Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

BackgroundBreast cancer (BC) is a leading cause of mortality among women, underscoring the urgent need for improved therapeutic predictio. Developing a precise prognostic model is crucial. The role of Endoplasmic Reticulum Stress (ERS) in cancer suggests its potential as a critical factor in BC development and progression, highlighting the importance of precise prognostic models for tailored treatment strategies.MethodsThrough comprehensive analysis of ERS-related gene expression in BC, utilizing both single-cell and bulk sequencing data from varied BC subtypes, we identified eight key ERS-related genes. LASSO regression and machine learning techniques were employed to construct a prognostic model, validated across multiple datasets and compared with existing models for its predictive accuracy.ResultsThe developed ERS-model categorizes BC patients into distinct risk groups with significant differences in clinical prognosis, confirmed by robust ROC, DCA, and KM analyses. The model forecasts survival rates with high precision, revealing distinct immune infiltration patterns and treatment responsiveness between risk groups. Notably, we discovered six druggable targets and validated Methotrexate and Gemcitabine as effective agents for high-risk BC treatment, based on their sensitivity profiles and potential for addressing the lack of active targets in BC.ConclusionOur study advances BC research by establishing a significant link between ERS and BC prognosis at both the molecular and cellular levels. By stratifying patients into risk-defined groups, we unveil disparities in immune cell infiltration and drug response, guiding personalized treatment. The identification of potential drug targets and therapeutic agents opens new avenues for targeted interventions, promising to enhance outcomes for high-risk BC patients and paving the way for personalized cancer therapy

The characteristic and size–frequency distribution of rocks at the Zhurong landing site, Mars

The rock characteristic and size–frequency distribution (SFD) on Mars are important for understanding the geologic and geomorphic history of the surface, for evaluating the trafficability of roving, and for planning the potential infrastructure construction. Tianwen-1, China’s first autonomous Mars exploration mission, formed an excavated depression during touchdown, which has been the deepest depression on the Martian surface so far compared with others. According to the images captured using the Navigation and Terrain Cameras (NaTeCams) onboard the rover, Zhurong, the SFD of rocks is calculated and compared inside the excavated depression, within and out of the blast zone. For the first time, the rock size distribution inside the excavated depression is obtained, exposing the geological features of the shallow subsurface on Mars at a depth of tens of centimeters, which will surely be important for future drilling missions. It is found that the rock abundance in the depression is smaller than the original abundance on the surface, and the distribution of rocks in the blast zone on the surface is greatly influenced by the touchdown. In addition, based on the fractal dimension of rock sizes, the rocks (>10 mm) at the shallow subsurface of the Zhurong landing site may experience two different geological processes

Quality assurance for Chinese herbal formulae: standardization of IBS-20, a 20-herb preparation

<p>Abstract</p> <p>Background</p> <p>The employment of well characterized test samples prepared from authenticated, high quality medicinal plant materials is key to reproducible herbal research. The present study aims to demonstrate a quality assurance program covering the acquisition, botanical validation, chemical standardization and good manufacturing practices (GMP) production of IBS-20, a 20-herb Chinese herbal formula under study as a potential agent for the treatment of irritable bowel syndrome.</p> <p>Methods</p> <p>Purity and contaminant tests for the presence of toxic metals, pesticide residues, mycotoxins and microorganisms were performed. Qualitative chemical fingerprint analysis and quantitation of marker compounds of the herbs, as well as that of the IBS-20 formula was carried out with high-performance liquid chromatography (HPLC). Extraction and manufacture of the 20-herb formula were carried out under GMP. Chemical standardization was performed with liquid chromatography-mass spectrometry (LC-MS) analysis. Stability of the formula was monitored with HPLC in real time.</p> <p>Results</p> <p>Quality component herbs, purchased from a GMP supplier were botanically and chemically authenticated and quantitative HPLC profiles (fingerprints) of each component herb and of the composite formula were established. An aqueous extract of the mixture of the 20 herbs was prepared and formulated into IBS-20, which was chemically standardized by LC-MS, with 20 chemical compounds serving as reference markers. The stability of the formula was monitored and shown to be stable at room temperature.</p> <p>Conclusion</p> <p>A quality assurance program has been developed for the preparation of a standardized 20-herb formulation for use in the clinical studies for the treatment of irritable bowel syndrome (IBS). The procedures developed in the present study will serve as a protocol for other poly-herbal Chinese medicine studies.</p

Toll-like receptor 2 and Toll-like receptor 4 exhibit distinct regulation of cancer cell stemness mediated by cell death-induced high-mobility group box 1

Background: High-mobility group box 1 (HMGB1), a common extracellular damage associated molecular pattern molecule, is overexpressed in several solid tumors including pancreatic carcinoma. We previously observed that radiotherapy induced dying cells secrete HMGB1 and accelerate pancreatic carcinoma progression through an unclear mechanism.Methods: Using the Millicell system as an in vitro co-culture model, we performed quantitative reverse transcriptase-polymerase chain reaction, western blot and sphere forming ability analyses to access the effect of dying-cell-derived HMGB1 on CD133(+) cancer cell stemness in vitro and in vivo. Interactions between HMGB1 and Toll-like receptor 2(TLR2)/TLR4 were studied by co-immunoprecipitation. Western blot and short-hairpin RNA-based knockdown assays were conducted to detect HMGB1 and TLR2/TLR4 signaling activity.Findings: Radiation-associated, dying-cell-derived HMGB1 maintained stemness and contributed to CD133(+) cancer stemcell self-renewal in vitro and in vivo. In overexpressing and silencing experiments, we demonstrated that the process was activated by TLR2 receptor, whereas TLR4 antagonized HMGB1-TLR2 signaling. Wnt/beta-catenin signaling supported the HMGB1-TLR2 mediated stemness of CD133(+) cancer cells.Interpretation: Our results show how irradiation-induced cell death might enhance the stemness of resident cancer cells, and indicate HMGB1-TLR2 signaling as a potential therapeutic target for preventing pancreatic cancer recurrence. (c) 2018 Haitao Zhu. Published by Elsevier B.V

CD8(+) T Cells Involved in Metabolic Inflammation in Visceral Adipose Tissue and Liver of Transgenic Pigs

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPR(dn) , hIAPP and PNPLA3(I148M) . Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8(+) T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs' liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.Peer reviewe

Dedifferentiation process driven by radiotherapy-induced HMGB1/TLR2/YAP/HIF-1α signaling enhances pancreatic cancer stemness

Differentiated cancer cells reacquiring stem cell traits following radiotherapy may enrich cancer stem cells and accelerate tumor recurrence and metastasis. We are interested in the mechanistic role of dying cells-derived HMGB1 in CD133− pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133− pancreatic cancer cells, from either sorted from patient samples or established cell lines, into cancer stem-like cells (iCSCs). Using an in vitro coculture model, X-ray irradiation induced dying cells to release HMGB1, which further promoted CD133− pancreatic cancer cells regaining stem cell traits, such as higher sphere forming ability and expressed higher level of stemness-related genes and proteins. Inhibiting the expression and activity of HMGB1 attenuated the dedifferentiation stimulating effect of irradiated, dying cells on C133− pancreatic cancer cells in vitro and in PDX models. Mechanistically, HMGB1 binding with TLR2 receptor functions in a paracrine manner to affect CD133− pancreatic cancer cells dedifferentiation via activating Hippo-YAP pathway and HIF-1α expression in oxygen independent manner in vitro and in vivo. We conclude that X-ray irradiation induces CD133− pancreatic cancer cell dedifferentiation into a CSC phenotype, and inhibiting HMGB1 may be a strategy to prevent CSC enrichment and further pancreatic carcinoma relapse.</p

New Polyketides With Anti-Inflammatory Activity From the Fungus Aspergillus rugulosa

Two new polyketide compounds, asperulosins A and B (1–2), and one new prenylated small molecule, asperulosin C (3), along with nine known compounds (4–12), were isolated and identified from a fungus Aspergillus rugulosa. Their structures were extensively elucidated via HRESIMS, 1D, and 2D NMR analysis. The absolute configurations of the new compounds were determined by the comparison of their electronic circular dichroism (ECD), calculated ECD spectra, and the detailed discussion with those in previous reports. Structurally, compounds 1 and 2 belonged to the polyketide family and were from different origins. Compound 2 was constructed by five continuous quaternary carbon atoms, which occur rarely in natural products. All of the isolates were evaluated for anti-inflammatory activity against the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Among those, compounds 1 and 5 showed a significant inhibitory effect on NO production with IC50 values of 1.49 ± 0.31 and 3.41 ± 0.85 μM, respectively. Additionally, compounds 1 and 5 markedly increased the secretion of anti-inflammatory cytokine IL10 while suppressing the secretion of pro-inflammatory cytokines IL6, TNF-α, IFN-γ, MCP-1, and IL12. Besides, 1 and 5 inhibited the transcription level of pro-inflammatory macrophage markers IL6, IL1β, and TNF-α while remarkably elevating the anti-inflammatory factor IL10 and M2 macrophage markers ARG1 and CD206. Moreover, 1 and 5 restrained the expression and nuclear translocation of NF-κB, as well as its downstream signaling proteins COX-2 and iNOS. All these results suggest that 1 and 5 have potential as anti-inflammatory agents, with better or comparable activities than those of the positive control, dexamethasone

Substantial transition to clean household energy mix in rural China

The household energy mix has significant impacts on human health and climate, as it contributes greatly to many health- and climate-relevant air pollutants. Compared to the well-established urban energy statistical system, the rural household energy statistical system is incomplete and is often associated with high biases. Via a nationwide investigation, this study revealed high contributions to energy supply from coal and biomass fuels in the rural household energy sector, while electricity comprised ∼20%. Stacking (the use of multiple sources of energy) is significant, and the average number of energy types was 2.8 per household. Compared to 2012, the consumption of biomass and coals in 2017 decreased by 45% and 12%, respectively, while the gas consumption amount increased by 204%. Increased gas and decreased coal consumptions were mainly in cooking, while decreased biomass was in both cooking (41%) and heating (59%). The time-sharing fraction of electricity and gases (E&G) for daily cooking grew, reaching 69% in 2017, but for space heating, traditional solid fuels were still dominant, with the national average shared fraction of E&G being only 20%. The non-uniform spatial distribution and the non-linear increase in the fraction of E&G indicated challenges to achieving universal access to modern cooking energy by 2030, particularly in less-developed rural and mountainous areas. In some non-typical heating zones, the increased share of E&G for heating was significant and largely driven by income growth, but in typical heating zones, the time-sharing fraction was <5% and was not significantly increased, except in areas with policy intervention. The intervention policy not only led to dramatic increases in the clean energy fraction for heating but also accelerated the clean cooking transition. Higher income, higher education, younger age, less energy/stove stacking and smaller family size positively impacted the clean energy transition

MMP28 (epilysin) as a novel promoter of invasion and metastasis in gastric cancer

Background\ud The purpose of this study was to investigate invasion and metastasis related genes in gastric cancer.\ud \ud Methods\ud The transwell migration assay was used to select a highly invasive sub-line from minimally invasive parent gastric cancer cells, and gene expression was compared using a microarray. MMP28 upregulation was confirmed using qRT-PCR. MMP28 immunohistochemistry was performed in normal and gastric cancer specimens. Invasiveness and tumor formation of stable cells overexpressing MMP28 were tested in vitro and in vivo.\ud \ud Results\ud MMP28 was overexpressed in the highly invasive sub-cell line. Immunohistochemistry revealed MMP28 expression was markedly increased in gastric carcinoma relative to normal epithelia, and was significantly associated with depth of tumor invasion, lymph node metastasis and poorer overall survival. Ectopic expression of MMP28 indicated MMP28 promoted tumor cell invasion in vitro and increased gastric carcinoma metastasis in vivo.\ud \ud Conclusions\ud This study indicates MMP28 is frequently overexpressed during progression of gastric carcinoma, and contributes to tumor cell invasion and metastasis. MMP28 may be a novel therapeutic target for prevention and treatment of metastases in gastric cancer