Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.

We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.

Hypertrophy of ligamentum flavum (LF) contributes to lumbar spinal stenosis (LSS) and is caused mainly by fibrosis. Recent data indicate that miR-155 plays a crucial role in the pathogenesis of different fibrotic diseases. This study aimed to test the hypothesis that miR-155 exerts effects on LF thickness by regulating collagen expression. We found that LF thickness and the expression of collagen I and, collagen III were higher in LF from LSS patients than in LF from lumbar disc herniation (LDH) patients (P < 0.01). The expression of miR-155 was significantly higher in LF from LSS group than in LF from LDH group (P < 0.01). miR-155 level was positively correlated with LF thickness (r = 0.958, P < 0.01), type I collagen level (r = 0.825, P < 0.01), and type III collagen level (r = 0.827, P < 0.01). miR-155 mimic increased mRNA and protein expression of collagen I and collagen III in fibroblasts isolated from LF, while miR-155 sponge decreased mRNA and protein expression of collagen I and III in fibroblasts. In conclusions, miR-155 is a fibrosis-associated miRNA and may play important role in the pathogenesis of LF hypertrophy.

We examined the influence of two K ATP channel openers, diazoxide and an analog (NNC 55-0118), on experimental ␤-cell damage induced by streptozotocin (STZ; 0.5 mmol/l). Rat pancreatic islets were exposed to diazoxide or NNC 55-0118 for 30 min and were further incubated for 30 min after the addition of STZ. The islets were then washed and cultured for 24 h. Islets exposed to STZ alone showed extensive morphological damage, reduced glucose oxidation, low insulin content, and severely impaired glucose-stimulated insulin secretion and proinsulin biosynthesis. Islets treated with STZ in the presence of the channel openers (0.03-0.30 mmol/l) showed dose-dependent preservation of the morphology and improved glucose oxidation rates, insulin content, and secretion. NNC 55-0118 was capable of fully counteracting the STZ impairment, whereas diazoxide had a less protective effect. NNC 55-0118 did not counteract STZ-induced depression of islet NAD levels when examined 2 h after STZ exposure, which suggests that the mechanism of action by NNC 55-0118 is not through an inhibition of poly(ADP-ribose) polymerase. The results illustrate that K ATP channel openers can protect insulinproducing cells against toxic damage, an effect that may be of use in subjects with ongoing insulitis. Diabetes 49:1131-1136, 2000 I n human autoimmune diabetes, the insulin-producing ␤-cells are generally thought to be destroyed by cytotoxic T-cells that are driven by an antigen-specific process (1,2). In experiments with isolated islets, we have found that glucose increases the expression of ␤-cell autoantigens (3) and that diazoxide lowers the antigen amount (4). Against this background, we conducted a clinical trial and observed that a 3-month supplementary treatment with diazoxide had a beneficial effect on residual ␤-cell function in patients with new-onset type 1 diabetes (5). "␤-cell rest" may thus protect islet cells from autoimmune destruction (6) and may help to explain the remission phenomenon often noted subsequent to the initiation of insulin treatment.Diazoxide and other K ATP channel openers such as cromakalim and pinacidil have been used in experimental studies of the ischemic heart, and beneficial cardioprotective effects have been observed (7-9). Although the exact mechanism of this phenomenon is not understood, an opening of mitochondrial K + channels seems to be involved that results in dissipation of the inner mitochondrial membrane potential. This leads to net oxidation of the mitochondria with an apparent reduction in energy wastage (7,9,10).Diazoxide is known to act on K ATP channels in the plasma membrane of ␤-cells (11). It hyperpolarizes the membrane and inhibits the energy-consuming process of insulin secretion (12). Recently, exposure of ␤-cells to diazoxide has also been found to engage mitochondrial K ATP channels (13). In the present study, we examined the influence of diazoxide and NNC 55-0118, a new K ATP channel opener analog, on experimental ␤-cell damage induced by streptozotocin (STZ), an agent known to cause ene...

MicroRNAs (miRNAs) play critical roles in human cancers including osteosarcoma (OS). miR-92a has been found to be a cancer-related miRNA in many cancer types and it is upregulated in OS cell lines. However, the expression and biological function of miR-92a in OS have not been investigated. In this study, we showed that miR-92a expression was increased in OS tissues, and its high expression was correlated with clinical stage, T classification and histological differentiation. Furthermore, patients with high expression of miR-92a had a significantly poorer survival rate. Functionally, miR-92a overexpression promoted the proliferation and cell cycle progression, and inhibited apoptosis in MG-63 cells. While inhibition of miR-92a showed contrary effects with reduced proliferation, cell cycle arrest at G1 phase and increased apoptosis in U2OS cells. Moreover, we confirmed that miR-92a inhibition reversed the tumor growth of OS cells in nude mice. Phosphatase and tensin homolog (PTEN), a well-known tumor suppressor, was confirmed to be the direct downstream target of miR-92a in OS. Notably, miR-92a consequently regulated the expression of the downstream targets of PTEN/AKT signaling pathway including p-Akt(Ser473), mTOR, p-p27(Thr157) and p-MDM2(Ser166). Furthermore, PTEN knockdown abrogated the functional effects of miR-92a silencing on the proliferation, apoptosis and cell cycle progression in OS cells. Thus, miR-92a that exerts an oncogenic role by targeting PTEN/AKT pathway in OS potentially acts as a biomarker and drug-target.