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Purpose: Both EGFR and PI3K-Akt signaling pathways have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signaling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signaling. Experimental Design: We utilized cell-based models to study Notch signaling in drug-induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumors were used to evaluate the antitumor effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. Results: We found that EGFR/Notch targeting bispecific antibodies exhibited a notable antistem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in triple-negative breast cancer cell line–based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumor effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumors. Mechanistically, bispecific antibody treatment inhibits the stem cell–like subpopulation, reduces tumor-initiating cell frequency, and downregulates the mesenchymal gene expression. Conclusions: These findings suggest that the coblockade of EGFR and Notch signaling has the potential to increase the response to PI3K inhibition, and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment.

With the ever-increasing demands for functional and sustainable foods from the general public, there is currently a paradigm shift in the food industry toward the production of novel protein-based diet. Food scientists are therefore motivated to search for natural protein sources and innovative technologies to modify their chemical structure for desirable functionality and thus utilization. Deamidation is a viable, efficient, and attractive approach for modifying proteins owing to its ease of operating, specificity, and cost-effective processes. Over the past three decades, the knowledge of protein deamidation for food applications has evolved drastically, including the development of novel approaches for deamidation, such as protein-glutaminase and ion exchange resin, and their practices in new protein substrate. Thanks to deamidation, enhanced functionalities of food proteins from cereals, legumes, milk, oil seeds and others, and thereby their processabilities as food ingredients have been achieved. Moreover, deamidated proteins have been used to fabricate engineered food colloids, including self-assembled protein particles, protein-metallic complexes, and protein-carbohydrate complexes, which have demonstrated tailored physicochemical properties to modulate oral perception, improve gastrointestinal digestion and bioavailability, and protect and/or deliver bioactive nutrients. Novel bioactivity, altered digestibility, and varied allergenicity of deamidated proteins are increasingly recognized. Therefore, deamidated proteins with novel techno-functional and biological properties hold both promise and challenges for future food applications, and a comprehensive review on this area is critically needed to update our knowledge and provide a better understanding on the protein deamidation and its emerging applications.

Right atrial appendage aneurysms (RAAAs) are rare heart malformations, presenting as isolated anomalies or co-existing with other structural heart diseases. We describe a rare case of RAAA complicated with an atrial septal defect (ASD). The diagnosis was established using transthoracic echocardiography and confirmed using cardiac magnetic resonance imaging. To treat the ASD and reduced right atrium volume load, ASD transcatheter closure was performed. On echocardiography performed 3 months post discharge, the RAAA was observed to have reduced in size compared to that presurgery. Six years later, she was in good condition without any adverse events.

The world is experiencing one of the most difficult moments in history with COVID‐19, which has rapidly developed into a worldwide pandemic with a significant health and economic burden. Efforts to fight the virus, including prevention and treatment, have never stopped. However, no specific drugs or treatments have yet been found. Antibody drugs have never been absent in epidemics such as SARS, MERS, HIV, Ebola, and so on in the past two decades. At present, while research on the SARS‐CoV‐2 vaccine is in full swing, antibody drugs are also receiving widespread attention. Several antibody drugs have successfully entered clinical trials and achieved impressive therapeutic effects. Here, we summarize the therapeutic antibodies against SARS‐CoV‐2, as well as the research using ACE2 recombinant protein or ACE2‐Ig fusion protein., Several antibody drugs have successfully entered clinical trials and achieved impressive therapeutic effects. Due to the rapid progress in the field of therapeutic antibodies for COVID‐19 treatment, we summarized the neutralizing antibody drugs and fusion protein drugs that have attracted high attention at present, discussed the existing problems in the current application of antibodies drugs for COVID‐19, and prospected the future research direction in this field.

The human epidermal growth factor receptor (EGFR) targeting chimeric monoclonal antibody, cetuximab (Erbitux®), is a widely used drug in the treatment of metastatic colorectal cancer. However, the activation of the extensive crosstalk among the EGFR family receptors as well as other tyrosine kinase receptors (RTKs) impairs the efficacy of the drug by fueling acquired resistance. To identify the responsible potential activation pathway underlying cetuximab resistance and generate novel treatment strategies, cetuximab-resistant colorectal cancer cell lines were generated and validated and a functional RNAi screen targeting human RTKs was used to identify extensive receptor tyrosine kinase signaling networks established in resistant cancer cells. MET, Axl, and IGF-1R were identified as contributors to the acquired resistance to cetuximab. Targeting vectored immunoprophylaxis (VIPs) to different RTKs were generated and characterized. Different VIP approaches were evaluated in vivo with parental and cetuximab-resistance xenografts and the RTKs in resistant cancer xenografts were inhibited with VIPs via re-sensitization to cetuximab treatment. Combination of VIPs was more broadly efficacious, mechanistically, due to co-blocking the EGFR/Axl/MET signaling pathway, which was cross-activated in the resistant cell lines. Moreover, a VIP-based procedural treatment strategy not only eliminated the tumor but also afforded long-lasting protection from tumor recurrence and resistance. Overall, EGFR-related RTK pathway-network activation represents a novel mechanism underlying cetuximab resistance. A broad VIP combination strategy and VIP-based procedural treatment strategy may be a recommended addition to cetuximab-based targeted therapy. Our results establish a new principle to achieve combined RTK inhibition and reverse drug resistance using a VIP approach.

Brown adipose tissue (BAT) thermogenesis increases energy expenditure (EE). Expanding the volume of active BAT via transplantation holds promise as a therapeutic strategy for morbid obesity and diabetes. Brown adipose progenitor cells (BAPCs) can be isolated and expanded to generate autologous brown adipocyte implants. However, the transplantation of brown adipocytes is currently impeded by poor efficiency of BAT tissue formation in vivo and undesirably short engraftment time. In this study, we demonstrated that transplanting BAPCs into limb skeletal muscles consistently led to the ectopic formation of uncoupling protein 1 (UCP1)(+pos) adipose tissue with long-term engraftment (>4 mo). Combining VEGF with the BAPC transplant further improved BAT formation in muscle. Ectopic engraftment of BAPC-derived BAT in skeletal muscle augmented the EE of recipient mice. Although UCP1 expression declined in long-term BAT grafts, this deterioration can be reversed by swimming exercise because of sympathetic activation. This study suggests that intramuscular transplantation of BAPCs represents a promising approach to deriving functional BAT engraftment, which may be applied to therapeutic BAT transplantation and tissue engineering.—Liu, Y., Fu, W., Seese, K., Yin, A., Yin, H. Ectopic brown adipose tissue formation within skeletal muscle after brown adipose progenitor cell transplant augments energy expenditure.

The TIGIT (T cell immunoreceptor with Ig and ITIM domains) protein is a co-inhibitory receptor that has been reported to suppress autoreactive T and B cells to trigger immunological tolerance. We generated a new recombinant protein by connecting the extracellular domain of murine TIGIT to the Fc region of the rat immunoglobulin IgG2a. The fusion protein was then characterized. The results suggested that among mice with lupus that were treated with the TIGIT-Ig fusion protein, the onset of proteinuria was delayed, serum concentrations of autoantibodies, such as antinuclear antibodies, were reduced without a decrease in the total IgG concentrations, and the survival rate was significantly increased compared to those of the controls. In conclusion, TIGIT-Ig administration showed promising results for both the prevention and treatment of autoimmune diseases in mice. This indicates that treatment with recombinant human TIGIT-Ig shows promise as an effective way to treat human autoimmune diseases.

In three-dimensional space, current target tracking algorithms based on wireless sensor networks are mainly non-iterative and operated with only current measurement result. A typical example is the least square algorithm. Compared with iterative algorithms which use historical information, such as extended Kalman filter, non-iterative algorithms always achieve lower accuracy but can avoid the dependence upon prior knowledge of system noises. In this letter, we firstly proposed a minimum residual localization algorithm based on particle swarm optimization, which is a non-iterative algorithm. Then, a data-fitting strategy is adopted to convert the non-iterative algorithm into iterative one without knowledge of system noise. Hence, the historical information can be used to improve the accuracy of non-iterative algorithm significantly. Simulation results show that the proposed algorithm acquires better localization result with strong adaptability for different motion.

The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti–HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody. Cancer Res; 75(1); 159–70. ©2014 AACR.

Coverage completeness is an important indicator for quality of service in wireless sensor networks (WSN). Due to limited energy and diverse working conditions, the sensor nodes have different lifetimes which often cause network holes. Most of the existing methods expose large limitation and one-sidedness because they generally consider only one aspect, either coverage rate or energy issue. This paper presents a novel method for coverage hole detection with residual energy in randomly deployed wireless sensor networks. By calculating the life expectancy of working nodes through residual energy, we make a trade-off between network repair cost and energy waste. The working nodes with short lifetime are screened out according to a proper ratio. After that, the locations of coverage holes can be determined by calculating the joint coverage probability and the evaluation criteria. Simulation result shows that compared to those traditional algorithms without consideration of energy problem, our method can effectively maintain the coverage quality of repaired WSN while enhancing the life span of WSN at the same time.

With the development of the wireless communication technology and intelligent mobile phone, the positioning services based on Wi-Fi and mobile phone are increasingly demanded. In this paper, a Wi-Fi fingerprint localization method is proposed on the basis of important access points (IAP). For the Wi-Fi fingerprint, Wi-Fi access point with the highest received signal strength (RSS) is denoted as the important access point. At the localization stage, the fingerprints are chosen with the same IAP as the estimated fingerprint from the database. Then, the distance and the AP repetition of the fingerprints are used to calculate the similarity degree. The location of the fingerprint which matches the estimated fingerprint well can be regarded as the estimated location. Experimental results show that the proposed algorithm can achieve high accuracy in indoor environment.

Dysfunction of the epidermal growth factor receptor (EGFR) family, is the key process in tumorigenesis, and anti-EGFR therapeutic strategies such as cetuximab therapy now are used in the treatment of cancer. However, resistance to cetuximab is commonly reported. Comprehensive blockade of EGFR signaling using different antibodies might be critical to treat cancer effectively and limit drug resistance with potent novel mechanisms. Here, we launch a screen of a phage display library to isolate a novel anti-EGFR antibody, YAH627. YAH627 exhibits superior efficacy in inhibiting EGFR activation, particularly by blocking EGF/HRG-induced EGFR/HER3 heterodimerization and signaling, verifying it as an impressive candidate for clinical translation as a therapeutic antibody. Moreover, we use epitope analysis validates that the epitope of this antibody is within domains II and IV of EGFR and traps EGFR in a silent conformation. Moreover, combining YAH627 with cetuximab produces synergistic antitumor activity in vitro and in vivo. Taken together, our report establishes that YAH627 possesses a novel mechanism of action that, in combination with cetuximab, may achieve clinical efficacy in EGFR-driven cancers.

Although promising progress has been made with dual HER2 blockade in patients with HER2-positive breast cancer, whether the strategy of combined HER2 blockade increases the risk of severe diarrhea remains inclusive. In the present study, we investigated the overall incidence and risk of severe diarrhea when patients were treated with a combination of anti-HER2 therapies compared to anti-HER2 monotherapy. Studies that evaluated the administration of an anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination therapy (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) in breast cancer were identified from the PubMed database (1966–2013), the Cochrane library, abstracts presented at the American Society of Clinical Oncology annual conference (2004–2013), and the Web of Science database (1998–2013). Eligible studies were those in which the only systematic difference between the study arms was the type of anti-HER2 therapy used. Incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random effects or fixed-effects models based on the heterogeneity of the included studies. Seven trials were considered eligible. The overall incidence results for severe diarrhea in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 3.48 % (95 % CI: 11.60–15.37 %) and 8.68 % (95 % CI: 7.33–10.03 %), respectively. The odds ratio (OR) of severe diarrhea between anti-HER2 combination therapy and monotherapy was 1.67 (95 % CI: 1.38 −5.57, p = 0.00001). This meta-analysis provides evidence that the incidence rates of severe diarrhea are comparable between anti-HER2 combination therapy and anti-HER2 monotherapy.

Previously, we reported on the crystal structures of the Fab fragments of two food and drug administration approved therapeutic antibodies, Infliximab and Adalimumab, in complex with TNFα. The structurally identified epitopes on TNFα reveal the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the adalimumab epitope. Structural analysis, the phage display antibody isolation technology, step-by-step antibody optimization, complementarity-determining region residues random mutagenesis, phage ELISA, binding affinity characterization, and cell signaling assays were used for the development and optimization of the novel anti-TNFα antibodies. Moreover, one of the novel antibodies, hAta09, has a superior inhibitory effect on TNFα function and signaling. Taken together, our report established that the novel anti-TNFα antibody hAta09 may achieve clinical efficacy in a TNFα-associated disease.

This paper proposes a topology control method based on formation maintenance and nodes in different groups, which mainly involves issues on the network topology variation caused by the inconsistent velocities of all nodes and communication failure between local nodes and different groups in mobile robot team. It embodies the important role of formation maintenance associated with making groups when topology changes. The simulation result has demonstrated that this method can make effective preservation and restoration on the mobile network communication link.

This paper, based on the application background of the interaction of wireless communication network and UnderWater Sensor Networks(UWSNs), with a view to the positive influence on the performance of UWSNs while multi-gateways on surface as well as their positions vary, regarding the delay, energy consumption and packet loss ratio of network as the optimization goal, the relation model of the number of gateways and network performance is derived. Furthermore, the optimized position of gateways has been determined through a Genetic Algorithm(GA). The simulation results indicate that network delay, energy consumption and loss rate of packet can be efficiently improved by means of multiple gateways, verifying the effectiveness of the model proposed in this paper.

Indoor target localization is an essential and fundamental issue for wireless sensor networks (WSN). However, it is rather difficult for WSN to maintain the localization accuracy in line-of-sight (LOS) and non-line-of-sight (NLOS) mixed environment. NLOS propagation always leads to larger ranging error than LOS does. When the target moves in the rooms and corridors, the signal transmission state will switch frequently between LOS and NLOS. It is a challenging task to deal with this situation because the ranging error characteristics under LOS and NLOS conditions are quite different. In this paper, we propose an interacting multiple model-extended Kalman filter (IMM-EKF) algorithm to improve the localization accuracy for moving target in indoor environment. In the IMM structure, two Kalman filters (KF) are adopted in parallel to accurately smoothen the distance measurement. The proposed algorithm can adapt to the dynamically changing condition between LOS and NLOS due to the two KFs' interaction so that large NLOS ranging errors are further reduced. Once the estimated ranges are obtained, the EKF is employed to estimate the target's location. Empirical measurement results are obtained from typical office environment to verify the effectiveness of the proposed algorithm. Experimental results illustrate that the IMM smoother can efficiently mitigate the NLOS effects on ranging errors and achieve high localization accuracy.