Calcium-binding protein S100P promotes tumor progression but enhances chemosensitivity in breast cancer

Background: Chemoresistance remains one of the obstacles to overcome in the treatment of breast cancer. S100 calcium-binding protein P (S100P) has been observed to be overexpressed in several cancers and has been associated with drug resistance, metastasis, and prognosis. However, the role of S100P in chemoresistance in breast cancer has not been thoroughly determined. Methods: Immunohistochemistry was used to evaluate the expression level of S100P protein in 22 pairs (pre-chemo and post-chemo) of breast cancer tissue from patients who underwent neoadjuvant chemotherapy. The influence of S100P on the biological behavior and chemosensitivity of breast cancer cells was then investigated. Results: The protein level of S100P in breast cancer tissue was significantly higher than in benign fibroadenoma (p<0.001). The S100P expression level was shown to be decreased by 46.55% after neoadjuvant chemotherapy (p=0.015). Subgroup analysis revealed that S100P reduction (57.58%) was mainly observed in the HER2+ tumors (p=0.027). Our in-vitro experiments showed that the knockdown of S100P suppressed the proliferation, adhesion, migration and invasion abilities of T47D and SK-BR-3 breast cancer cells. We further demonstrated that this knockdown increased the chemoresistance to paclitaxel and cisplatin in SK-BR-3 cells. We found that S100P exerted its function by activating NF-κB, CCND1 and Vimentin, but downregulating E-cadherin. Conclusions: S100P promotes the aggressive properties of breast cancer cells and may be considered as a promising therapeutic target. Moreover, S100P can be used to predict the therapeutic effect of chemotherapy in HER2+ breast cancer patients

Tim-3 promotes cell aggressiveness and paclitaxel resistance through the NF-κB /STAT3 signalling pathway in breast cancer cells

Objective: Although T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3) has been recognized as a promising target for cancer immunotherapy, its exact role in breast cancer has not been fully elucidated. Methods: Tim-3 gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells. Results: In a pooled analysis of The Cancer Genome Atlas (TCGA) database, Tim-3 gene expression levels were significantly higher (P<0.001) in breast cancer tissue, compared with normal tissues. Tim-3 was a prognosis indicator in breast cancer patients [relapse-free survival (RFS), P=0.004; overall survival (OS), P=0.099]. Tim-3 overexpression in Tim-3low breast cancer cells promoted aggressiveness of breast cancer cells, as evidenced by enhanced proliferation, migration, invasion, tight junction deterioration and tumor-associated tubal formation. Tim-3 also enhanced cellular resistance to paclitaxel. Furthermore, Tim-3 exerted its function by activating the NF-κB/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (CCND1), C-Myc, matrix metalloproteinase-1(MMP1), TWIST, vascular endothelial growth factor (VEGF) upregulation, concomitant with E-cadherin downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression. Conclusions: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy

Post-capitalist property

When writing about property and property rights in his imagined post-capitalist society of the future, Marx seemed to envisage ‘individual property’ co-existing with ‘socialized property’ in the means of production. As the social and political consequences of faltering growth and increasing inequality, debt and insecurity gradually manifest themselves, and with automation and artificial intelligence lurking in the wings, the future of capitalism, at least in its current form, looks increasingly uncertain. With this, the question of what property and property rights might look like in the future, in a potentially post-capitalist society, is becoming ever more pertinent. Is the choice simply between private property and markets, and public (state-owned) property and planning? Or can individual and social property in the (same) means of production co-exist, as Marx suggested? This paper explores ways in which they might, through an examination of the Chinese household responsibility system (HRS) and the ‘fuzzy’ and seemingly confusing regime of land ownership that it instituted. It examines the HRS against the backdrop of Marx’s ideas about property and subsequent (post-Marx) theorizing about the legal nature of property in which property has come widely to be conceptualized not as a single, unitary ‘ownership’ right to a thing (or, indeed, as the thing itself) but as a ‘bundle of rights’. The bundle-of-rights idea of property, it suggests, enables us to see not only that ‘individual’ and ‘socialized’ property’ in the (same) means of production might indeed co-exist, but that the range of institutional possibility is far greater than that between capitalism and socialism/communism as traditionally conceived

Stemazole Promotes Oligodendrocyte Precursor Cell Survival In Vitro and Remyelination In Vivo

Maintaining the normal function of oligodendrocyte precursor cells (OPCs) and protecting OPCs from damage is the basis of myelin regeneration in multiple sclerosis (MS). In this paper, we investigated the effect of stemazole, a novel small molecule, on the promotion of oligodendrocyte precursor cell survival and remyelination. The results show that stemazole enhanced the survival rate and the number of clone formation in a dose-dependent manner and decreased the percentage of cell apoptosis. In particular, the number of cell clones was increased up to 6-fold (p &lt; 0.001) in the stemazole group compared with the control group. In vivo, we assessed the effect of stemazole on recovering the motor dysfunction and demyelination induced by cuprizone (CPZ). The results show that stemazole promoted the recovery of motor dysfunction and the repair of myelin sheaths. Compared with the CPZ group, the stemazole group showed a 30.46% increase in the myelin area (p &lt; 0.001), a 37.08% increase in MBP expression (p &lt; 0.01), and a 1.66-fold increase in Olig2 expression (p &lt; 0.001). Histologically, stemazole had a better effect than the positive control drugs. In conclusion, stemazole promoted OPC survival in vitro and remyelination in vivo, suggesting that this compound may be used as a therapeutic agent against demyelinating disease

Uncovering the Pharmacological Mechanism of Stemazole in the Treatment of Neurodegenerative Diseases Based on a Network Pharmacology Approach

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer&rsquo;s disease and Parkinson&rsquo;s disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases

Glacier variations and their response to climate change in an arid inland river basin of Northwest China

Glaciers are a critical freshwater resource of river recharge in arid areas around the world. In recent decades, glaciers have shown evidence of retreat due to climate change, and the accelerated ablation of glaciers and associated impacts on water resources have received widespread attention. Glacier variations result from climate change, so they can serve as an indicator of climate change. Considering the climatic differences in different elevation ranges, it is worthwhile to explore whether different responses exist between glacier area and air temperature in each elevation zone. In this study, we selected a typical arid inland river basin (Sugan Lake Basin) in the western Qilian Mountains of Northwest China to analyze the glacier variations and their response to climate change. The glacier area data from 1989 to 2016 were delineated using Landsat Thematic Mapper (TM), Enhanced TM+ (ETM+) and Operational Land Imager (OLI) images. We compared the relationships between glacier area and air temperature at seven meteorological stations in the glacier-covered areas and in the Sugan Lake Basin, and further analyzed the relationship between glacier area and mean air temperature of the glacier surfaces in July–August in the elevation range of 4700–5500 m a.s.l. by the linear regression method and correlation analysis. In addition, based on the linear regression relationship established between glacier area and air temperature in each elevation zone, we predicted glacier areas under future climate scenarios during the periods of 2046–2065 and 2081−2100. The results indicate that the glaciers experienced a remarkable shrinkage from 1989 to 2016 with a shrinkage rate of −1.61 km2/a (−0.5%/a), and the rising temperature is the decisive factor dominating glacial retreat; there is a significant negative linear correlation between glacier area and mean air temperature of the glacier surfaces in July–August in each elevation zone from 1989 to 2016. The variations in glaciers are far less sensitive to changes in precipitation than to changes in air temperature. Due to the influence of climate and topographic conditions, the distribution of glacier area and the rate of glacier ablation first increased and then decreased in different elevation zones. The trend in glacier shrinkage will continue because air temperature will continue to increase in the future, and the result of glacier retreat in each elevation zone will be slightly slower than that in the entire study area. Quantitative glacier research can more accurately reflect the response of glacier variations to climate change, and the regression relationship can be used to predict the areas of glaciers under future climate scenarios. These conclusions can offer effective references for assessing glacier variations and their response to climate change in arid inland river basins in Northwest China as well as other similar regions in the world

Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma

Abstract Background Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, and PI3K) inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers. Early studies demonstrated that protein kinase C-β (PKCβ) inhibitors alter phosphorylation level the Bruton’s tyrosine kinase (BTK), which leads to enhanced BTK signaling. Here, for the first time, we investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL. Methods In vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effects of enzastaurin and ibrutinib were also evaluated in vivo. Results Combination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of DLBCL cells, including reduction of proliferation, promoting apoptosis, inducting G1 phase arrest, preventing cell invasion and migration, and down-regulating activation of downstream signaling. More importantly, whole-transcriptome changes results showed that combination therapy worked synergistically to regulate whole-transcriptome expression compared with enzastaurin and ibrutinib alone. Co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathway. Furthermore, the mRNA expression analysis further indicated that co-treatment significantly decreased the mRNA levels of NOTCH1. The combination effect in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment also was demonstrated in vivo. Conclusions Combination of enzastaurin and ibrutinib had synergistic anti-tumor effects in DLBCL, independent of molecular subtype. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be a new treatment strategy for DLBCL