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1.
Nat Commun ; 15(1): 3084, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600059

RESUMO

Irrigation is a land management practice with major environmental impacts. However, global energy consumption and carbon emissions resulting from irrigation remain unknown. We assess the worldwide energy consumption and carbon emissions associated with irrigation, while also measuring the potential energy and carbon reductions achievable through the adoption of efficient and low-carbon irrigation practices. Currently, irrigation contributes 216 million metric tons of CO2 emissions and consumes 1896 petajoules of energy annually, representing 15% of greenhouse gas emissions and energy utilized in agricultural operations. Despite only 40% of irrigated agriculture relies on groundwater sources, groundwater pumping accounts for 89% of the total energy consumption in irrigation. Projections indicate that future expansion of irrigation could lead to a 28% increase in energy usage. Embracing highly efficient, low-carbon irrigation methods has the potential to cut energy consumption in half and reduce CO2 emissions by 90%. However, considering country-specific feasibility of mitigation options, global CO2 emissions may only see a 55% reduction. Our research offers comprehensive insights into the energy consumption and carbon emissions associated with irrigation, contributing valuable information that can guide assessments of the viability of irrigation in enhancing adaptive capacity within the agricultural sector.

2.
Sci Total Environ ; 921: 171211, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38408658

RESUMO

Intense warming profoundly alters precipitation phase patterns and intensity in High Mountain Asia (HMA). While snowfall climatology and precipitation extremes have been studied, there is a lack of understanding of snowfall extremes within HMA. Here, we investigate the spatial and temporal variability of non-extreme and extreme snowfall in hydrological years 1979-2020 using multi-source meteorological data, compare weather systems during extreme and non-extreme snowfall events, and identify key circulation factors that influence fluctuations in mean annual snowfall and extreme snowfall. The snowfall amount (-0.13 d/mm), days (-0.56 d/a), and fraction (-0.0012) were significantly reduced in HMA, with a shorter snowfall season (-0.52 d/a). Some extreme snowfall metrics (maximum 1-day snowfall and maximum 3-day snowfall) were insensitive to climate change, whereas the maximum consecutive snowfall days (-0.007 d/a), snowfall amount (-0.0023 mm/a), heavy snowfall days (S95pD; 0.0087 d/a), and extremely heavy snowfall days (S99pD; -0.1019 d/a) showed significant decreases. Synthetic analyses show that extreme snowfall events were more likely to occur within a narrow temperature range (-5 °C to 3 °C) with higher relative humidity and precipitation compared to non-extreme events. A stepwise regression method was used to determine that the fluctuation in the average annual snowfall was closely related to the Atlantic Multidecadal Oscillation, whereas the variation in extreme snowfall was mainly influenced by the Southern Oscillation Index. Our research provides a reference for assessing the potential impacts of climate change on a regional scale for risk management and disaster adaptation.

3.
Sci Total Environ ; 921: 170913, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354818

RESUMO

Meteorological drought is a crucial driver of various types of droughts; thus, identifying the spatiotemporal characteristics of meteorological drought at the basin scale has implications for ecological and water resource security. However, differences in drought characteristics between river basins have not been clearly elucidated. In this study, we identify and compare meteorological drought events in 34 major river basins worldwide using a three-dimensional drought-clustering algorithm based on the standardised precipitation evapotranspiration index on a 12-month scale from 1901 to 2021. Despite synchronous increases in precipitation and potential evapotranspiration (PET), with precipitation increasing by more than three times the PET, 47 % (16/34) of the basins showed a tendency towards drought in over half their basin areas. Drought events occurred frequently, with more than half identified as short-term droughts (lasting less than or equal to three months). Small basins had a larger drought impact area, with major drought events often originating from the basin boundaries and migrating towards the basin centre. Meteorological droughts were driven by changes in sea surface temperature (SST), especially the El Niño Southern Oscillation (ENSO) or other climate indices. Anomalies in SST and atmospheric circulation caused by ENSO events may have led to altered climate patterns in different basins, resulting in drought events. These results provide important insights into the characteristics and mechanisms of meteorological droughts in different river basins worldwide.

4.
Sci Total Environ ; 912: 168813, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38030016

RESUMO

The development of drought has spatial and temporal synchronization. Previous studies usually explore the spatial and temporal evolution of drought separately. Moreover, existing approaches are based on a fixed overlapping area and do not consider the variable drought cluster area during development. This study proposes an improved and simple approach to derive dynamic overlapping area threshold for 3-dimensional droughts extraction. Based on the one monthly Nonparametric Standardized Precipitation Index (NSPI), this improved approach was applied for investigating the migration characteristics of meteorological drought events in the Loess Plateau of China. Then, Random Forest and Extreme Gradient Boosting model with Shapley additive explanation values were used to quantify the importance of driving factors on the dynamics of drought characteristics. The results showed that: (1) the improved approach has a better performance on identifying prolonged droughts than the method using a fixed overlap area threshold; (2) spatially, meteorological drought events with high severity (DS), long duration (DD), large effected area (DA) and fast migration velocity (DV) mainly occur in the central region; (3) temporally, droughts are expected to aggravate with significantly increased DS and DA which are mainly caused by increased temperature and vegetation; and (4) meteorological droughts have a preferred westward migration direction and three dominant migration paths, which are crucial for local drought prevention and control. The findings of this study provide new perspectives on drought migration characteristics, which are important for the exploration of drought-driven mechanisms, risk assessment and future prediction.

5.
Biol Direct ; 18(1): 48, 2023 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-37592296

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have been shown to play diverse biological functions in the progression of multiple diseases. However, the impacts of circRNAs on breast cancer (BC) progression remains unclear. Therefore, the objective of this paper is to investigate the role and mechanisms of a functional circRNA in BC metastasis and immune escape. METHODS: This study used a circRNA microarray and identified a novel circRNA hsa_circ_0067842. The validation and characteristics of hsa_circ_0067842 were investigated using qRT-PCR, sanger sequencing, RNase R treatment, actinomycin D treatment and fluorescence in situ hybridization (FISH). Gain- and loss-of-function assays were performed to evaluate the biological function of hsa_circ_0067842 in BC progression and immune escape. Mechanistically, the interaction between hsa_circ_0067842 and HuR was explored by RNA pull down, mass spectrometry (MS), subcellular component protein extraction and immunofluorescence (IF). The regulatory mechanisms of hsa_circ_0067842/HuR/CMTM6/PD-L1 axis were investigated by qRT-PCR, western blot, FISH, immunoprecipitation and rescue assays. RESULTS: The expression of hsa_circ_0067842 was upregulated in BC tissues and cells, which was found to be significantly associated with poor prognosis, regardless of other clinical covariates. Function assays showed that hsa_circ_0067842 promoted the migration and invasion capacities of BC cells. Moreover, co-culture experiment with peripheral blood mononuclear cells (PBMCs) showed that hsa_circ_0067842 played a role in the immune escape of BC cells. Mechanistically, our study showed that hsa_circ_0067842 interacted with HuR, affecting its nuclear translocation, thus enhancing the stability of CMTM6. CMTM6 not only enhances the migration and invasion ability of BC cells, but also affects the ubiquitination of PD-L1 and inhibits its degradation. CONCLUSION: Collectively, our results demonstrated that hsa_circ_0067842 promoted BC progression through the HuR/CMTM6/PD-L1 axis, providing new insight and a potential target for BC prognosis and therapy.


Assuntos
Neoplasias da Mama , RNA Circular , Evasão Tumoral , Humanos , Antígeno B7-H1/genética , Hibridização in Situ Fluorescente , Leucócitos Mononucleares , RNA Circular/genética , Neoplasias da Mama/patologia , Metástase Neoplásica
7.
Sci Rep ; 12(1): 18853, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344741

RESUMO

Climate change will have an impact on not only flood magnitude but also on flood timing. This paper studies the shifting in flood timing at 6167 gauging stations from 1970 to 2010, globally. The shift in flood timing and its relationship with three influential factors (maximum 7-day precipitation, soil moisture excess, and snowmelt) are investigated. There is a clear global pattern in the mean flooding date: winter (Dec-Feb) across the western Coastal America, western Europe and the Mediterranean region, summer (Jun-Aug) in the north America, the Alps, Indian Peninsula, central Asia, Japan, and austral summer (Dec-Feb) in south Africa and north Australia area. The shift in flood timing has a trend from - 22 days per decade (earlier) to 28 days per decade (delayed). Earlier floods were found extensively in the north America, Europe and northeast Australia while delayed floods were prevailing in the Amazon, Cerrado, south Africa, India and Japan. Earlier flood timing in the north America and Europe was caused by earlier snowmelt while delayed extreme soil moisture excess and precipitation have jointly led to delayed floods around the monsoon zone, including south Africa, India and Japan. This study provides an insight on the shifting mechanism of flood timing, and supports decisions on the global flood mitigation and the impact from future climate change.


Assuntos
Mudança Climática , Inundações , Estações do Ano , Solo , Previsões
8.
Sci Rep ; 12(1): 17258, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36241758

RESUMO

Agricultural irrigation consumes most of the fresh water in the China-Pakistan Economic Corridor (CPEC), directly affecting water resource management and allocation. Irrigation water demand is a key component of regional water resources management. We analyzed spatiotemporal variation in irrigation water requirement, irrigation demand index (IDI), and the proposed regional optimization of irrigation water use based on the Bayesian probability network. Results showed that: (1) The IDI in the study area increased slightly (trend slope = 0.028 a-1) as the effective precipitation increased by 63% during this period, and total irrigation water requirement (IR) decreased from 277.61 km3 in 2000 to 240 km3 in 2015. (2) Cotton had the highest crop IDI, followed by maize and wheat. (3) According to the comprehensive scenario analysis, improving the crop planting structure (by moderately increasing the planting proportion of maize in the CPEC) is conducive to improving regional water and food security by enhancing the grain yield (+ 9%), reducing the malnourished proportion of the population (low state + 7.2%), and bolstering water-saving irrigation technologies in Pakistan as well as water conveyance systems in Pakistan. Our results form an important baseline in determining the way forward on sustainable water resource utilization management in the CPEC.


Assuntos
Irrigação Agrícola , Agricultura , Irrigação Agrícola/métodos , Agricultura/métodos , Teorema de Bayes , China , Paquistão , Água , Zea mays
10.
Small Methods ; 6(6): e2200154, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35460217

RESUMO

Exosomes have emerged as potential biomarkers for pancreatic cancer (PaC). However, it is still challenging to get quantitative detection of exosomes with the specific surface receptors. In this study, a highly sensitive detection system is first constructed for the direct quantitation of specific exosomes in real samples using hierarchical surface-enhanced Raman scattering substrate (H-SERS substrate) and rapid enrichment strategy magnetic beads @ exosomes @ SERS detection probes (MEDP). It is found that the detection system (MEDP @ H-SERS substrate) could provide a 3.5 times higher SERS intensity compared with MEDP sandwich immunocomplex only. Moreover, LRG1-positive exosomes (LRG1-Exos) and GPC1-positive exosomes (GPC1-Exos) are chosen to distinguish PaC through exosome proteomics and database screening. The lower limit of detection (LOD) is 15 particles µL-1 using the MEDP @ H-SERS substrate. Significantly, the detection in clinical samples shows that the innovative combination of LRG1-Exos and GPC1-Exos could improve the diagnostic efficiency of PaC, with an area under the operating characteristic curve (AUC) of 0.95. Even for the early-stage PaC, the diagnostic accuracy is still high (AUC = 0.95). Collectively, the findings indicate that the MEDP @ H-SERS substrate has great potential for the early diagnosis of PaC.


Assuntos
Exossomos , Neoplasias Pancreáticas , Detecção Precoce de Câncer , Humanos , Imunoensaio , Neoplasias Pancreáticas/diagnóstico , Análise Espectral Raman , Neoplasias Pancreáticas
11.
Expo Health ; 14(2): 431-446, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35128147

RESUMO

Surface ozone (O3) is an oxidizing gaseous pollutant; long-term exposure to high O3 concentrations adversely affects human health. Based on daily surface O3 concentration data, the spatiotemporal characteristics of O3 concentration, exposure risks, and driving meteorological factors in 347 cities and 10 major countries (China, Japan, India, South Korea, the United States, Poland, Spain, Germany, France, and the United Kingdom) worldwide were analyzed using the MAKESENS model, Moran' I analysis, and Generalized additive model (GAM). The results indicated that: in the boreal spring season from 2015 to 2020, the global O3 concentration exhibited an increasing trend at a rate of 0.6 µg/m3/year because of the volatile organic compounds (VOCs) and NOx changes caused by human activities. Due to the lockdown policies after the outbreak of COVID-19, the average O3 concentration worldwide showed an inverted U-shaped growth during the study period, increasing from 21.9 µg/m3 in 2015 to 27.3 µg/m3 in 2019, and finally decreasing to 25.9 µg/m3 in 2020. According to exposure analytical methods, approximately 6.32% of the population (31.73 million people) in the major countries analyzed reside in rapidly increasing O3 concentrations. 6.53% of the population (32.75 million people) in the major countries were exposed to a low O3 concentration growth environment. Thus, the continuous increase of O3 concentration worldwide is an important factor leading to increasing threats to human health. Further we found that mean wind speed, maximum temperature, and relative humidity are the main factors that determine the change of O3 concentration. Our research results are of great significance to the continued implementation of strict air quality policies and prevention of population hazards. However, due to data limitations, this research can only provide general trends in O3 and human health, and more detailed research will be carried out in the follow-up. Supplementary Information: The online version contains supplementary material available at 10.1007/s12403-022-00463-7.

12.
Ambio ; 51(5): 1199-1218, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34751934

RESUMO

Water is essential for human activities and economic development, and the water environment significantly influences ecological balance and global climate. China and Southeast Asia are the most populous areas in the world, and their water resources are deteriorating day by day. We focus on five representative cities such as, Beijing, Jakarta, Hanoi, Kathmandu and Manila to investigate water-environmental problems with the ultimate goal of providing recommendations for sustainable urban water management. The study found that (1) the water environment of all cities has been polluted to varying levels, while the pollution has improved in Beijing and Jakarta, and the situation in other regions is severe. (2) The aquatic biodiversity has reduced, and its pollution is mainly caused by organic pollutants and decreasing river flow. In addition, numerous people live in megacities without access to clean surface water or piped drinking water, which greatly increases the use of groundwater. Further, frequent floods in the world leads to serious damage to urban infrastructure and further deterioration of water environment quality. To address these problems, countries and organizations have begun to construct wastewater treatment plants and develop water-saving technology to ensure healthy and sustainable development of water environment. The results and practical recommendations of this study can provide scientific insights for future research and management strategies to address water quality challenges during ongoing policy debates and decision-making processes.


Assuntos
Qualidade da Água , Recursos Hídricos , China , Cidades , Humanos , Filipinas , Abastecimento de Água
13.
Front Cardiovasc Med ; 8: 710500, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458337

RESUMO

Background: The recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines redefined blood pressure levels 130-139/80-89 mmHg as stage 1 hypertension. However, the association of stage 1 hypertension with cardiovascular disease (CVD) and its age-specific differences among the rural women in Liaoning province remains unclear. It needs to be quantified in considering guideline adoption in China. Methods: In total, 19,374 women aged ≥35 years with complete data and no cardiovascular disease at baseline were followed in a rural community-based prospective cohort study of Liaoning province, China. Follow-up for the new cases of CVD was conducted from the end of the baseline survey to the end of the third follow-up survey (January 1, 2008-December 31, 2017). Adjusted Cox proportional hazards models were applied to estimate the Hazard Ratios (HR) and 95% Confidence Intervals (CI) with the normal blood pressure as a reference. Results: During the median follow-up period of 12.5 years, 1,419 subjects suffered all-cause death, 748 developed CVD, 1,224 participants suffered stroke and 241 had Myocardial Infarction (MI). Compared with normal BP, Stage 1 hypertension had a HR (95% CI) of 1.694 (1.202-2.387) in CVD mortality, 1.575 (1.244-1.994) in the incidence of stroke. The results obtained that the risk of CVD mortality and incidence of stroke was significantly associated with stage 1 hypertension in rural women aged ≥45 years after adjusting for other potential factors. However, in participants aged 35-44 years, stage 1 hypertension was not associated with an increased risk of cardiovascular disease. Conclusions: The newly defined stage 1 hypertension is associated with an increased risk of CVD mortality and also incidence of stroke in the rural women aged ≥45 years population of Liaoning province. This study can be a good reference for health policy makers and clinicians workers to make evidence-based decisions toward lowering burden of cardiovascular disease more efficient, timely measures on prevention and control of stage 1 hypertension in China.

14.
Cell Death Dis ; 12(7): 670, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34218256

RESUMO

Breast cancer is the major cause of cancer death worldwide in women. Patients with metastasis have poor prognosis and the mechanisms of breast cancer metastasis are not completely understood. Long non-coding RNAs (lncRNAs) have been shown to have crucial roles in breast cancer development and progression. However, the underlying mechanisms by which lncRNA-driven breast cancer metastasis are unknown. The main objective of this paper is to explore a functional lncRNA and its mechanisms in breast cancer. Here we identified a novel lncRNA AC073352.1 that was significantly upregulated in breast cancer tissues and was associated with advanced TNM stages and poor prognosis in breast cancer patients. In addition, AC073352.1 was found to promote the migration and invasion of breast cancer cells in vitro and enhance breast cancer metastasis in vivo. Mechanistically, we elucidated that AC073352.1 interacted with YBX1 and stabilized its protein expression. Knock down of YBX1 reduced breast cancer cell migration and invasion and could partially reverse the stimulative effects of AC073352.1 overexpressed on breast cancer metastasis. Moreover, AC073352.1 might be packaged into exosomes by binding to YBX1 in breast cancer cells resulting in angiogenesis. Collectively, our results demonstrated that AC073352.1 promoted breast cancer metastasis and angiogenesis via binding YBX1, and it could serve as a promising, novel biomarker for prognosis and a therapeutic target in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular , Neovascularização Patológica , RNA Longo não Codificante/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Células MCF-7 , Invasividade Neoplásica , Metástase Neoplásica , RNA Longo não Codificante/genética , Transdução de Sinais , Proteína 1 de Ligação a Y-Box/genética
15.
Sci Rep ; 11(1): 15032, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294830

RESUMO

Extreme precipitation events exhibit an increasing trend for both the frequency and magnitude on global and regional scales and it has already proven the impact of man-made global warming on the extreme precipitation amplification. Based on the observed datasets and global climate model (GCM) output, this study has evaluated the impact from anthropogenic forcing on the trend and temporal non-uniformity (i.e. increase in unevenness or disparity) of the precipitation amounts (PRCPTOT), extremes (R95p and RX5day) and intensity (SDII) in Central Asia (CA) from 1961 to 2005. Results indicate that radiative forcing changes, mainly driven by human activities, have significantly augmented the extreme precipitation indices in CA. The median trend with the influence of anthropogenic activities for the PRCPTOT, SDII, R95p and RX5day amounted to 2.19 mm/decade, 0.019 mm/decade, 1.39 mm/decade and 0.21 mm/decade during the study period, respectively. A statistically insignificant decrease in non-uniformity was noticed for the PRCPTOT, SDII and RX5day in Central CA (CCA) and Western CA (WCA), while Eastern CA (ECA) was the only region with a statistically significant increase in non-uniformity of the PRCPTOT, SDII, R95p and RX5day by 4.22%, 3.98%, 3.73% and 3.97%, respectively from 1961 to 2005 due to anthropogenic forcing. These results reflect the difference in various regions regarding the impact of anthropogenic forcing on the non-uniformity of extreme precipitation events in CA, which might help to fully understand the role of anthropogenic forcing in the changes of the precipitation extremes in CA and contribute to the development of water resource management strategies.

16.
Sci Total Environ ; 784: 147193, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-33905922

RESUMO

A systematic understanding of the dynamics of surface water resources and terrestrial water storage (TWS) is extremely important for human survival in Central Asia (CA) and maintaining the balance of regional ecosystems. Although several remote sensing products have been used to map surface water, the spatial resolution of some of them (hundreds of meters) is not sufficient to identify small surface water bodies, with monitoring data only being available for a few years or less. Thus, long-term continuous monitoring of surface water dynamics has not yet been achieved. To address this, we used all available Landsat images and the adjacent-years interpolation method to describe the dynamics of surface water in CA with a 30-m spatial resolution during 1990-2019. Subsequently, based on the multiple stepwise regression model, the climatic changes and human activity drivers affecting the surface water were systematically assessed. The permanent surface water areas (PSWA) of downstream countries with water scarcity decreased over time. The PSWA of Kazakhstan continues to decline at a maximum rate of 1189 km2/a. Additionally, human activities represented by population and reservoir areas are the dominant drivers affecting surface water resources in CA. The relationship between TWS and PSWA in CA and the constraints on social and economic development provided by the available water resources are discussed. The findings demonstrate that more than one-third of the croplands in CA are suffering from declining SWAs and TWS. The water crisis in CA has intensified, and the spatial mismatch between water and land resources is expected to remain one of the biggest challenges for future social and economic development in CA. Our dataset and findings provide high-precision surface water dynamics data that could be valuable for mitigating the water crisis in CA and provide a current scientific reference for achieving the United Nations' Sustainable Development Goals.

17.
Biotechnol Prog ; 37(4): e3158, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33891804

RESUMO

Site specific integration (SSI) expression systems offer robust means of generating highly productive and stable cell lines for traditional monoclonal antibodies. As complex modalities such as antibody-like molecules comprised of greater than two peptides become more prevalent, greater emphasis needs to be placed on the ability to produce appreciable quantities of the correct product of interest (POI). The ability to screen several transcript stoichiometries could play a large role in ensuring high amounts of the correct POI. Here we illustrate implementation of an SSI expression system with a single site of integration for development and production of a multi-chain, bi-specific molecule. A SSI vector with a single copy of all of the genes of interest was initially selected for stable Chinese hamster ovary transfection. While the resulting transfection pools generated low levels of the desired heterodimer, utilizing an intensive clone screen strategy, we were able to identify clones having significantly higher levels of POI. In-depth genotypic characterization of clones having the desirable phenotype revealed that a duplication of the light chain within the landing pad was responsible for producing the intended molecule. Retrospective transfection pool analysis using a vector configuration mimicking the transgene configuration found in the clones, as well as other vector configurations, yielded more favorable results with respect to % POI. Overall, the study demonstrated that despite the theoretical static nature of the SSI expression system, enough heterogeneity existed to yield clones having significantly different transgene phenotypes/genotypes and support production of a complex multi-chain molecule.


Assuntos
Cricetulus , Animais , Células CHO , Cricetinae , Proteínas Recombinantes/genética , Estudos Retrospectivos , Transfecção , Transgenes
18.
MAbs ; 13(1): 1850395, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33459147

RESUMO

We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.


Assuntos
Anticorpos Biespecíficos/imunologia , Complexo CD3/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Enterotoxina/imunologia , Animais , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Hibridomas , Macaca fascicularis/imunologia , Macaca fascicularis/metabolismo , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Neoplasias/metabolismo , Engenharia de Proteínas/métodos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacocinética , Anticorpos de Cadeia Única/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/metabolismo
19.
Eur Radiol ; 31(2): 1140-1150, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32856164

RESUMO

OBJECTIVES: This study was conducted to establish and validate a non-contrast T1 map-based radiomic nomogram for predicting major adverse cardiac events (MACEs) in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). METHODS: This retrospective study included 157 consecutive patients (training sets, 109 patients; test sets, 48 patients) with acute STEMI undergoing PCI. An open-source radiomics software was used to segment the myocardium on the non-contrast T1 mapping and extract features. A radiomic signature was constructed to predict MACEs using the least absolute shrinkage and selection operator method. The performance of the radiomic nomogram for predicting MACEs in both the training and test sets was evaluated by its discrimination, calibration, and clinical usefulness. RESULTS: The radiomic signature showed a good prognostic ability in the training sets with an AUC of 0.94 (95% CI, 0.86 to 1.00) and F1 score of 0.71, which was confirmed in the test sets with an AUC of 0.90 (95% CI, 0.74 to 1.00) and F1 score of 0.62. The nomogram consisting of the radiomic scores and cardiac troponin I showed good discrimination ability in the training and test sets with AUCs of 0.96 (95% CI, 0.91 to 1.00; F1 score, 0.71) and 0.94 (95% CI, 0.83 to 1.00; F1 score, 0.70), respectively. CONCLUSIONS: The non-contrast T1 map-based radiomic nomogram is a useful tool for the prediction of MACEs in patients with acute STEMI undergoing PCI that can assist clinicians for optimised risk stratification of individual patients. KEY POINTS: • Radiomic signature improved MACE prediction in acute STEMI patients. • T1 mapping-derived radiomic signature outperformed conventional cardiac MRI parameters in predicting MACEs in acute STEMI patients. • The non-contrast T1 mapping-based radiomic nomogram can be used for prediction of MACEs and improvement of risk stratification in acute STEMI.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Imageamento por Ressonância Magnética , Nomogramas , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia
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