Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

BACKGROUND: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested. METHODS: The antibody was modified using EBNA cells cotransfected with beta-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes. RESULTS: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgammaRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgammaRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgammaRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model. CONCLUSION: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial

Targeted killing of colorectal cancer cell lines by a humanised IgG1 monoclonal antibody that binds to membrane-bound carcinoembryonic antigen

The distribution of carcinoembryonic antigen (CEA) in colorectal cancer (CRC) differs from that in normal colorectal tissue, being found on all borders of the cell membrane and hence enabling access to intravenous antibody, making CEA a good target for antibody-based therapy. The distinctive anti-CEA antibody, PR1A3, binds only membrane-bound CEA. Humanised PR1A3 (hPR1A3) was assessed both in vitro cytotoxicity and binding assays with colorectal cancer cell lines expressing varying levels of CEA. Human peripheral blood mononuclear cells (PBMCs) and purified natural killer (NK) cells were used as effectors. The in vitro assays demonstrated hPR1A3 CEA-specific binding and antibody-dependent and CEA-specific killing of human colorectal cancer cell lines by human PBMCs. The effect increased with increasing concentration of antibody and surface CEA, and was lost by using the parent murine IgG1 PR1A3. Killing was also blocked by antibody to the Fc-γIIIA receptor. Purified human NK cells were effective at much lower effector:target ratios than unfractionated PBMCs, indicating that NK cells were the main mediators of hPR1A3-based CEA-specific killing. The results support the development of hPR1A3 for therapy of colorectal cancer

Osmoregulators proline and glycine betaine counteract salinity stress in canola

Salt inundation leads to increased salinization of arable land in many arid and semi-arid regions. Until genetic solutions are found farmers and growers must either abandon salt-affected fields or use agronomic treatments that alleviate salt stress symptoms. Here, field experiments were carried out to study the effect of the osmoregulators proline at 200 mg L-1 and glycine betaine at 400 mg L-1 in counteracting the harmful effect of soil salinity stress on canola plants grown in Egypt. We assessed growth characteristics, yield and biochemical constituents. Results show first that all growth characters decreased with increasing salinity stress but applied osmoregulators alleviated these negative effects. Second, salinity stress decreased photosynthetic pigments, K and P contents, whilst increasing proline, soluble sugars, ascorbic acid, Na and Cl contents. Third, application of osmoregulators without salt stress increased photosynthetic pigments, proline, soluble sugars, N, K and P contents whilst decreasing Na and Cl contents. It is concluded that the exogenously applied osmoregulators glycine betaine and proline can fully or partially counteract the harmful effect of salinity stress on growth and yield of canola.© INRA and Springer-Verlag, France 2012

Perspectives for a mixed two-qubit system with binomial quantum states

The problem of the relationship between entanglement and two-qubit systems in which it is embedded is central to the quantum information theory. This paper suggests that the concurrence hierarchy as an entanglement measure provides an alternative view of how to think about this problem. We consider mixed states of two qubits and obtain an exact solution of the time-dependent master equation that describes the evolution of two two-level qubits (or atoms) within a perfect cavity for the case of multiphoton transition. We consider the situation for which the field may start from a binomial state. Employing this solution, the significant features of the entanglement when a second qubit is weakly coupled to the field and becomes entangled with the first qubit, is investigated. We also describe the response of the atomic system as it varies between the Rabi oscillations and the collapse-revival mode and investigate the atomic inversion and the Q-function. We identify and numerically demonstrate the region of parameters where significantly large entanglement can be obtained. Most interestingly, it is shown that features of the entanglement is influenced significantly when the multi-photon process is involved. Finally, we obtain illustrative examples of some novel aspects of this system and show how the off-resonant case can sensitize entanglement to the role of initial state setting.Comment: 18 pages, 9 figure

Integrating the Role of Green Fiscal Policies With Energy Prices Volatility and Energy Efficiency: Presenting a COVID-19 Perspective

Energy and other related sectors are changing in China. This study attempted to estimate the energy product price volatility with energy efficiency during COVID-19 with the role of green fiscal policies. For this, we applied unit-root tests, ADCC-GARCH, and CO-GARCH techniques to infer the study findings. The results showed that energy price volatility was significantly connected until 2018. More so, the green fiscal policies were significantly connected between energy product price volatility and energy efficiency during COVID-19 (2019–2020). From energy products, the crude oil price volatility was significant at 16.4%, heating oil volatility was significant at 18.2%, natural oil price volatility was 9.7%, gasoline price volatility was 28.7%, and diesel price volatility was 34.1% significant with energy efficiency, due to the intervening role of green fiscal policies. The findings of this study are robust in comparison to previous studies. Multiple stakeholders can take guidelines from the findings of the recent study. As per our best understanding and knowledge, if suggested recommendations are implemented effectively, these results will help to enhance energy efficiency through green fiscal policies in the post-COVID period. Copyright © 2022 Yin, Anser, Abbas, Ashraf, Ahmad, Jamshid and Osabohien.Special Funds for the Basic Research and Development Program in the Central Non-profit Research Institutesof Chin

Systemic risk and macroeconomic fat tails

We propose a mechanism for shock amplification that potentially can account for fat tails in the distribution of the growth rate of national output. We argue that extreme macroeconomic events, such as the Great Depression and the Great Recession, were preceded by significant turmoil in the banking system. We have developed a model of bank network formation and presented numerical simulations that show that, for the benchmark case, aggregate credit follows a random walk. When we introduce fire sales the model does not only produce larger variations in the growth of aggregate credit but also shows that there is an asymmetry between booms and busts that is also consistent with empirical evidence

Pharmacological Evaluation and Synthesis of New Sulfonamides Derivatives Based on 1,4-Benzodioxane

We report here the synthesis of a series of N-aryl-2,3-dihydrobenzo[1,4]dioxine-6-sulfonamide and its N-substituted derivatives with benzyl chloride and ethyl iodide. Initially, 2,3-dihydrobenzo[1,4]dioxine-6-sulfonyl chloride (1) was subjected to react with various aryl amines (2a-e) to afford parent compounds N-aryl-2,3-dihydrobenzo[1,4]dioxine-6-sulfonamide (3a-e). At second step, these parent compounds were reacted with benzyl chloride (4) and ethyl iodide (5) as to synthesize N-benzyl-N-aryl-2,3-dihydrobenzo[1,4]dioxine-6-sulfonamide (6a-e) and N-ethyl-N-aryl-2,3-dihydrobenzo[1,4]dioxine-6-sulfonamide (7a-e) in the presence of lithium hydride and N,Nꞌ-dimethylformamide respectively. FT-IR, Nuclear Magnetic Resonance (1H-NMR) and Mass Spectrometry (MS) techniques were used to investigate the structures of these synthesized compounds. A fingerprinted study was conducted against some enzymes like butyrylcholin-esterase (BChE), acetylcholinesterase (AChE) and lipoxygenase (LOX). This study revealed that most of them demonstrated a moderate activity against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) however promisingly a good activity against lipoxygenase enzyme was observed. Finally, an antimicrobial and hemolytic activities of these sulfonamides were probed which confirmed that the parent sulfonamides 3b have the proficient antimicrobial activities, while the derivatives 6a, 7a, 7b and 7c explored a good activity against the selected panel of bacterial and fungal species. All the compounds were further computationally docked against (LOX), (BChE) and (AChE) enzymes and these interaction highlighted the importance of sulfonamides in the inhibition of the target enzymes

State history and economic development: evidence from six millennia

The presence of a state is one of the most reliable historical predictors of social and economic development. In this article, we complete the coding of an extant indicator of state presence from 3500 BCE forward for almost all but the smallest countries of the world today. We outline a theoretical framework where accumulated state experience increases aggregate productivity in individual countries but where newer or relatively inexperienced states can reach a higher productivity maximum by learning from the experience of older states. The predicted pattern of comparative development is tested in an empirical analysis where we introduce our extended state history variable. Our key finding is that the current level of economic development across countries has a hump-shaped relationship with accumulated state history