Abstract
Tumors invade the surrounding tissues to progress, but the heterogeneity of cell types at the tumor-stroma interface and the complexity of their potential interactions hampered mechanistic ...insight required for efficient therapeutic targeting. Here, combining single-cell and spatial transcriptomics on human basal cell carcinomas, we define the cellular contributors of tumor progression. In the invasive niche, tumor cells exhibit a collective migration phenotype, characterized by the expression of cell-cell junction complexes. In physical proximity, we identify cancer-associated fibroblasts with extracellular matrix-remodeling features. Tumor cells strongly express the cytokine Activin A, and increased Activin A-induced gene signature is found in adjacent cancer-associated fibroblast subpopulations. Altogether, our data identify the cell populations and their transcriptional reprogramming contributing to the spatial organization of the basal cell carcinoma invasive niche. They also demonstrate the power of integrated spatial and single-cell multi-omics to decipher cancer-specific invasive properties and develop targeted therapies.
Prostate cancer (PCa) represents a major cause of cancer mortality among men in developed countries. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor ...eventually progresses into castration-resistant PCa; in this condition, tumor cells acquire the ability to escape cell death and develop resistance to current therapies. Thus, new therapeutic approaches for PCa management are urgently needed. In this setting, natural products have been extensively studied for their anti-PCa activities, such as tumor growth suppression, cell death induction, and inhibition of metastasis and angiogenesis. Additionally, numerous studies have shown that phytochemicals can specifically target the androgen receptor (AR) signaling, as well as the PCa stem cells (PCSCs). Interestingly, many clinical trials have been conducted to test the efficacy of nutraceuticals in human subjects, and they have partially confirmed the promising results obtained in vitro and in preclinical models. This article summarizes the anti-cancer mechanisms and therapeutic potentials of different natural compounds in the context of PCa prevention and treatment.
The aim of this paper is to study the relationship between military spending and sovereign debt in a panel of 13 European countries. In particular, under the assumption of the interdependence of ...military spending between US and European countries, we analyse whether US military spending affected European sovereign debt in the period 1988-2013. The empirical estimation is based on different steps: (i) a unit root test; (ii) an Arellano-Bond panel estimation and a linear fixed effect model; and (iii) a FMOLS estimation to highlight the long run relationship between debt and relevant variables. General results highlight that debt burden of European countries is: (1) positively associated with US military burden and (2) negatively associated with average military burden of other European countries.
On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by ...the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only low-level production of IFN-α. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, was independent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7 triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response.
The positive clinical threshold of human papillomavirus (HPV) tests validated for primary cervical cancer screening (CCS) is designed to offer an optimal balance between clinical sensitivity and ...specificity. However, there may be a gap between the analytical sensitivity of the test and the positive clinical threshold, referred to here as the “gray‐zone.” This study aims to determine the prevalence and significance of HPV results obtained in the gray‐zone in routine practice. Cervical samples obtained in our institution for CCS over a 22‐month‐period were tested with the Alinity m HR‐HPV Assay (Abbott). Clinical and biological data, including cytological results and patients' HPV history were collected. Of the 6101 samples collected, 1.7% had an HPV result in the gray‐zone (102 patients). The proportion of gray‐zone results varied according to HPV genotype, reaching 11.8% of samples with detectable HPV DNA in the case of HPV31/33/52/58 genotypes. Reflex cytologies showed no abnormalities or Atypical Squamous Cells of Undetermined Significance results in 74.6% and 17.9% of cases, respectively. A previous or subsequent HPV‐positive result with a (possibly) identical genotype was observed in 58% and 38% of cases, respectively. Two women with a history of persistent HPV detection had a CIN2+ lesion 1 year after the gray‐zone result. In conclusion, the proportion of HPV results in the gray‐zone varies according to genotype. No cytological abnormality is observed in the majority of cases, but a few rare patients with a history of persistent HPV infection should be closely monitored even if the HPV result is transiently located in the gray‐zone.
Cation exchange is an increasingly common pathway for nanoparticle synthesis, as it modifies the composition in a controllable way while maintaining other key features, including crystal structure ...and morphology. However, cation exchange pathways can compete with other nanoparticle formation pathways, depending on the system and reaction conditions. Simple strategies for monitoring such reactions can therefore be informative. Here, we use benchtop light scattering with a laser pointer as a simple tool to monitor putative cation exchange reactions and to help differentiate, in real time, between pathways that involve cation exchange versus pathways that involve dissolution and reprecipitation. We use the transformation of digenite copper sulfide into manganese sulfide as a model system. When a laser pointer shines through the reaction flask as digenite copper sulfide nanoparticles react with Mn2+ at 100 °C, light scattering is observed continuously, indicating that nanoparticles are present during the entire reaction as would be required for a cation exchange pathway. At higher temperatures, light scattering disappears and then reappears, indicating that nanoparticles are not always present and that a different pathway involving dissolution and reprecipitation is operable. Using this approach, along with additional control experiments, we were able to identify the threshold temperature below which zincblende MnS, a metastable polymorph, forms through a cation exchange pathway. We were also able to establish that at higher temperatures, the thermodynamically favored product, rocksalt MnS, forms through a dissolution/reprecipitation pathway. These results provide useful insights into the temperature dependence of a model cation exchange reaction and suggest that light scattering could provide high-level insights, in real time on the benchtop, into nanoparticle reaction pathways that involve postsynthetic modifications where multiple competing pathways could be possible.
•In the presence of an armed conflict a reduction in the size of SWFs is between 25 % and 37 %.•There is a positive association between MSCI World Index and the size of SWFs.•There is positive ...association between the GDP of the originating country and the size of SWFs.•The higher is the global integration of the originating country, the larger is the size of the SWFs.
The objective of this study is to explicate the determinants that influence the size of Sovereign Wealth Funds (SWFs), with a particular focus on investigating the consequences arising from a country's engagement in a conflict. We exploit a panel of 28 SWFs for the period 2008–2018. In fact, of particular interest is the inverse correlation estimated between the size of SWFs and the participation of the originating country in armed conflicts. The quantitative reduction in the size of SWFs in the presence of an armed conflict has been estimated to range between 25 % and 37 %. One general finding is that the impact of financial market dynamics on the size of SWFs, while of comparable magnitude to the influence of the domestic economy, exhibits a greater degree of stability.
•A method for mapping energy/resource flows of manufacturing systems is proposed.•Key performance indicators highlighting the inefficiencies are developed.•The method supports defining corrective ...actions to improve production efficiency.•Case study results show a significant saving of energy and resources.
The assessment and monitoring of energy and resource efficiency is an essential activity toward the implementation of sustainable manufacturing practices. Existing energy/resource assessment methods and tools are not based on a comprehensive approach, lack on the use of specific key performance indicators, are dedicated to expert stakeholders and do not provide useful suggestions for improving production systems. This paper proposes an innovative method, called Resources Value Mapping that aims to map and classify activities and related energy/resource consumptions according to lean philosophy principles (value-added, non value-added, waste). A user-friendly map and two efficiency indicators (Cost Index and Muda Index) are proposed to quantitatively support the identification of criticalities related to activities, processes, lines, plants, etc., and to successively guide the decision-making process during the improvement strategies implementation. The method has been used to analyze a manufacturing plant that produces cooking appliances. The case study demonstrated the applicability of the method in real industrial contexts and its effectiveness in identifying the energy/resource flows (electricity and compressed air), departments (sheet department) and lines (mechanical and hydraulic presses) for which the waste and non value-added consumptions are prominent. The analysis highlighted that less of 20% of the resources consumed during the process creates value, offering wide margins for improvement. Finally, it aided the definition of an action plan leading to relevant reduction of resource consumptions, economic savings and environmental benefits.
The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, ...IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2
fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2
fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2
myeloid cells, CCR7
LAMP3
dendritic cells, and CXCR4 expressed on both CD8
Tc17 cells and keratinocytes, respectively. The SFRP2
fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.
5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that regulates cellular energy homeostasis, glucose, fatty acid uptake, and oxidation at low cellular ATP levels. AMPK ...plays an important role in several molecular mechanisms and physiological conditions. It has been shown that AMPK can be dysregulated in different chronic diseases, such as inflammation, diabetes, obesity, and cancer. Due to its fundamental role in physiological and pathological cellular processes, AMPK is considered one of the most important targets for treating different diseases. Over decades, different AMPK targeting compounds have been discovered, starting from those that activate AMPK indirectly by altering intracellular AMP:ATP ratio to compounds that activate AMPK directly by binding to its activation sites. However, indirect altering of intracellular AMP:ATP ratio influences different cellular processes and induces side effects. Direct AMPK activators showed more promising results in eliminating side effects as well as the possibility to engineer drugs for specific AMPK isoforms activation. In this review, we discuss AMPK targeting drugs, especially concentrating on those compounds that activate AMPK by mimicking AMP. These compounds are poorly described in the literature and still, a lot of questions remain unanswered about the exact mechanism of AMP regulation. Future investigation of the mechanism of AMP binding will make it possible to develop new compounds that, in combination with others, can activate AMPK in a synergistic manner.
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