Backgroundc-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity.MethodWe generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH).ResultsABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH.ConclusionsThe preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2138-z) contains supplementary material, which is available to authorized users.

Force feedback gloves have found many applications in fields such as teleoperation and virtual reality. In order to enhance the immersive feeling of interaction with remote or virtual environments, glove-like haptic devices are used, which enable users to touch and manipulate virtual objects in a more intuitive and direct way via the dexterous manipulation and sensitive perception capabilities of human hands. In this survey, we aim to identify the gaps between existing force feedback gloves and the desired ones that can provide robust and realistic sensation of the interaction with diverse virtual environments. By examining existing force feedback gloves, the pros and cons of existing design solutions to the major sub-systems including sensing, actuation, control, transmission and structure are discussed. Future research topics are put forward with design challenges being elaborated. Innovative design solutions are needed to enable the utility of wearable haptic gloves in the upcoming virtual reality era.

The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. In the last decade, the etiological role of human papillomavirus (HPV) infection in the development of cervical dysplasia and cancer has been well established.1-4 The frequency of HPV infection in women with a diagnosis of atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL) is approximately 50, 80, and 95%, respectively. 5-7Still, only a fraction of HPV-infected women will develop high-grade lesions and cervical cancer. 8HPV infections compromise normal cellular proliferation through degradation of the tumor suppressor proteins p53 and pRB by viral proteins E6 and E7, respectively. In addition, HPV infection has been shown to induce abnormal centrosome duplication early in the infection process.9 -12 HPV infection of replicating immature cells prevents epithelial maturation and differentiation, leading to continued replication and accumulation of genetic abnormalities. 2,13,14 Chromosomal instability at a numerical or structural level is a hallmark of malignant tumors.9 Deletion, duplication, and amplification of various genomic regions have been demonstrated in cervical cancer by comparative genomic hybridization and fluorescence in situ hybridization (FISH) methods. [15][16][17][18] In an internal study, we assessed biopsy specimens showing high-grade dysplasia and cancer with FISH probes to 35 unique loci and identified 2 loci, the 3q26 region (comprising H-TERC gene) and the 8q24 region (comprising c-MYC gene), which showed highest frequency of copy number gains in high-grade dysplasia and cancer. Because these loci are frequently altered in cervical cancer tumorigenesis, 16,17,19,20 we hypothesized that they might be useful markers for the detection of cervical dysplasia and carcinoma.To explore this further, we created a fluorescence in situ hybridization assay that allows for the simultaneous Supported by a grant from Abbott Molecular (to K.C.H.).

Purpose: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods. Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N ¼ 206) and whole-exome sequencing (WES, N ¼ 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N ¼ 206) and transcriptome profiling (RNAseq, N ¼ 64). EGFR protein expression was determined by immunohistochemistry (IHC, N ¼ 34). Significant correlations among various methods were determined using Cohen's kappa (k ¼ 0.61-0.80 defines substantial agreement) or R 2 statistics. Results: EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (k ¼ 0.702). High concordance was also observed when comparing FISH to WES (k ¼ 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. Conclusions: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.

Objective Many lupus autoantigens contain small, highly structured RNAs, and studies have shown that the RNA components of lupus autoantigens activate production of type I interferon by dendritic cells (DCs) in vitro via the Toll‐like receptor (TLR)–myeloid differentiation factor 88 pathway. This study was undertaken to examine whether U1 RNA possesses adjuvant activity in vivo. Methods U1 RNA was affinity purified from K562 cells. C57BL/6 or OT‐II mice were immunized with 4‐hydroxy‐3‐nitrophenyl acetyl (NP)–conjugated keyhole limpet hemocyanin (NP‐KLH) or ovalbumin323–337 peptide, using either U1 RNA or aluminum hydroxide (alum) as the adjuvant. Activation of DCs and lymphocytes was measured using flow cytometry. NP‐specific antibody responses were measured using enzyme‐linked immunosorbent assay. Antigen‐specific T cell proliferation was determined using 3H‐thymidine incorporation. Results Similar to the results with the standard adjuvant, alum, U1 RNA coadministered with NP‐KLH enhanced production of NP‐specific IgM and IgG (on days 8 and 16 postinjection, respectively). Moreover, proliferation of antigen‐specific CD4+ T cells was enhanced to comparable levels in the mice immunized with either U1 RNA or alum. Injection of U1 RNA into the footpad of mice resulted in DC recruitment to draining lymph nodes and induction of DC maturation. U1 RNA, at 24 hours' postinjection, also increased expression of the early activation marker CD69 in both B and T lymphocytes. Pretreatment of U1 RNA with RNase or coadministration with a TLR‐7 antagonist inhibited the effects of this adjuvant. Conclusion A small RNA of cellular origin can drive DC maturation, B and T cell activation/proliferation, and antibody responses to exogenous antigens. These results support the idea that U1 RNA is an endogenous adjuvant, helping to explain the striking predilection of lupus autoantibodies for RNA–protein complexes such as Sm/RNP.