Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. ...Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-β (TGF-β) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8+ T cells in vitro and in vivo to enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-β neutralizing activity in vitro and sequesters plasma TGF-β in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8+ T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.
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A bifunctional fusion protein, HCW9218, was created using tissue factor-based scaffold technology. HCW9218 comprises the extracellular domains of human transforming growth factor-β receptor II and human interleukin-15 (IL-15)/IL-15 receptor α. This fusion protein represents a potent anti-cancer immunotherapeutic to simultaneously provide immune stimulation and lessen immunosuppressive activities associated with tumors.
Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells ...with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy.
The increase in the life expectancy of dogs in response to the evolution of veterinary medicine regarding the prevention and treatment of diseases is remarkable. Likewise, the rise of pathologies ...that affect animals of advanced age is evident, such as mammary neoplasms, which affect mainly females, elderly, unspayed or noncastrated after several estrous cycles, without racial predisposition. This research aims to collect data from the analysis of clinical data and histopathological reports of female dogs treated in Dourados, Mato Grosso (Brazil) with mammary tumors. In this survey, it was observed that of 15 female dogs with mammary neoplasia, 87% had malignant neoplasia while 13% had benign neoplasia. The caudal abdominal breasts (M4) were the most affected. Tumor sizes varied between one and five centimeters in diameter, with tumors measuring up to three centimeters being the most recurrent, and the only two benign tumors measuring 1.5 cm. Thus, it is concluded that the caudal abdominal breasts (M4) were the most affected with breast neoplasms, malignant neoformations are the most common and neoplasms with benign conformations have smaller sizes.
O aumento na expectativa de vida dos cães em resposta à evolução da medicina veterinária com relação à prevenção e tratamento de doenças é notável. Assim também, é evidente a ascensão de patologias que acometem animais com idade avançada, como o caso das neoplasias mamárias, que abala principalmente fêmeas, idosas, não castradas ou castradas após diversos ciclos estrais, sem predisposição racial. Esta pesquisa tem como objetivo levantar dados a partir da análise de dados clínicos e laudos histopatológicos de cadelas atendidas em Dourados, Mato Grosso com tumor mamário. Neste levantamento, observou-se que de 15 cadelas com neoplasia mamária, 87% apresentaram neoplasia maligna enquanto 13% apresentaram neoplasia benigna. As mamas abdominais caudais (M4) foram as mais acometidas. Os tamanhos tumorais variaram entre um e cinco centímetro de diâmetro, sendo que os tumores com tamanho de até três centímetros foram os mais recorrentes. Os dois únicos tumores benignos mediram 1,5 cm. Contudo, conclui-se que as mamas abdominais caudais (M4) foram as mais acometidas com neoplasias mamárias. Neoformações malignas são as mais comuns e neoplasias com conformações benignas possuem tamanhos menores.
The purpose of the Internet of Things (IoT), is to make permanent and inclusive the access and interaction with a great variety of devices connected to Internet: the network of networks. The Internet ...of Things has a lot of applications as for example those for household, vigilance, sensor monitoring, actuators, intelligent displays, vehicles, among others. This in turn allows for the potential development of a large number of applications consuming information coming from these connected objects, which in turn are capable to provide new services to the citizens, enterprises and the public administration. The purpose of this research work is the development of an architecture based on the internet of things (IoT) that allows the use of sensors with the capacity to collect information related to environmental variables and additionally permitting the easy integration with any other types of sensors associated with measurements for a smart city environment, with the aim of providing data on which the conditions of the different environments of a smart city can be determined. Using this information as a tool we intend to improve the process in decision making, starting with the improvements in city design to the increase and improvement of commodities for the city inhabitants.
El artículo tiene el objetivo de ofrecer a los estudiantes de sociología elementos gnoseológicos y didácticos de la sociología de la cultura como una disciplina dinámica y relevante para el estudio ...de fenómenos sociales contemporáneos y se enfatiza en la importancia de los análisis de la producción, reproducción y transformación de la cultura en diferentes contextos sociales. Se sugieren diversas estrategias metodológicas para su enseñanza y sus correlatos con los escenarios desde donde se realizan las indagaciones. Se destaca la importancia de utilizar ejemplos concretos y actuales que se vinculen con la experiencia de los estudiantes y la necesidad de presentar la disciplina de manera relevante y actualizada para fomentar su participación activa para el desarrollo de habilidades analíticas y de investigación. Se busca promover una comprensión más profunda de la cultura y su influencia en la sociedad, preparando a los estudiantes para enfrentar los desafíos sociales y culturales de su entorno.
This study aims to estimate the average annual rate of soil loss by rainfall in terms of spatial distribution and sediment rate using RUSLE and GIS techniques. Additionally, remote sensing and ...available soil property information are applied for erosion analysis. The work reveals a very severe type of soil erosion, with the highest mean rate in the steep areas. Annual mean erosion in many parts of the basin is in the range of 0 to 9237.0 t/km2/year with an average of 403 t/km2/year. Approximately 45% (in the upper basin) of the total area has moderate to high soil loss by water, especially in five catchments, namely Serranoyacu, Naranjos, Naranjillo, Yuracyacu, and Tonchima at 886.8 t/km2/yr, 985.1 t/km2/yr, 691.3 t/km2/yr, 567.3 t/km2/yr, and 506.9 t/km2/yr, respectively. Catchment-wise soil loss estimates suggest that these areas are experiencing much higher soil loss in comparison to others; hence, these catchments are prioritized for soil conservation efforts. Sediment rate assessments indicate high sediment deposition along the flow direction of the mainstream of the catchment; in the upper Mayo part, the highest sediment rates are in Yuracyacu, Serranoyacu and Tonchima. Finally, the parts most vulnerable to increased erosion rate are the central part of the basin, which indicates progressive sediment deposition.
Air pollution has many adverse effects on health and is associated with an increased risk of mortality. Desert dust outbreaks contribute directly to air pollution by increasing particulate matter ...concentrations. We investigated the influence of desert dust outbreaks on air quality in Santa Cruz de Tenerife, a city located in the dust export pathway off the west coast of North Africa, using air-quality observations from a six-year period (2012–2017). During winter intense dust outbreaks PM 10 mean (24-h) concentrations increased from 14 μ g m − 3 to 98 μ g m − 3 , on average, and PM 2 . 5 mean (24-h) concentrations increased from 6 μ g m − 3 to 32 μ g m − 3 . Increases were less during summer outbreaks, with a tripling of PM 10 and PM 2 . 5 daily mean concentrations. We found that desert dust outbreaks reduced the height of the marine boundary layer in our study area by >45%, on average, in summer and by ∼25%, on average, in winter. This thinning of the marine boundary layer was associated with an increase of local anthropogenic pollution during dust outbreaks. NO 2 and NO mean concentrations more than doubled and even larger relative increases in black carbon were observed during the more intense summer dust outbreaks; increases also occurred during the winter outbreaks but were less than in summer. This has public health implications; local anthropogenic emissions need to be reduced even further in areas that are impacted by desert dust outbreaks to reduce adverse health effects.
Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the ...growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-β (TGF-β) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.
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An immunotherapeutic molecule, HCW9218, demonstrated anti-tumor efficacy by eliminating chemotherapy-induced senescent cells and reducing the off-target effects mediated by chemotherapy. HCW9218 represents a potent anti-cancer immunotherapeutic for use in combination with approved therapies to improve the health span and life span of treated patients.
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