Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, smooth muscle cell proliferation, cell apoptosis, necrosis, fibrosis, and local inflammation. Immune and ...inflammatory responses have significant effects on every phase of atherosclerosis, and increasing evidence shows that immunity plays a more important role in atherosclerosis by tightly regulating its progression. Therefore, understanding the relationship between immune responses and the atherosclerotic microenvironment is extremely important. This article reviews existing knowledge regarding the pathogenesis of immune responses in the atherosclerotic microenvironment, and the immune mechanisms involved in atherosclerosis formation and activation.
NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine ...(N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.
Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m
twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m
twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).
A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio HR, 0.76; 95% CI, 0.63 to 0.93; stratified log-rank
0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07;
2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8%
29.2%;
043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4;
1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74;
.0004). The most common all-grade adverse events were diarrhea (N+C 83%
L+C 66%) and nausea (53%
42%). Discontinuation rates and HRQoL were similar between groups.
N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
To achieve preferential effects against cancer cells but less damage to normal cells is one of the main challenges of cancer research. In this review, we explore the roles and relationships of ...oxidative stress-mediated apoptosis, DNA damage, ER stress, autophagy, metabolism, and migration of ROS-modulating anticancer drugs. Understanding preferential anticancer effects in more detail will improve chemotherapeutic approaches that are based on ROS-modulating drugs in cancer treatments.
Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival ...after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10−5. Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10−5) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment.
What's new?
Although many prognostic predictors have been identified, the factors that determine patient differences in breast cancer progression and survival are not fully understood. This study addresses the important role of cancer immune control in promoting human breast cancer survival. Using genetic, cell‐based, and multi‐omic analyses, the authors find that one of the most significant SNP, rs1024176 at 1q24.2 could be a functional variant regulating XCL1 gene expression and thus recruiting type 1 dendritic cells to the breast tumor microenvironment. These findings reveal a pathway to prevent breast cancer progression through XCL1‐induced type 1 dendritic cells recruitment in the tumor microenvironment.
Abstract
The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor ...immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.
Dendrobium officinale Kimura et Migo is a valuable and homologous medicine and food traditional Chinese medicine. Currently there are few studies on the anti‐inflammatory activity of lipophilic ...components. The aim of this study was to explore the anti‐inflammatory effect and mechanism of the lipophilic compounds in Dendrobium officinale. Six compounds were isolated and identified, including three bibenzyl compounds, dendrocandin U, dendronbibisline B, erianin, and three lignans, (−)‐syringaresinol, (+)‐syringaresinol‐O‐β‐D‐glucopyranoside, 5‐methoxy‐(+)‐isolariciresinol. Among them, dendronbibisline B and 5‐methoxy‐(+)‐isolariciresinol were isolated from Dendrobium officinale for the first time. Besides, we found dendrocandin U, dendronbibisline B and (−)‐syringaresinol exhibited the anti‐inflammation to inhibit nitric oxide secretion induced by lipopolysaccharide (LPS)/interferon (IFN‐γ) in MH−S cells. Furthermore, dendrocandin U could inhibit the expression of tumor necrosis factor‐α (TNF‐α), Cluster of Differentiation 86 (CD86), and reduce inflammatory morphological changes of macrophages. Meanwhile, we confirmed that the anti‐inflammation mechanism of dendrocandin U was to inhibit M1 polarization by suppressing toll‐like receptor 4 (TLR4)/recombinant myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF‐κB) signaling pathway. In this paper, dendrocandin U with significant anti‐inflammatory activity was found from Dendrobium officinale, which could provide a basis for the study of its anti‐inflammatory drugs.
The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA ...degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Here, the expression of LSM1 mRNA in breast cancer was estimated using The Cancer Genome Atlas (TCGA), Oncomine, TIMER and bc‐GenExMiner databases. We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in breast cancer (BRCA) patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease‐free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.
Exosomal microRNAs (miRNAs) are novel, non-invasive biomarkers for facilitating communication and diagnosing cancer. However, only a few studies have investigated their function and role in the ...clinical diagnosis of breast cancer. To address this gap, we established a stable cell line, MDA-MB-231-CD63-RFP, and recruited 112 female participants for serum collection. We screened 88 exosomal miRNAs identified through microarray analysis of 231-CD63 and literature screening using real-time PCR; only exosomal miR-92b-5p was significantly increased in patients with breast cancer. It had a significant correlation with stage and discriminated patients from the control with an AUC of 0.787. Exosomal miR-92b-5p impacted the migration, adhesion, and spreading ability of normal human mammary epithelial recipient cells through the downregulation of the actin dynamics regulator MTSS1L. In clinical breast cancer tissue, the expression of MTSS1L was significantly inversely correlated with tissue miR-92b-5p, and high expression of MTSS1L was associated with better 10-year overall survival rates in patients undergoing hormone therapy. In summary, our studies demonstrated that exosomal miR-92b-5p might function as a non-invasive body fluid biomarker for breast cancer detection and provide a novel therapeutic strategy in the axis of miR-92b-5p to MTSS1L for controlling metastasis and improving patient survival.
It is a green and sustainable path to establish cheap solid waste-based catalyst to establish peroxymonosulfate (PMS) catalytic system for the degradation of carbamazepine (CBZ) in water. In this ...study, durable copper tailing waste residue-based catalyst (CSWR) was prepared, and efficient CSWR/PMS system was constructed for catalytic degradation of CBZ for first time. The morphology and structure of CSWR changed from clumps to porous and loose amorphous by alkali leaching and medium temperature calcination. The reconstructed surface of the CSWR exposes more active sites promotes the catalytic reaction and increases the degradation rate of CBZ by more than 39.8 times. And the CSWR/PMS achieved a CBZ removal of nearly 99.99 % in 20 min. In particular, perovskite-type iron-calcium compounds were formed, which stimulated the production of more HO• and SO4•− in the system. DFT calculation shows that CSWR has stronger adsorption energy and electron transfer ability to PMS molecules, which improved the degradation efficiency of the system. In general, this study proposed a means of high-value waste utilization, which provided a new idea for the preparation of solid waste based environmental functional materials and is expected to be widely used in practical wastewater treatment.
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•An engineering green CSWR-2/PMS-based AOPs was established for the first time.•CSWR-2 has superior electron transfer efficiency.•CSWR-2/PMS has high degradation efficiency of carbamazepine.•CSWR-2 is durable and reusable.•High value-added utilization of solid waste is realized.
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•Various types of bonds (e.g., H-bond and Ca–O) exist at the C-S-H–silica interface.•An atomic-level ITZ with a low density exists at the C-S-H–silica interface.•H2O and Ca2+ diffuse ...in a faster rate in the ITZ than those in the bulk C-S-H.•The interfacial bond strength is inversely related to the water content of C-S-H.•A three-stage interfacial fracture: crack propagation, chain bridging, and complete failure.
The interfacial characteristics between cement paste and silica are far from being fully understood, especially from the nanoscale perspective. Herein, molecular models were used to provide comprehensive insights into the interfacial characteristics between calcium silicate hydrate (C-S-H, the main binding phase of cement paste) and silica. Chemically, various types of bonds existed at the interface, including H-bonds and Ca–O bonds, and proton (H+) exchange occurred between C-S-H and silica. An increase in the water content of C-S-H could depress the deprotonation of the Si-OH groups on the silica surface. Structurally, an atomic-level interfacial transition zone (ITZ) with a low density was identified, which was attributed to the rich presence of –OH groups at the C-S-H–silica interface. The water molecules and calcium ions in the ITZ diffused faster than those in the bulk C-S-H. Mechanically, the interfacial bond strength was inversely related to the water content of C-S-H, with the higher water content reducing the interfacial interactions. Under loading, the interfacial fracture underwent three stages: crack propagation, atomic chain bridging (responsible for the interfacial residual strength), and complete failure. These atomic-level findings provide hitherto unknown mechanisms of the interfacial interactions between cement paste and silica.
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