A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer.

The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can induce the degradation of c-MET protein in cancer cells, including MKN45, a gastric cancer cell line, and A549, a lung cancer cell line. BsAb inhibited hepatocyte growth factor (HGF)-mediated proliferation, migration, and antiapoptosis, and downregulated HGF-stimulated phosphorylation of c-MET, protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2). BsAb can also rescue T cell activation. Furthermore, xenograft analysis revealed that BsAb markedly inhibits the growth of subcutaneously implanted tumors and chronic inflammation. On the basis of these results, we have identified a potential bispecific drug, which can effectively target c-MET and PD-1 for the treatment of human solid cancers.

Association of Cytotoxic T-lymphocyte Antigen-4 Polymorphisms with Malignant Bone Tumor Risk: A Meta-analysis.

BACKGROUND: Previous studies have assessed the association between the Cytotoxic T-lymphocyte Antigen- 4(CTLA-4) polymorphism with the risk of malignant bone tumor, but the conclusions were inconsistent. We aimed to clarify association of cytotoxic T-lymphocyte antigen-4 polymorphisms with malignant bone tumors risk by performing a meta-analysis. MATERIALS AND METHODS: The databases including PubMed, EMBase databases and the Cochrane Library were searched to identify the eligible studies prior to January 30 2016. Odds ratio (OR) with 95% confidence interval (95%CI) were used to estimate the strengths of the association between the CTLA-4 polymorphism and the malignant bone tumor risks. The meta-analysis was performed by STATA 12.0. RESULTS: Four individual studies with a total of 1003 cases with malignant bone tumors and 1162 controls were included in our meta-analysis. The results of meta-analysis on those data demonstrated that CTLA-4 +49G>A polymorphism was associated with the risk of Ewing's sarcoma and osteosarcoma strongly (A vs. G: : OR=1.36, 95%CI:1.20-1.54, p=0.000; AA+AG vs. GG: OR=1.35, 95%CI:1.14-1.61, p=0.001; AA vs. GG: OR=2.24, 95%CI:1.67-2.99, p=0.000; AA vs. AG+GG: OR=2.00, 95%CI:1.53-2.62, p=0.000), but CTLA-4 -318C/T polymorphism was not associated with the risk of malignant bone tumor (C vs. T: OR=0.76, 95%CI:0.76-1.08, p= 0.262; CC+CT vs. TT: OR=0.70, 95%CI:0.41-1.20, p=0.198; CC vs. TT: OR=0.69, 95%CI:0.40-1.19, p= 0.183; CC vs. CT+TT: OR=0.92, 95%CI:0.75-1.13, p= 0.419). Subgroup analysis showed that there are significantly positive correlations between CTLA-4 +49G>A polymorphism and increased risks of malignant bone tumors in large size of sample (A vs. G: OR=1.347, 95%CI: 1.172,1.548, p=0.000; AA vs. GG: OR=2.228, 95%CI: 1.608,3.085, p=0.000), Ewing's Sarcoma or Osteosarcoma (A vs. G: OR=1.361, 95%CI: 1.201,1.540, p=0.000; AA vs. GG: OR=2.236, 95%CI: 1.674,2.986, p=0.000), and PCR-RFLP or Sequencing(A vs. G: OR=1.361, 95%CI: 1.201,1.540, p=0.000; AA vs. GG: OR=2.236, 95%CI: 1.674,2.986, p=0.000), but CTLA-4 -318C/T polymorphism was not associated with the risk of malignant bone tumors in diagnosis, genotype method, and sample size (all p>0.05). CONCLUSIONS: CTLA-4 +49A/G variant was associated with an increased risk of developing the malignant bone tumors, such as Ewing's sarcoma and osteosarcoma. However, it failed to show any association between CTLA-4 -318C/T polymorphism and the risk of malignant bone tumors. Future large-scale studies remain to be done to confirm our conclusions.

In vitro model test and preliminary clinical application of a new method of ultrasonographic imaging: Vascular enhancement technology.

Vascular enhancement technology (VET) is a new form of ultrasonographic technology that can optimize images by enhancing the B-mode display with information derived from power Doppler. We designed an in vitro model to evaluate the accuracy and application method of VET and to apply this technology preliminarily in vivo in the vascular periphery. An in vitro model was designed with a flow pump system to simulate blood flow in soft tissue and the intracranial vasculature. Modeling vessels were imaged by traditional B mode, color Doppler flow imaging and VET. The diameter of the various silicon tubes was measured to verify the accuracy of VET. For in vivo application, 15 normal subjects and 26 patients suspected of having carotid artery plaques and cerebrovascular disease were examined using these three image modes. The imaging effects were observed and compared. VET imaging could clarify the lumens of the modeling vessels and reduce artifacts. The caliber of three sizes of silicon tubing was also measured accurately by VET. Of 15 normal subjects, sound artifacts in large vessels were inhibited and the intermedia membrane was clearly displayed by VET. The boundaries of carotid plaques were manifested by VET with well-defined edges. Three cases of hypoechoic soft plaque on the anterior wall missed in B-mode imaging were detected by VET. Intracranial scanning with VET identified cerebral vascular disease, including cerebral stenosis, arteriovenous malformations and aneurysms. The size and shape of the focus displayed by VET coincided with that observed using digital subtraction arteriography. VET is helpful in improving detection of the boundary of vessels and visualization of the microvasculature.

Evaluation of transcranial color-coded duplex sonography for cerebral artery stenosis or occlusion.

BACKGROUND AND PURPOSE: Cerebral artery stenosis or occlusion is the most common etiological factor in patients with acute cerebral ischemia, but the rate of early diagnosis is low. The purpose of the study is to evaluate the diagnostic accuracy of transcranial color-coded sonography (TCCS) for cerebral artery stenosis with digital subtraction angiography used as the gold standard of reference. METHODS: Seventy-eight patients who were suspected of cerebrovascular disease were involved in the study. Major cerebral arteries were observed through the transcranial echo window by TCCS. The course, shape of the color blood beam and velocity were given special attention. The hemodynamic parameter was measured and analyzed. The findings of TCCS were compared with the results of digital subtraction angiography, according to a double-blind design. A 4-fold table was used as the statistical analysis method to evaluate TCCS. The indexes included sensitivity, specificity, accuracy and false-positive rate. RESULTS: Imaging of TCCS revealed that the blood flow beam narrowed where the artery had stenosis and looked like girdling. The velocity of the foci increased abnormally, while the velocity before and after the foci decreased. Severe stenosis and the long stenotic segment may show discontinuity of the blood flow beam. The velocity of the foci did not noticeably increase or decrease. The blood flow beam of the occlusive artery cannot be seen and the frequency spectrum cannot be obtained, but the other artery was well visualized at the same time. Analysis of the diagnostic value of TCCS according to the 4-fold table included the validity index, with a sensitivity, specificity, false-positive rate, false-negative rate, accuracy, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and Youden index of 72.9%, 82.9%, 17.1%, 27.0%, 78.2%, 79.4%, 77.3%, 4.3, 0.3 and 0.56, respectively. The reliability index included the agreement rate and kappa value, which were 78.2% and 0.56, respectively. CONCLUSIONS: TCCS could be considered a valuable method for the screening diagnosis of cerebral artery stenosis or occlusion.

Carotid and transcranial color-coded duplex ultrasonography for the diagnosis of dural arteriovenous fistulas.

BACKGROUND AND PURPOSE: Dural arteriovenous fistulas (DAVF) can affect a variety of cerebral venous structures and can present at various clinical stages. This study was designed to introduce the characteristic manifestation of DAVF detected with both carotid and transcranial color-coded duplex ultrasonography (CDUS) and to evaluate the diagnostic value of CDUS in DAVF. METHODS: Nineteen patients with DAVF confirmed by cerebral angiography were studied with CDUS. The sonogram and spectrum of the affected area were observed. Hemodynamic parameters such as peak systolic velocity, end-diastolic velocity, mean velocity and resistance index (RI) were measured and recorded in the feeding artery, draining vein and extracranial artery. All results were compared with cerebral angiography. Fifty healthy volunteers were enrolled as a control group. Related hemodynamic changes were compared between the patients and normal controls. RESULTS: The blood flow of fistulas presented as an irregular mosaic color bolus with a clear boundary detected with CDUS. Blood flow imaging of fistulas was abnormal in 12 cases and absent in 7 cases. The detection rate was 63% (12/19). Fifty-three main feeding arteries (73.6%) were detected by ultrasonography. All the venous drainages through the transverse sinus and superior ophthalmic vein were detected, while the ones through the superior sagittal sinus and cortical vein were not. There was a significant difference in average diameter, flow velocity and RI of the occipital artery and superficial temporal artery between the patients and normal controls (p < 0.05). CONCLUSIONS: CDUS could indicate DAVF by analyzing both imaging results of the diseased region and hemodynamic changes of the relative vasculature. It is a promising technique for the diagnosis and follow-up study of DAVF.