Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics

Constitutively activated STAT3 protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study, PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low micromolar range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nmol/L by surface plasmon resonance, and showed no effect in a kinome screen (>100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized three-dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAF). In this coculture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D cocultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells

Impact of high fat diets, prebiotics and probiotics on gut microbiota and immune function, with relevance to elderly populations

According to WHO, the number of people over 60 years of age is set to rise to 2 billion by 2050. Dysbiosis of microbial composition and impaired immune function have been observed in elderly persons compared to younger adults. As a result, the aging population has a higher disease risk than other age groups. In addition, high fat intakes have been observed to exert negative effects on microbial composition and immune function in murine studies. Elderly people have higher fat intakes than recommended levels, and this may make them more vulnerable to disease risk. Therefore, the impact of high fat consumption on elderly populations may be of relevance. Prebiotics and probiotics have been shown to have positive effects on microbiota composition and immune function in the elderly. This review describes aged-related changes in gut microbiome of elderly persons. It will also summarise studies concerning the impact of prebiotics, probiotics and high fat diets on microbiota composition and immune function

Nutrition and the ageing brain: moving towards clinical applications

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3 Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required

Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response

Adipose tissue has been classified based on its morphology and function as white, brown, or beige/brite. It plays an essential role as a regulator of systemic metabolism through paracrine and endocrine signals. Recently, multiple adipocyte subtypes have been revealed using RNA sequencing technology, going beyond simply defined morphology but also by their cellular origin, adaptation to metabolic stress, and plasticity. Here, we performed an in-depth analysis of publicly available single-nuclei RNAseq from adipose tissue and utilized a workflow template to characterize adipocyte plasticity, heterogeneity, and secretome profiles. The reanalyzed dataset led to the identification of different subtypes of adipocytes including three subpopulations of thermogenic adipocytes, and provided a characterization of distinct transcriptional profiles along the adipocyte trajectory under thermogenic challenges. This study provides a useful resource for further investigations regarding mechanisms related to adipocyte plasticity and trans-differentiation

A Geant4/Garfield++ and Geant4/Degrad Interface for the Simulation of Gaseous Detectors

For several years, attempts have been made to interface Geant4 and other software packages with the aim of simulating the complete response of a gaseous particle detector. The present paper illustrates different possibilities to interface Geant4 with two such packages, Garfield++ and Degrad. The basic idea is to use the Geant4 physics parameterization feature and to implement a Garfield++ or Degrad based detector simulation as an external model. With the Geant4/Degrad interface, detailed simulations of the X-ray interaction in gaseous detectors, including shell absorption by photoelectric effect, subsequent Auger shake-off, and fluorescence emission, become possible. The Geant4/Garfield++ interface can be used for photons and charged particles of all kinetic energies. Depending on the particular physics case, either the Geant4 PAI model, the Heed PAI model or both Geant4 and Heed are responsible for primary ionization and the production of the conduction electrons. For the case in which the Geant4 PAI model is used in conjunction with the Heed PAI model, a more detailed analysis is performed. Parameters, such as the lower production cut of the PAI model and the lowest electron energy limit of the physics list have to be set correctly. The paper demonstrates how to determine these parameters with the help of the W value and Fano factor of the gas mixture. The simulation results of this Geant4/Heed PAI model interface are then verified against the results obtained with the standalone software packages

Interfacing Geant4, Garfield++ and Degrad for the Simulation of Gaseous Detectors

International audienceFor several years, attempts have been made to interface Geant4 and other software packages with the aim of simulating the complete response of a gaseous particle detector. In such a simulation, Geant4 is always responsible for the primary particle generation and the interactions that occur in the non-gaseous detector material. Garfield++ on the other hand always deals with the drift of ions and electrons, amplification via electron avalanches and finally signal generation. For the ionizing interaction of particles with the gas, different options and physics models exist. The present paper focuses on how to use Geant4, Garfield++ (including its Heed and SRIM interfaces) and Degrad to create the electron–ion pairs stemming from the ionization of the gas. Software-wise, the proposed idea is to use the Geant4 physics parameterization feature, and to implement a Garfield++ or Degrad based detector simulation as an external model. With a Degrad model, detailed simulations of the X-ray interaction in gaseous detectors, including shell absorption by photoelectric effect, subsequent Auger cascade, shake-off and fluorescence emission, become possible. A simple Garfield++ model can be used for photons (Heed), heavy ions (SRIM) and relativistic charged particles or MIPs (Heed). For non-relativistic charged particles, more effort is required, and a combined Geant4/Garfield++ model must be used. This model, the Geant4/Heed PAI model interface, uses the Geant4 PAI model in conjunction with the Heed PAI model. Parameters, such as the lower production cut of the Geant4 PAI model and the lowest electron energy limit of the physics list have to be set correctly. The paper demonstrates how to determine these parameters for certain values of the W parameter and Fano factor of the gas mixture. The simulation results of this Geant4/Heed PAI model interface are then verified against the results obtained with the stand-alone software packages

Interfacing Geant4, Garfield+ plus and Degrad for the simulation of gaseous detectors

© 2019 For several years, attempts have been made to interface Geant4 and other software packages with the aim of simulating the complete response of a gaseous particle detector. In such a simulation, Geant4 is always responsible for the primary particle generation and the interactions that occur in the non-gaseous detector material. Garfield++ on the other hand always deals with the drift of ions and electrons, amplification via electron avalanches and finally signal generation. For the ionizing interaction of particles with the gas, different options and physics models exist. The present paper focuses on how to use Geant4, Garfield++ (including its Heed and SRIM interfaces) and Degrad to create the electron–ion pairs stemming from the ionization of the gas. Software-wise, the proposed idea is to use the Geant4 physics parameterization feature, and to implement a Garfield++ or Degrad based detector simulation as an external model. With a Degrad model, detailed simulations of the X-ray interaction in gaseous detectors, including shell absorption by photoelectric effect, subsequent Auger cascade, shake-off and fluorescence emission, become possible. A simple Garfield++ model can be used for photons (Heed), heavy ions (SRIM) and relativistic charged particles or MIPs (Heed). For non-relativistic charged particles, more effort is required, and a combined Geant4/Garfield++ model must be used. This model, the Geant4/Heed PAI model interface, uses the Geant4 PAI model in conjunction with the Heed PAI model. Parameters, such as the lower production cut of the Geant4 PAI model and the lowest electron energy limit of the physics list have to be set correctly. The paper demonstrates how to determine these parameters for certain values of the W parameter and Fano factor of the gas mixture. The simulation results of this Geant4/Heed PAI model interface are then verified against the results obtained with the stand-alone software packages.keywords: Gaseous detectors, Monte-carlo simulation, Particle interactions, Software engineering, Geant4status: publishe