Unfolded protein response signature unveils novel insights into breast cancer prognosis and tumor microenvironment.

BACKGROUND: The critical role of the unfolded protein response (UPR) in tumorigenesis is widely acknowledged, yet the precise molecular mechanisms underlying its contribution to breast cancer (BC) have not been fully elucidated. The present study aimed to comprehensively explore the expression characteristics and prognostic significance of UPR-related genes in breast cancer METHODS: The transcriptome and clinical data of breast cancer were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively. Differential expression analysis was conducted on UPR-related genes, and the resulting genes were employed for consensus clustering analysis. A breast cancer prognosis risk model was constructed using univariate, least absolute shrinkage and selection operator (LASSO), and multivariable Cox regression analyses. Difference in survival outcomes between groups were analyzed Kaplan-Meier survival analysis, and receiver operating characteristic (ROC) curve was used to assess predictive performance. The relationship between the risk model and clinical-pathological characteristics, immune infiltration, immunotherapy response, and drug sensitivity was assessed. RESULTS: Differential expression analysis identified 10 UPR-related genes that were differentially expressed in breast cancer. Using the expression matrix of these genes, two molecular subtypes of breast cancer were characterized, which displayed significant differences in prognostic and immune infiltration characteristics. Drawing from the gene expression profiles that distinguish between the molecular subtypes, a prognostic risk scoring model comprising eight genes was developed. This model stratified BC patients from both the training and validation cohorts into high-risk and low-risk groups. Patients in the low-risk group had better prognoses, while those with advanced clinical stage and T stage exhibited higher risk scores. The high- and low-risk groups exhibited notable disparities in immune cell infiltration and the expression of multiple immune checkpoint-related genes. Additionally, the low-risk group demonstrated elevated immunophenoscore, Merck18, CD274, and CAF scores compared to the high-risk group, along with a lesser sensitivity to chemotherapy drugs. These results suggest that patients within the low-risk group may potentially benefit more from immunotherapy and chemotherapy interventions. CONCLUSIONS: This study developed a novel UPR-derived risk signature, which could robustly predict the survival outcome, immune microenvironment, and chemotherapy response of patients with breast cancer.

Graphite-Embedded Lithium Iron Phosphate for High-Power-Energy Cathodes.

Lithium iron phosphate (LiFePO4) is broadly used as a low-cost cathode material for lithium-ion batteries, but its low ionic and electronic conductivity limit the rate performance. We report herein the synthesis of LiFePO4/graphite composites in which LiFePO4 nanoparticles were grown within a graphite matrix. The graphite matrix is porous, highly conductive, and mechanically robust, giving electrodes outstanding cycle performance and high rate capability. High-mass-loading electrodes with high reversible capacity (160 mA h g-1 under 0.2 C), ultrahigh rate capability (107 mA h g-1 under 60 C), and outstanding cycle performance (>95% reversible capacity retention over 2000 cycles) were achieved, providing a new strategy toward low-cost, long-life, and high-power batteries. Adoption of such material leads to electrodes with volumetric energy density as high as 427 W h L-1 under 60 C, which is of great interest for electric vehicles and other applications.

Semiliquid electrolytes with anion-adsorbing metal-organic frameworks for high-rate lithium batteries.

Adding particles of metal-organic frameworks (MOFs) into liquid electrolytes leads to semiliquid electrolytes, where nanoporous MOFs enclose anions while facilitating lithium-ion conduction. The improved transport efficiency of lithium-ions in semiliquid electrolytes boosts effective reaction kinetics, mitigates polarization, and produces affinitive electrolyte-electrode interfaces, which afford enhanced cycle durability for high-rate lithium batteries.

CVD-assisted fabrication of hierarchical microparticulate Li2TiSiO5-carbon nanospheres for ultrafast lithium storage.

Particular recent interest has been given to the Li2TiSiO5 (LTSO) anode material owing to its low lithiation potential (0.28 V vs. Li/Li+) and decent theoretical capacity (308 mA h g-1). However, its poor electronic conductivity (∼10-7 S m-1) fundamentally limits the utilization of this material, and current strategies fail to tackle such issues in practical ways. Herein, a hierarchical microparticulate LTSO-carbon composite (LTSO/C) is fabricated by chemical vapor deposition (CVD), where microsized LTSO/C particles assembled from nanospheres guarantee a practical tap density of ∼1.3 g mL-1. Meanwhile, significantly elevated conductivity of LTSO/C (∼103 S m-1) is achieved by a thin layer (15 nm) of graphitic carbon growth on LTSO, which is theoretically catalyzed by the surface functional groups on the parent LTSO. The electrochemical characterization of LTSO/C reveals a superior graphite-like volumetric capacity of 441.1 mA h cm-3 and Li4Ti5O12-like rate capability (120.1 mA h cm-3 at 4.5 A g-1), providing inspiring guidance for designing analogous Ti or Si-based compounds for ultrafast lithium storage materials.

Tin-graphene tubes as anodes for lithium-ion batteries with high volumetric and gravimetric energy densities.

Limited by the size of microelectronics, as well as the space of electrical vehicles, there are tremendous demands for lithium-ion batteries with high volumetric energy densities. Current lithium-ion batteries, however, adopt graphite-based anodes with low tap density and gravimetric capacity, resulting in poor volumetric performance metric. Here, by encapsulating nanoparticles of metallic tin in mechanically robust graphene tubes, we show tin anodes with high volumetric and gravimetric capacities, high rate performance, and long cycling life. Pairing with a commercial cathode material LiNi0.6Mn0.2Co0.2O2, full cells exhibit a gravimetric and volumetric energy density of 590 W h Kg-1 and 1,252 W h L-1, respectively, the latter of which doubles that of the cell based on graphite anodes. This work provides an effective route towards lithium-ion batteries with high energy density for a broad range of applications.

Protective effects of Asiatic acid against pelvic inflammatory disease in rats.

Asiatic acid (AA) is one of the major components of the Chinese herb Centella asiatica and exerts a variety of pharmacological activities. However, the pharmacological effects of AA on pelvic inflammatory disease (PID) remain unknown. The purpose of the present study was to investigate the therapeutic efficacy and potential mechanisms of AA on PID in rats. A total of 75 female Sprague Dawley rats were randomly divided into the following five groups: A control group; a PID group; a PID + AA 5 mg/kg group; a PID + AA 35 mg/kg group; and a PID + AA 75 mg/kg group. Changes in cytokine and chemokine levels, myeloperoxidase (MPO) activity, nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) activation, oxidative stress and cleaved caspase-3 were measured. AA treatment significantly decreased the excessive production of cytokines and chemokines and suppressed MPO activity and the activation of NLRP3 inflammasome, NF-κB and caspase-3, as well as oxidative stress. These results suggest that AA exhibits potent anti-inflammatory and antioxidant effects in rats with pathogen-induced PID and that the mechanism of these anti-inflammatory effects may be associated with the suppression of NLRP3 inflammasome activation and the NF-κB pathway.

Reversible Photocontrol of Thrombin Activity by Replacing Loops of Thrombin Binding Aptamer using Azobenzene Derivatives.

The photoisomerization of azobenzenes provides a general means for the photocontrol of many important biomolecular structures and organismal functions. For temporal and spatial control activity of thrombin binding aptamer (TBA) by light, azobenzene derivatives were carefully selected as light-triggered molecular switches to replace TT loops and the TGT loop of TBA to reversibly control enzyme activity. These molecules interconverted between the trans and cis states under alternate UV and visible light irradiation, which consequently triggered reversible formation of G-quadruplex morphology. In addition, we investigated the impact of three azobenzene derivatives on stability, thrombin binding ability, and anticoagulant properties. The result showed that 4,4'-bis(hydroxymethyl)azobenzene at the TGT loop position significantly photoregulated affinity to thrombin and blood clotting in human plasma, which provided a successful strategy to control blood clotting in human plasma and a further evidence for design of TBA analogues with pivotal positions of modifications.

Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors.

Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58 ±â€¯0.15 µM, 0.47 ±â€¯0.06 µM and 0.74 ±â€¯0.12 µM, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.

Oncogenic long noncoding RNA landscape in breast cancer.

BACKGROUND: Few long noncoding RNAs (lncRNAs) that act as oncogenic genes in breast cancer have been identified. METHODS: Oncogenic lncRNAs associated with tumourigenesis and worse survival outcomes were examined and validated in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Then, the potential biological functions and expression regulation of these lncRNAs were studied via bioinformatics and genome data analysis. Moreover, progressive breast cancer subtype-specific lncRNAs were investigated via high-throughput sequencing in our cohort and TCGA validation. To elucidate the mechanisms of the regulation of these lncRNAs, genomic alterations from the TCGA, Broad, Sanger and BCCRC data, as well as epigenetic modifications from GEO data, were then applied and examined to meet this objective. Finally, cell proliferation assays, flow cytometry analyses and TUNEL assays were applied to validate the oncogenic roles of these lncRNAs in vitro. RESULTS: A cluster of oncogenic lncRNAs that was upregulated in breast cancer tissue and was associated with worse survival outcomes was identified. These oncogenic lncRNAs are involved in regulating immune system activation and the TGF-beta and Jak-STAT signalling pathways. Moreover, TINCR, LINC00511, and PPP1R26-AS1 were identified as subtype-specific lncRNAs associated with HER-2, triple-negative and luminal B subtypes of breast cancer, respectively. The up-regulation of these oncogenic lncRNAs is mainly caused by gene amplification in the genome in breast cancer and other solid tumours. Finally, the knockdown of TINCR, DSCAM-AS1 or HOTAIR inhibited breast cancer cell proliferation, increased apoptosis and inhibited cell cycle progression in vitro. CONCLUSIONS: These findings enhance the landscape of known oncogenic lncRNAs in breast cancer and provide insights into their roles. This understanding may potentially aid in the comprehensive management of breast cancer.

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety.

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a-j, 13a-j). All the compounds were evaluated for the IC50 values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC50 values of 1.1µM, 0.92µM and 8.77-14.3µM. Structure-activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.

The timing of surgical treatment of knee dislocations: a systematic review.

PURPOSE: Traumatic knee dislocations (KDs) are unusual yet limb-threatening injuries; the timing of surgical intervention is still debated. A systematic review was performed to determine the optimal timing of surgery with respect to injury pattern. METHODS: A comprehensive search of Medline, EMBASE, and Cochrane Central Register of Controlled Trials was performed for studies published between 1 January 1974 and 20 April 2014 on the surgical management of "knee dislocation" and "multiligament knee injuries". Surgical timing was classified as acute, chronic, or staged. A systematic review was performed for patients with KD-III according to Schenck's classification using individual patient data. RESULTS: Twelve studies including 150 patients (153 knees) with KDs fulfilled the study requirements. Sixty-nine cases with KD-IIIM and 84 cases with KD-IIIL were identified. Excellent or good results were demonstrated in 79.1 % (34 cases) of cases managed with staged treatment versus 58.4 % (45 cases) of cases undergoing acute surgery (p = 0.02), and versus 45.5 % (15 cases) of cases undergoing chronic surgery (p = 0.002). No statistically significant difference was found in the percentage of excellent or good results between the acute and chronic surgery groups (n.s.), or between the KD-IIIM and KD-IIIL groups (n.s.). CONCLUSION: Staged treatment yields the best clinical results for patients with KD-III. No statistically significant difference was shown in the clinical results between acute surgery and chronic surgery groups. LEVEL OF EVIDENCE: IV.

High levels of BCOX1 expression are associated with poor prognosis in patients with invasive ductal carcinomas of the breast.

This study was to examine the breast cancer-overexpressed gene 1 (BCOX1) expression in invasive ductal carcinomas (IDC) of the breast and its value in the prognosis of the disease. The levels of BCOX1 expression in 491 paired IDC and surrounding non-tumor breast tissues as well as 40 paired fresh specimens were evaluated by tissue microarray, immunohistochemistry and quantitative RT-PCR. The potential associations of high BCOX1 expression with clinicopathological variables and the overall survival of these patients were analyzed. The relative levels of BCOX1 mRNA transcripts in the IDC breast tissues were significantly higher than that in the corresponding non-tumor tissues (P = 0.005). The anti-BCOX1 was predominantly stained in the cytoplasm of breast tissue cells and the levels of BCOX1 expression in the majority of breast cancer tissues were obviously higher than that in the corresponding non-tumor breast tissues. High levels of BCOX1 expression were found in 59.5% (292/491) of breast cancer tissues. The high BCOX1 expression was significantly associated with high histological grade (P = 0.037), positive expression of human epidermal growth factor receptor 2 (HER2, P = 0.031) and triple negative breast cancer (P = 0.027). The high BCOX1 expression in breast cancers was significantly associated with a shorter overall survival of these patients (P = 0.023), particularly in patients with triple negative breast cancer (P = 0.005). Therefore, the high BCOX1 expression may serve as a novel marker of poor prognosis and a potential therapeutic target for patients with IDC of the breast.

[EFFECTIVENESS OF ONE-STAGE REPAIR AND RECONSTRUCTION OF TRAUMATIC DISLOCATION OF KNEE JOINT COMBINED WITH MULTIPLE LIGAMENT INJURIES].

OBJECTIVE: To investigate the effectiveness of one-stage repair and reconstruction of multiple ligament injuries of the knee under arthroscopy. METHODS: Between March 2007 and March 2009, 25 patients (25 knees) with multiple ligament injuries of the knee underwent one-stage repair and reconstruction under arthroscopy. Of 25 cases, 16 were male and 9 were female with an average age of 29.6 years (range, 18-43 years). The causes of injury were traffic accident injury in 20 cases, falling injury from height in 3 cases, and sport injury in 2 cases. The time between injury and surgery was 8-14 days (mean, 10.5 days). The preoperative Lysholm score was 37.92 ± 3.57. The X-ray film and MRI examinations showed that 17 patients had tears of anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and medial collateral ligament, and 8 patients had tears of ACL, PCL, and posterolateral corner (PLC); 5 cases had medial meniscus injury and 7 cases had lateral meniscus injury. The ACL, PCL, and PLC were reconstructed under arthroscopy with autologous tendon or allogeneic tendon, and the MCL was repaired. Early active and passive functional exercises were done postoperatively. RESULTS: All the incisions healed by first intention, and there was no complications of infection and deep venous thrombosis. Twenty-five patients were followed up 24-78 months (mean, 50.9 months). Six patients had knee stiff postoperatively; after manipulation under anesthsia, 5 patients lost less than 15° of flexion and only 1 patient lost 26° of flexion. At last follow-up, the stability of the knee joint was significantly improved. There were significant differences in the anterior drawer test, posterior drawer test, Lachman test, and varus stress and valgus stress testing at 30° between at last follow-up and at preoperation (P < 0.05). The postoperative Lysholm score was 87.84 ± 4.85, which was significantly better than the preoperative score (t = 52.053, P = 0.000). The International Knee Documentation Committee (IKDC) rating was nearly normal in 16 cases (64%), abnormal in 8 cases (32%), and obviously abnormal in 1 case (4%). CONCLUSION: One-stage repair and reconstruction of multiple ligament injuries of the knee under arthroscopy can effectively restore the function of the knee joint, and the effectiveness is reliable.