of treatment for major non-small cell lung cancer (NSCLC) patients. However, cisplatin resistance is still a challenging issue, and the molecular mechanisms underlying this resistance remain to be fully explored. CLEC4M, a Ca2+-dependent C-type lectin, has recently been found to correlate with tumourigenesis. This study mainly focused on whether CLEC4M impacts clinical prognosis and how CLEC4M contributes to cisplatin resistance in NSCLC. Our results found that CLEC4M was correlated with poor prognosis in patients with lung cancer. In addition, a positive association between CLEC4M expression and the IC50 values of cisplatin was found, which suggests that CLEC4M may impact cisplatin sensitivity. In vitro results from cultured A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown led to higher sensitivity to cisplatin in these cells. Further experiments showed that the underlying mechanisms included inhibition of cisplatin-induced cell apoptosis by CLEC4M and improved DNA repair capacity by upregulating XPA and ERCC1 expression. In addition, CLEC4M was able to promote cell migration with or without cisplatin treatment. Collectively, these findings suggest the potential clinical significance of CLEC4M inhibition in overcoming cisplatin resistance in NSCLC patients.

A case report of intraventricular and intrathecal tigecycline infusions for an extensively drug-resistant intracranial Acinetobacter baumannii infection.

RATIONALE: The treatment of intracranial Acinetobacter baumannii infections is made difficult by multidrug-resistance poor drug penetration through the blood-brain barrier (BBB). Although tigecycline appears to be effective against A baumannii, it is only administered intravenously because it does not readily cross the BBB. The addition of intraventricular (IVT) or intrathecal infusions of tigecycline could revolutionize clinical therapy for intracranial A baumannii infections. However, there are few reports on the successful use of such treatments. PATIENT CONCERNS: We report the case of a 17-year-old male who presented with high fever and neck rigidity after intracranial drainage. DIAGNOSIS: Intracranial infection with extensively drug-resistant A baumannii after intracranial drainage. INTERVENTIONS: On the advice of a clinical pharmacist, the patient was administered intrathecal infusions of tigecycline after treatment failure with IVT tigecycline. OUTCOMES: The patient's body temperature returned to normal. Thereafter, the patient was in good clinical condition without signs of cerebrospinal fluid infection and tuberculosis. LESSONS: However, when central nervous system infections fail IVT tigecycline, clinicians should consider changing to intrathecal tigecycline infusions rather than raising the dose of IVT tigecycline. In addition, the co-administration of tigecycline with other drugs that can penetrate the BBB should not be ruled out.

l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia.

BACKGROUND AND PURPOSE: Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation. EXPERIMENTAL APPROACH: A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual-specificity protein phosphatases (DUSPs) and MAPK pathways. KEY RESULTS: Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l-homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-α. CONCLUSIONS AND IMPLICATIONS: This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK1/2 /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta-analysis.

Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens.

[Establishment of mouse model of humoral immune response using rabbit red blood cells as the antigen].

OBJECTIVE: To establish a mouse model of humoral immune response by immunization with rabbit red blood cells (RRBCs). METHODS: The mice were immunized with RRBCs and the serum hemolysin level was measured by micro-hemolysis spectrophotometry. RESULTS: The peak time needed for hemolysin production against RRBCs was 6 days after the immunization, and 20% RRBCs in a total volume of 0.2 ml was optimal for intraperitoneal injection. Hydrocortisone (25 mg/kg) and cyclophosphamide (20 mg/kg) inhibited hemolysin production. Mannatide (4 mg/kg) produced no significant effect on serum hemolysin level in normal mice, but significantly potentiated hemolysin production in immunosuppressed mice induced by cyclophosphamide (20 mg/kg). CONCLUSION: Intraperitoneal RRBC injection is feasible for establishing mouse models of humoral immune response.