Overexpression of HER2 has been reported in many types of cancer, making it a perfect candidate for targeted immunotherapy. The combination of two FDA approved monoclonal antibodies (mAbs), ...trastuzumab and pertuzumab, has more robust anti-tumor activity in patients with HER2-overexpressing breast cancer. We recently produced a new humanized anti-HER2 mAb, hersintuzumab, which recognizes a different epitope than trastuzumab and pertuzumab on HER2. This mAb, in combination with trastuzumab, exhibits more potent anti-tumor activity than each parental mAb alone. Here we have developed a novel bispecific anti-HER2 antibody (BsAb) designated as trasintuzumab, composed of trastuzumab and hersintuzumab, using dual variable domain immunoglobulin (DVD-Ig) technology. Both variable domains of trasintuzumab are fully functional and have similar affinities to the parental mAbs and are also able to bind to natural HER2 on the surface of several HER2-expressing cell lines. Trasintuzumab was found to inhibit the growth of different types of tumor cell lines through suppression of the AKT and ERK signaling pathways as efficiently as the combination of the parental mAbs. It also induced tumor regression as potently as the combination of the two mAbs in nude mice bearing ovarian and gastric cancer xenografts. Our data suggest that trasintuzumab may be a promising BsAb therapeutic candidate for the treatment of HER2-overexpressing cancers.
Anthropogenic activities cause metal pollution worldwide. Plants can absorb and accumulate these metals through their root system, inducing stress as a result of excess metal concentrations inside ...the plant. Ethylene is a regulator of multiple plant processes, and is affected by many biotic and abiotic stresses. Increased ethylene levels have been observed after exposure to excess metals but it remains unclear how the increased ethylene levels are achieved at the molecular level. In this study, the effects of cadmium (Cd) exposure on the production of ethylene and its precursor 1-aminocyclopropane-1-carboxylic acid (ACC), and on the expression of the ACC Synthase (ACS) and ACC Oxidase (ACO) multigene families were investigated in Arabidopsis thaliana.
Increased ethylene release after Cd exposure was directly measurable in a system using rockwool-cultivated plants; enhanced levels of the ethylene precursor ACC together with higher mRNA levels of ethylene responsive genes: ACO2, ETR2 and ERF1 also indicated increased ethylene production in hydroponic culture. Regarding underlying mechanisms, it was found that the transcript levels of ACO2 and ACO4, the most abundantly expressed members of the ACO multigene family, were increased upon Cd exposure. ACC synthesis is the rate-limiting step in ethylene biosynthesis, and transcript levels of both ACS2 and ACS6 showed the highest increase and became the most abundant isoforms after Cd exposure, suggesting their importance in the Cd-induced increase of ethylene production.
Cadmium induced the biosynthesis of ACC and ethylene in Arabidopsis thaliana plants mainly via the increased expression of ACS2 and ACS6. This was confirmed in the acs2-1acs6-1 double knockout mutants, which showed a decreased ethylene production, positively affecting leaf biomass and resulting in a delayed induction of ethylene responsive gene expressions without significant differences in Cd contents between wild-type and mutant plants.
The Internet provides copyright holders with new sales and promotional channels for their content, while also providing consumers with new opportunities to illegally obtain free copies of this ...content. Unfortunately, disentangling these two effects is extremely difficult.
In this paper we attempt to disentangle these two effects by applying fixed effects and first difference models to a new dataset quantifying changes in broadband Internet penetration and DVD sales at a local level from 2000 to 2003. We then compare our results to those reported in
Liebowitz (2008), who uses similar models in a similar time period on a similar product category: music CDs.
Unlike Liebowitz, who finds a strong negative impact of broadband penetration on music sales, our results show that increased broadband penetration leads to a significant
increase in DVD sales. Using the most conservative results, 9.3% of the $14.1 billion increase in DVD sales during our study period can be attributed to increased broadband penetration. One interpretation of these results is that the difference arises from differences in the ability to pirate these two types of content: while Internet music piracy was easy and rampant from 2000 to 2003, Internet movie piracy was difficult and of generally low quality in this time period. If this interpretation is true it would suggest that, in the absence of piracy, the Internet has an overall strong positive impact on media sales.
Screen time and physical activity behaviours develop during the crucial early childhood period (0-5 years) and impact multiple health and developmental outcomes, including psychosocial wellbeing. ...Social skills, one component of psychosocial wellbeing, are vital for children's school readiness and future mental health. This study investigates potential associations of screen time and outdoor play (as a proxy for physical activity) with social skills. Cross sectional data were available for 575 mothers with a child (54% boys) aged 2-5 years. Mothers reported their child's screen time, outdoor play time and social skills (Adaptive Social Behavior Inventory; ASBI). Multiple linear regression analyses assessed associations of screen and outdoor play time (Model 1) and compliance with screen time and physical activity recommendations (Model 2) with three ASBI subscales. Boys and girls spent a mean of 2.0 and 2.2 hours per day in screen time, and 3.3 and 2.9 hours per day in outdoor play, respectively. Girls scores for express and comply skills were significantly higher than boys (p<0.005). After applying the Benjamini-Hochberg Procedure to adjust for multiple associations, children's television/DVD/video viewing was inversely associated with their compliant scores (B = -0.35 95% CI -0.26, -0.14; p = 0.001) and outdoor play time was positively associated with both expressive (B = 0.20 95% CI 0.07, 0.34; p = 0.004) and compliant (B = 0.22 95% CI 0.08, 0.36; p = 0.002) scores. Findings indicate that television/DVD/video viewing may be adversely, and outdoor play favourably, associated with preschool children's social skills. Future research is required to identify the direction of causation and explore potential mechanisms of association.
•Inexpensive and large-scale SERS-active materials were easily fabricated from regular CD-R and DVD-R disks.•The nanostructured silver-coated materials were characterized and key parameters in the ...Raman enhancement were studied.•The Raman fingerprint of hemoglobin and exosomes was obtained in label-free conditions with the developed SERS substrates.•Potential lab-on-a-disk biosensing devices for Raman analysis in point-of-care settings are suggested.
A central aspect to fully reach the biosensing scope of plasmonics beyond the research environment is its implementation in inexpensive and homogeneous functional nanostructured materials that can be manufactured in a large-scale fashion. Herein, we study the capabilities of consumer-grade compact disk technology for label-free SERS analysis of complex biological targets. Substrates from regular recordable disks (CD-R and DVD-R) coated with silver exhibit significant Raman enhancement. The magnitude of this enhancement depends on the nanostructure on the polycarbonate substrate, the silver thickness, and the excitation wavelength. The Raman fingerprint of hemoglobin and exosome samples were experimentally obtained in label-free conditions, which demonstrates the biosensing potential of this approach and suggests prospective developments towards fully exploiting the bioanalytical capabilities of SERS in point-of-care settings.
Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently ...target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biology. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each specificity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.
Recent papers have shown that, in contrast to the long tail theory, movie sales remain concentrated in a small number of hits. These papers have argued that concentrated sales can be explained, in ...part, by heterogeneity in quality and increasing returns from social effects. Our research analyzes an additional explanation: how incomplete information may skew sales patterns. We use the movie broadcast on pay-cable channels as an exogenous shock to the availability of information, and analyze how this shock changes the resulting sales distribution.
Our data show that the pay-cable broadcast shifts the distribution of DVD sales toward long tail movies, suggesting an information spillover from the broadcast. We develop a learning-based movie discovery model to precisely quantify the two mechanisms of movie discovery: word-of-mouth from previous sales and information spillover from broadcast. We use this model to estimate the lost DVD sales due to incomplete information. Our study contributes to the literature by analyzing how information provided in one channel can change the assortment of the same products demanded in another channel.
Nanostructures provide a simple, effective, and low‐cost route to enhance the light‐trapping capability of optoelectronic devices. In recent years, nano‐optical structures have been widely used in ...perovskite optoelectronic devices to greatly enhance the device performance. However, the inherent instability of perovskite materials hinders the practical application of these nanostructured optoelectronic devices. Here, in situ encapsulated moiré lattice perovskite photodetectors (PDs) by two nanograting‐structured soft templates with relative rotation angles is fabricated. The confinement growth of the two nanograting templates leads to crystal growth with moiré lattice structure, which improves the light‐harvesting ability of the perovskite crystal, thereby improving the device performance. The PD exhibits responsivity to 1026.5 A W−1. The Moiré lattice‐perovskite‐based PD maintained 95% of the initial performance after 223 days. After being continuously sprayed with water moist for 180 min, the performance is maintained at 95.7% of its initial level. The nanograting structure endows the device with high polarization sensitivity of Imax/Imin as high as 9.1.
Owing to its enhanced light collection ability, the Moiré‐lattice‐structured perovskite photodetectors (PDs) in situ encapsulated by two nano‐grating‐structured Polydimethylsiloxane show a responsivity up to 1026.5 A W−1. The PD still maintained 95% performance after exposure to air for 233 days. The Moiré‐lattice structures endow the PD a dichroism ratio of up to 9.1.
The “Supplementary Material” link on the abstract page for this article contains two freely downloadable video files. These are corrected versions of two tracks whose audio on the physical DVD is ...defective:
and
. Please use these in place of tracks 1 and 3 on the DVD. We apologize for the errors. These files have already been corrected in the “DVD Content” article for this website. However, the tracks have been made free here for
readers who have the DVD but don't have subscriber-level access to the online version of the issue.
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