Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK

No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21(WAF1/CIP1), leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21(WAF1/CIP1), either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21(WAF1/CIP1). Co-administration of BI-2536 and fasudil either in the LSL-KRAS(G12D) mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers

Análisis discursivo del marketing de microfilms en las redes sociales – tomando el caso de Proya como ejemplo

Treball de fi de màster en Discurs. Director: Dr. Teun A. van DijkEl marketing de microfilms es una forma de marketing muy popular en las redes sociales en los últimos años. Tiene un impacto positivo en la construcción de una imagen de marca y la evocación de conexión emocional entre la marca y el público. Sin embargo, la investigación académica previa en este ámbito ha tendido a ser vaga y dispersa, sin centrarse en prácticas de marketing específicas para un análisis en profundidad. Por lo tanto, este artículo utilizará como corpus el microfilm de marketing de Proya publicado en Weibo en el Día Internacional de la Mujer de 2021 a 2023, teniendo en cuenta el contexto social y los hallazgos de estudiosos anteriores, para analizar tres aspectos específicos del efecto de celebridad, el transporte narrativo y el marketing emocional desde una perspectiva discursiva, con el objetivo de obtener una comprensión más profunda y específica de cómo actúan estos factores que presentan en los microfilms y que influyen en la relación entre consumidores y marcas. Este trabajo está divido en cinco partes. La primera parte es la preparación antes de escribir el ensayo. Se divide en dos secciones principales. Una es un análisis del estado actual de la investigación previa sobre este tema, que aboga por la originalidad y solidez del ensayo. Y otra es el análisis de los antecedentes, que se centra en dos aspectos: el contexto social y las teorías relacionadas con el marketing de microfilms. La segunda parte se centra en el impacto del efecto de celebridad en este enfoque de marketing. La tercera parte se centra en el transporte narrativo, explorando su impacto en la audiencia a través de los factores de la autenticidad, la brevedad, la inversión, el humor y la popularidad de los contenidos. La cuarta parte examina la mecánica del marketing emocional. El análisis gira en torno a la participación de la audiencia, la representación de emociones, la emoción del apego y el llamamiento a la igualdad de género en los microfilms. La última parte examina las diferencias entre el marketing de Proya y el de otras marcas, en un intento de descubrir las características únicas de las prácticas de éxito de la marca

Enhanced oil recovery after polymer flooding by wettability alteration to gas wetness using numerical simulation

Polymer flooding, as one of the Enhanced Oil Recovery (EOR) methods, has been adopted in many oilfields in China and some other countries. Over 50% oil remains undeveloped in many oil reservoirs after polymer flooding. It has been a great challenge to find approaches to further enhancing oil recovery when polymer flooding is over. In this study, a new method was proposed to increase oil production using gas flooding with wettability alteration to gas wetness when polymer flooding has been completed. The rock wettability was altered from liquid- to gas-wetness during gas flooding. An artificial oil reservoir was constructed and many numerical simulations have been conducted to test the effect of wettability alteration on the oil recovery in reservoirs developed by water flooding and followed by polymer flooding. Production data from different scenarios, water flooding, polymer flooding after water flooding, gas flooding with and without wettability alteration after polymer flooding, were calculated using numerical simulation. The results demonstrate that the wettability alteration to gas wetness after polymer flooding can significantly enhance oil recovery and reduce water cut effectively. Also studied were the combined effects of wettability alteration and reservoir permeability on oil recovery

PEG-PDLLA micelle treatment improves axonal function of the corpus callosum following traumatic brain injury

The initial pathological changes of diffuse axonal injury following traumatic brain injury (TBI) include membrane disruption and loss of ionic homeostasis, which further lead to dysfunction of axonal conduction and axon disconnection. Resealing the axolemma is therefore a potential therapeutic strategy for the early treatment of TBI. Monomethoxy poly (ethylene glycol)-poly (D, L-lactic acid) di-block copolymer micelles (mPEG-PDLLA) have been shown to restore depressed compound action potentials (CAPs) of spinal axons and promote functional recovery after spinal cord injury. Here, we evaluate the effect of the micelles on repairing the injured cortical axons following TBI. Adult mice subjected to controlled cortical impact (CCI) were treated with intravenous injection of the micelles at 0 h or 4 h after injury. Evoked CAPs were recorded from the corpus callosum of coronal cortical slices at 2 days after injury. The CCI caused significant decreases in the amplitudes of two CAP peaks that were respectively generated by the faster myelinated axons and slower unmyelinated axons. Micelle treatment at both 0 h and 4 h after CCI resulted in significant increases in both CAP peak amplitudes. Injection of fluorescent dye-labeled micelles revealed high fluorescent staining in cortical gray and white matters underneath the impact site. Labeling membrane-perforated neurons by injecting a membrane impermeable dye Texas Red-labeled dextran into lateral ventricles at 2 h post-CCI revealed that immediate micelle injection after CCI did not reduce the number of dye-stained cortical neurons and dentate granule cells of the hippocampus, indicating its ineffectiveness in repairing plasma membrane of neuronal somata. We conclude that intravenous administration of mPEG-PDLLA micelles immediately or at 4 h after TBI allows brain penetration via the compromised blood brain-barrier, and thereby improves the function of both myelinated and unmyelinated axons of the corpus callosum

Colorimetric Integrated PCR Protocol for Rapid Detection of Vibrio parahaemolyticus

Rapid detection of pathogens is of great significance for food safety and disease diagnosis. A new colorimetric method for rapid and easy detection of Vibrio parahaemolyticus (V. parahaemolyticus or Vp) has been developed in this research. A specific sequence was designed and integrated with the forward primer for molecular detection of Vp. This specific sequence was tested and treated as the horseradish peroxidase (HRP)-mimicking DNAzyme and could be amplified during the polymerase chain reaction (PCR) process. The products of PCR including the sequence of HRP-mimicking DNAzyme could produce the distinguished color in the presence of catalysis substrates. The optical signal of the catalysis reaction, which is in a linear relationship with the initial template of Vp, could be determined with the naked eye or measured with Ultraviolet-visible (UV-vis) for qualitative and quantitative detections, respectively. Based on the optical signal intensity, rapid and easy detection of Vp was successfully achieved with satisfied sensitivity and specificity. Furthermore, the detection of tdh, trh, tlh and toxR virulence genes of two Vp species (Vp 33847 and Vp 17802) were all performed successfully with this developed colorimetric integrated PCR protocol, which demonstrated potential applicability for the rapid detection of other bacteria

Efficacy of sequential three-step empirical therapy for chronic cough

Background: Empirical three-step therapy has been proved in just one hospital. This study aimed to demonstrate applicability of the sequential empirical three-step therapy for chronic cough in different clinical settings. Methods: Sequential empirical three-step therapy was given to patients with chronic cough in one tertiary and three secondary care respiratory clinics. Recruiters were initially treated with methoxyphenamine compound as the first-step therapy, followed by corticosteroids as the second-step therapy and the combination of a proton-pump inhibitor and a prokinetic agent as the third-step therapy. The efficacy of the therapy was verified according to the changes in cough symptom score between pre- and post-treatment, and compared among the different clinics. Results: In total 155 patients in one tertiary clinic and 193 patients in secondary care clinics were recruited. The total dropout ratio is significantly higher in the secondary care clinics than that in the tertiary clinic (9.3% versus 3.2%, p = 0.023). The therapeutic success rate for cough was 38.7% at first-step therapy, 32.3% at second-step therapy and 20.0% at third-step therapy in the tertiary clinic, and comparable to corresponding 49.7%, 31.1% and 4.1% in secondary care clinics. Furthermore, the overall cough resolution rate was not significantly different (91.0% versus 85.0%, p = 0.091). However, the efficacy of the third-step therapy is much higher (20.0% versus 4.1%, p = 0.001) in the tertiary clinic than in the secondary care clinics. Conclusions: Sequential empirical three-step therapy is universally efficacious and useful for management of chronic cough in different clinical settings

Necrostatin-1 promotes ectopic periodontal tissue like structure regeneration in LPS-treated PDLSCs.

Necroptosis is a programmed necrosis, regulated by receptor interacting protein kinase 1(RIP1) and receptor interacting protein kinase 3(RIP3), and could be inhibited by necrostatin-1(Nec-1) specifically. This study aims to evaluate the effect of Nec-1 on LPS-treated periodontal ligament stem cells (PDLSCs). In the research, three groups were established: normal cultured PDLSCs, Porphyromonas gingivalis (Pg)-LPS stimulated PDLSCs and Pg-LPS+Nec-1 treated PDLSCs. The expression of RIP1 and RIP3 and osteogenic differentiation of PDLSCs in three groups were analyzed. Then, we constructed cell aggregates (CA) using PDLSCs, then PDLSCs-CA were combined with Bio-Oss in three groups were transplanted subcutaneously in nude mice to assess their potentials of periodontal tissue regeneration. The results showed that RIP1 and RIP3 were fully expressed in Pg-LPS stimulated PDLSCs and the level increased significantly. Nec-1 inhibited RIP1-RIP3 interaction, and further inhibited necroptosis of PDLSCs in inflammatory state. Moreover, Nec-1 pretreatment ameliorates the osteogenic differentiation of LPS-treated PDLSCs and can effectively promote the cementum like structure ectopic regenerative ability of PDLSCs in nude mice. These findings show RIP1/RIP3-mediated necroptosis is an important mechanism of cell death in PDLSCs. Nec-1 has a protective effect in reducing cell death and promotes ectopic periodontal tissue like structure regeneration by inhibiting necroptosis. Nec-1 is a hopeful therapeutic agent which protects cells from necroptosis and ameliorates functional outcome