Monoclonal antibody 12D5 inhibits eosinophil infiltration in the brain of Angiostrongylus cantonensis-infected BALB/c mice

Each of BALB/c mice was infected with 50 Angiostrongylus cantonensis larvae. One group of mice received an intraperitoneal injection of 50 μg 12D5 monoclonal antibody (mAb) against a 98 kDa antigen of adult worms at 10 days post-infection (dpi), with a booster injection of 25 μg at 12 dpi. Five mice from each group were sacrificed at 14 dpi for pathological examination and RNA extraction. The infiltration of eosinophils and severity of eosinophilic meningitis were reduced in 12D5 mAb-treated mice compared with the infected mice without 12D5 treatment. The levels of eotaxin mRNA expression in spleen significantly increased and the expression of the Th2-type cytokine IL-5 significantly decreased. However, the expression of IL-4 was not changed. 12D5 mAb can observably enhance the survival rate of infected mice and reduce symptoms of angiostrongyliasis. A. cantonensis infection is a major cause of eosinophilic meningoencephalitis. The results of this study could be helpful for the development of treatment of human angiostrongylosis.     

Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED(50) = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED(50) = 0.5nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.     

Chronic inflammatory demyelinating polyneuropathy mimicking diabetic neuropathy in a young female with type 2 diabetes mellitus

The presentations of chronic inflammatory demyelinating polyneuropathy (CIDP) overlap with those of diabetic peripheral neuropathy (DPN). We described a young girl with CIDP underlying type 2 diabetes mellitus, presenting with progressive numbness and limb weakness, who was initially misdiagnosed to have DPN. Finally immunosuppressive therapy got good response.     

miR-21 induces cell cycle at S phase and modulates cell proliferation by down-regulating hMSH2 in lung cancer

Purpose

MicroRNAs regulate critical genes associated with lung cancer. Human mutS homolog 2 (hMSH2), one of the core mismatch repair genes, is affected in lung cancer development. The aim of this study is to investigate the role of miR-21 in hMSH2 gene expression and the effect of miR-21 on cell proliferation and cell cycle in lung cancer.

Methods

The targets of miR-21 were predicted by a bioinformatics tool, and hMSH2 was validated as a direct target of miR-21 by luciferase activity assay. MiRNA mimics or inhibitors were used to stimulate or attenuate the effect of endogenous miR-21 on hMSH2 expression. MiR-21 and hMSH2 expressions were assessed with real-time RT-PCR and Western blotting. Cell cycle was determined by flow cytometry, and cell growth was analyzed by MTT assay and real-time cell analysis system.

Results

MiR-21 expression was inversely correlated with hMSH2 expression in human lung cancer cell lines. Further validation showed hMSH2 was directly regulated by miR-21. The up-regulation of miR-21 significantly promoted cell proliferation and revealed a higher proportion of cells at S phase. However, knockdown of miR-21 expression resulted in cell cycle arrest at G2/M phase and inhibited cell proliferation.

Conclusions

These data suggest miR-21 is a key regulator of hMSH2 and modulates cell cycle and proliferation by targeting hMSH2 in human lung cancer.     

S-1 combined with oxaliplatin as first line chemotherapy for chinese advanced gastric cancer patients

Background/Aims: To evaluate the efficacy and safety profile of S-1 combined with oxaliplatin (SOX) against unresectable advanced or metastatic gastric cancer. Methodology: Oxaliplatin was administered intravenously at 100mg/m2 for two hours on day 1 and S-1 was administered b.i.d. at 80mg/m2/day on days 1-14 followed by a 7-day rest during the 3-week schedule. Results: All 51 patients were assessed for efficacy and adverse events. The response and disease control rates were 41% and 90%, respectively. The response rate was significantly improved in patients with ECOG performance status of no more than 1, elevated CEA levels or unresected primary cancers. The median follow-up time was 11.8 months, the median time to progression was 6.8 months, the median overall survival was 11.8 months and the 1-year survival rate was 47.4%. Patients with diffused type exhibited significantly decreased time to progression and overall survival. The grade 3/4 adverse events were hematological toxicities, including neutropenia (13.7%), thrombocytopenia (13.7%) and anemia (11.8%). The incidence of grade 3/4 non-hematological events was low (≤2%). Conclusions: The SOX regimen (oxaliplatin, 100mg/m2 d1; S-1, 80mg/m2/day, b.i.d. d1-14, q3w) provided a favorable efficacy and safety profile in Chinese patients with advanced gastric cancer.     

Roles of Kupffer cells in liver transplantation

Kupffer cells, the resident macrophages of the liver, not only exert phagocytosis but also excrete proinflammatory cytokines. Large amounts of cytokines, produced by activated Kupffer cells, can induce aggravate liver ischemia/reperfusion (I/R) injury. Also, Kupffer cells that express protective genes protect from I/R injury after liver transplantation. Due to their key location, Kupffer cells might function as antigen-presenting cells and participate in transplantation immunity. They also seem to play a key role in innate immune responses and host defence through the expression and secretion of soluble inflammatory mediators. With this review we want to assist in improving the understanding of the contribution of Kupffer cells in liver I/R injury and the development of the transplantation immune. We hope that the delineation of the complex mechanisms of dysregulation may inspire the design and development of novel treatment approaches.