Bewertung der Kombinationsbehandlung Docetaxel und JQ1 in präklinischen 2D- und 3D-Modellen von Prostatakrebs

Prostate cancer (PCa) remains the most prevalent cancer in men globally, with an increasing burden worldwide. PCa is unique in its dependence on androgen-androgen receptor (AR) signaling for growth and progression, and hormonal therapies have greatly improved the survival of patients with metastatic prostate cancer (mPCa). However, almost all patients with mPCa are resistant to hormonal treatments and ultimately succumb to metastatic castration-resistant prostate cancer (mCRPC), even when new hormonal agents deplete serum androgen levels. Therefore, novel non-AR dependent therapeutic strategies should be explored. JQ1, a potent and selective Bromodomain and extra terminal domain (BET) inhibitor, is a potentially potent therapy for patients with mCRPC. Compared to new hormonal agents, JQ1 more potently abrogates BRD4 localization to the AR target loci and AR-mediated gene transcription. However, a recent study showed that JQ1 promotes PCa invasion and metastasis in a BET protein-independent manner when PCa cell growth is inhibited. Therefore, combination strategies with JQ1 might be more promising than JQ1 alone. This study shows that JQ1 and docetaxel might serve as an effective combination therapy for patients with mPCa. We assessed the combination therapy in 2D and 3D preclinical models, and we also evaluated the susceptibility of 2D-cultured LNCaP cells and 3D-cultured LNCaP cells/spheroids exposed to the same anti-cancer drug. In contrast to 2D LNCaP cells, the evaluation of LNCaP spheroids’ susceptibility was more complicated. The IC50 curves were not suitable for evaluating the susceptibility to drugs. Specifically for big-sized LNCaP spheroids, a low maximum inhibition and a low R-squared value were observed. Our results identified the different fitness of IC50 curves for 2D and 3D preclinical models and supported a potential combination treatment (docetaxel and JQ1) for PCa patients.Prostatakrebs (PCa) ist nach wie vor die häufigste Krebserkrankung bei Männern weltweit und nimmt weltweit zunehmend zu. PCa ist einzigartig in seiner Abhängigkeit vom Androgen-Androgen-Rezeptor (AR) -Signal für Wachstum und Progression, und Hormontherapien haben das Überleben von Patienten mit metastasiertem Prostatakrebs (mPCa) erheblich verbessert. Fast alle Patienten mit mPCa sind jedoch gegen hormonelle Behandlungen resistent und erliegen letztendlich metastasiertem kastrationsresistentem Prostatakrebs (mCRPC), selbst wenn neue hormonelle Wirkstoffe den Androgenspiegel im Serum senken. Daher sollten neuartige nicht AR-abhängige Therapiestrategien untersucht werden. JQ1, ein wirksamer und selektiver Bromodomänen- und extra terminaler (BET) Bromodomänenhemmer, ist eine potenziell wirksame Therapie für Patienten mit mCRPC. Im Vergleich zu neuen hormonellen Wirkstoffen hebt JQ1 die BRD4-Lokalisierung an den AR-Zielorten und die AR-vermittelte Gentranskription stärker auf. Eine kürzlich durchgeführte Studie zeigte jedoch, dass JQ1 die PCa-Invasion und -Metastasierung auf BET-Protein-unabhängige Weise fördert, wenn das PCa-Zellwachstum gehemmt wird. Daher sind Kombinationsstrategien mit JQ1 möglicherweise vielversprechender als JQ1 allein. Diese Studie zeigt, dass JQ1 und Docetaxel als wirksame Kombinationstherapie für Patienten mit mPCa dienen können. Wir bewerteten die Kombinationstherapie in präklinischen 2D- und 3D-Modellen und bewerteten auch die Empfindlichkeit von 2D-kultivierten LNCaP-Zellen und 3D-kultivierten LNCaP-Zellen / Sphäroiden, die demselben Krebsmedikament ausgesetzt waren. Im Gegensatz zu 2D-LNCaP-Zellen war die Bewertung der Empfindlichkeit von LNCaP-Sphäroiden komplizierter. Die IC50-Kurven waren zum Teil nicht geeignet, um die Wirksamkeit von Substanzen zu bewerten. Insbesondere bei großen LNCaP-Sphäroiden beobachteten wir eine niedrige maximale Hemmung und niedrige R-Quadrat-Werte. Unsere Ergebnisse identifizierten die unterschiedliche Eignung von IC50-Kurven für präklinische 2D- und 3D-Modelle und unterstützten auch eine mögliche Kombinationsbehandlung (Docetaxel und JQ1) für PCa-Patienten

Research on the impact of asteroid mining on global equity

In the future situation, aiming to seek more resources, human beings decided to march towards the mysterious and bright starry sky, which opened the era of great interstellar exploration. According to the Outer Space Treaty, any exploration of celestial bodies should be aimed at promoting global equality and for the benefit of all nations. Firstly, we defined global equity and set a Unified Equity Index (UEI) model to measure it. We merge the factors with greater correlation, and finally, get 6 elements, and then use the entropy method (TEM) to find the dispersion of these elements in different countries. Then use principal component analysis (PCA) to reduce the dimensionality of the dispersion, and then use the scandalized index to obtain the global equity. Secondly, we simulated a future with asteroid mining and evaluated its impact on Unified Equity Index (UEI). Then, we divided the mineable asteroids into three classes with different mining difficulties and values, identified 28 mining entities including private companies, national and international organizations. We considered changes in the asteroid classes, mining capabilities and mining scales to determine the changes in the value of minerals mined between 2025 and 2085. We convert mining output value into mineral transaction value through allocation matrix. Based on grey relational analysis (GRA). Finally, we presented three possible versions of the future of asteroid mining by changing the conditions. We propose two sets of corresponding policies for changes in future trends in global fairness with asteroid mining. We test the separate and combined effects of these policies and find that they are positive, strongly supporting the effectiveness of our model.Comment: 19 page

Revive, Restore, Revitalize: An Eco-economic Methodology for Maasai Mara

The Maasai Mara in Kenya, renowned for its biodiversity, is witnessing ecosystem degradation and species endangerment due to intensified human activities. Addressing this, we introduce a dynamic system harmonizing ecological and human priorities. Our agent-based model replicates the Maasai Mara savanna ecosystem, incorporating 71 animal species, 10 human classifications, and 2 natural resource types. The model employs the metabolic rate-mass relationship for animal energy dynamics, logistic curves for animal growth, individual interactions for food web simulation, and human intervention impacts. Algorithms like fitness proportional selection and particle swarm mimic organism preferences for resources. To guide preservation activities, we formulated 21 management strategies encompassing tourism, transportation, taxation, environmental conservation, research, diplomacy, and poaching, employing a game-theoretic framework. Using the TOPSIS method, we prioritized four key developmental indicators: environmental health, research advancement, economic growth, and security. The interplay of 16 factors determines these indicators, each influenced by our policies to varying degrees. By evaluating the policies' repercussions, we aim to mitigate adverse animal-human interactions and equitably address human concerns. We classified the policy impacts into three categories: Environmental Preservation, Economic Prosperity, and Holistic Development. By applying these policy groupings to our ecosystem model, we tracked the effects on the intricate animal-human-resource dynamics. Utilizing the entropy weight method, we assessed the efficacy of these policy clusters over a decade, identifying the optimal blend emphasizing both environmental conservation and economic progression.Comment: 25 pages, 16 figure

Modeling and simulation in supersonic three-temperature carbon dioxide turbulent channel flow

This paper pioneers the direct numerical simulation (DNS) and physical analysis in supersonic three-temperature carbon dioxide (CO2) turbulent channel flow. CO2 is a linear and symmetric triatomic molecular, with the thermal non-equilibrium three-temperature effects arising from the interactions among translational, rotational and vibrational modes under room temperature. Thus, the rotational and vibrational modes of CO2 are addressed. Thermal non-equilibrium effect of CO2 has been modeled in an extended three-temperature BGK-type model, with the calibrated translational, rotational and vibrational relaxation time. To solve the extended BGK-type equation accurately and robustly, non-equilibrium high-accuracy gas-kinetic scheme is proposed within the well-established two-stage fourth-order framework. Compared with the one-temperature supersonic turbulent channel flow, supersonic three-temperature CO2 turbulence enlarges the ensemble heat transfer of the wall by approximate 20%, and slightly decreases the ensemble frictional force. The ensemble density and temperature fields are greatly affected, and there is little change in Van Driest transformation of streamwise velocity. The thermal non-equilibrium three-temperature effects of CO2 also suppress the peak of normalized root-mean-square of density and temperature, normalized turbulent intensities and Reynolds stress. The vibrational modes of CO2 behave quite differently with rotational and translational modes. Compared with the vibrational temperature fields, the rotational temperature fields have the higher similarity with translational temperature fields, especially in temperature amplitude. Current thermal non-equilibrium models, high-accuracy DNS and physical analysis in supersonic CO2 turbulent flow can act as the benchmark for the long-term applicability of compressible CO2 turbulence.Comment: Carbon dioxide flow, Vibrational modes, Three-temperature effects, Supersonic turbulent channel flow