Background Anticoagulation of the extracorporeal circuit is required in continuous renal replacement therapy (CRRT). Heparin is the classic choice for anticoagulation, although it may increase the ...risk of bleeding. Regional citrate anticoagulation reduces the risk of bleeding, but may cause hypocalcemia and metabolic disturbances. Study Design Systematic review and meta-analysis of randomized controlled trials (RCTs). Setting & Population Patients admitted to the intensive care unit with acute kidney injury that required CRRT. Selection Criteria for Studies RCTs regardless of publication status or language. Intervention Regional citrate versus heparin anticoagulation in CRRT. Outcomes The primary outcomes were circuit survival time, the occurrence of major bleeding defined as a site of gross bleeding with a decrease in blood pressure or requiring transfusion of 2 or more units of red blood cells, metabolic alkalosis, hypocalcemia, and thrombocytopenia. The secondary outcome was cost. Results 6 RCTs with 488 patients were identified. Citrate anticoagulation was associated with a significant decrease in bleeding (RR, 0.34; 95% CI, 0.17-0.65). Circuit survival time, the incidence of metabolic alkalosis, and thrombocytopenia showed no significant difference between groups. Hypocalcemia was more common in patients receiving citrate, although no clinical adverse event was reported in the included studies. Limitations Significant heterogeneity in the primary outcome. Conclusion The efficacy of citrate and heparin anticoagulation for CRRT was similar. However, citrate anticoagulation decreased the risk of bleeding with no significant increase in the incidence of metabolic alkalosis. We recommend citrate as an anticoagulation agent in patients who require CRRT but are at high risk of bleeding.
Alterations in membrane proteins (MPs) and their regulated pathways have been established as cancer hallmarks and extensively targeted in clinical applications. However, the analysis of ...MP-interacting proteins and downstream pathways across human malignancies remains challenging. Here, we present a systematically integrated method to generate a resource of cancer membrane protein-regulated networks (CaMPNets), containing 63,746 high-confidence protein-protein interactions (PPIs) for 1962 MPs, using expression profiles from 5922 tumors with overall survival outcomes across 15 human cancers. Comprehensive analysis of CaMPNets links MP partner communities and regulated pathways to provide MP-based gene sets for identifying prognostic biomarkers and druggable targets. For example, we identify CHRNA9 with 12 PPIs (e.g., ERBB2) can be a therapeutic target and find its anti-metastasis agent, bupropion, for treatment in nicotine-induced breast cancer. This resource is a study to systematically integrate MP interactions, genomics, and clinical outcomes for helping illuminate cancer-wide atlas and prognostic landscapes in tumor homo/heterogeneity.
The nicotinic acetylcholine receptor (nAChR) was first characterized in 1970 as a membrane receptor of a neurotransmitter and an ion channel. nAChRs have been shown to be involved in smoking-induced ...cancer formation in multiple types of human cancer cells. In vitro and in vivo animal studies have shown that homopentameric nAChR inhibitors, such as methyllycaconitine and α-Bgtx, can attenuate nicotine-induced proliferative, angiogenic, and metastatic effects in lung, colon, and bladder cancer cells. Recent publications have shown that α9-nAChR is important for breast cancer formation, and in many in vivo studies, α9-nAChR-specific antagonists (e.g., α-ImI, α-ImI, Vc1.1, RgIA, and It14a) produced an analgesic effect. Vc1.1 functions in a variety of animal pain models and currently has entered phase II clinical trials. For cancer therapy, natural compounds such as garcinol and EGCG have been found to block nicotine- and estrogen-induced breast cancer cell proliferation through inhibition of the α9-nAChR signaling pathway. A detailed investigation of the carcinogenic effects of nAChRs and their specific antagonists would enhance our understanding of their value as targets for clinical translation.
The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast ...tumor samples were detected by real‐time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number × 103/μg) expression was 4.7‐fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (>40‐fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). Poor overall survival rate was correlated to the estrogen receptor positive (ER+, n = 20) patients with higher PRIM1 expression when compare to the ER− (n = 10) patients (Chi Square test, p = 0.03). Stable expression of PRIM1‐siRNA in the ER+ BT‐474 cells‐xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti‐tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT‐474‐xenografted tumor growth volume compared with control (n =5 per group, *p < 0.05). This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.
What's new?
Breast cancer formation is a gradual process that arises due to uncontrolled DNA replication in the initial stages. Here the authors find that PRIM1, the smallest subunit of the DNA primase complex responsible for synthesizing small RNA primers during DNA replication, was upregulated in breast cancer samples as compared to healthy tissue. PRIM1 levels negatively correlated with survival in women with estrogen‐positive breast cancer, indicating potential prognostic value of measuring PRIM1 levels in future clinical applications.
Oxyhemoglobin saturation by pulse oximetry (SpO2) has always played an important role in the diagnosis of symptoms. Considering that the traditional SpO2 measurement has a certain error due to the ...number of wavelengths and the algorithm and the wider application of machine learning and spectrum combination, we propose to use 12-wavelength spectral absorption measurement to improve the accuracy of SpO2 measurement. To investigate the multiple spectral regions for deep learning for SpO2 measurement, three datasets for training and verification were built, which were constructed over the spectra of first region, second region, and full region and their sub-regions, respectively. For each region under the procedures of optimization of our model, a thorough of investigation of hyperparameters is proceeded. Additionally, data augmentation is preformed to expand dataset with added noise randomly, increasing the diversity of data and improving the generalization of the neural network. After that, the established dataset is input to a one dimensional convolution neural network (1D-CNN) to obtain a measurement model of SpO2. In order to enhance the model accuracy, GridSearchCV and Bayesian optimization are applied to optimize the hyperparameters. The optimal accuracies of proposed model optimized by GridSearchCV and Bayesian Optimization is 89.3% and 99.4%, respectively, and trained with the dataset at the spectral region of six wavelengths including 650 nm, 680 nm, 730 nm, 760 nm, 810 nm, 860 nm. The total relative error of the best model is only 0.46%, optimized by Bayesian optimization. Although the spectral measurement with more features can improve the resolution ability of the neural network, the results reveal that the training with the dataset of the shorter six wavelength is redundant. This analysis shows that it is very important to construct an effective 1D-CNN model area for spectral measurement using the appropriate spectral ranges and number of wavelengths. It shows that our proposed 1D-CNN model gives a new and feasible approach to measure SpO2 based on multi-wavelength.
Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA ...levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (*, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22–26.54-fold; *, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0–100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0–100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.
Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.
To screen drugs that target CSCs ...to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.
We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib.
We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.
The green supply chain is an innovation that extends traditional sustainability initiatives to environmental activities in the supply chain and aims to minimize a product's environmental impact ...throughout its life cycle. The adoption of a green supply chain involves a complex decision-making process characterized by multiple criteria. The goal of the current study is to construct a decision framework by identifying a comprehensive set of consideration factors and their causal relationships. The consideration factors are deliberately drawn from a variety of different, yet related, theories and are grouped into an extensive Technology-Organization -Environment (TOE) framework. In accordance with the Decision Making Trial and Evaluation Laboratory (DEMATEL) method, the decision framework was analyzed for appropriateness through surveys of selected experts in the semiconductor industry. Because the semiconductor industry has a long history of heavy resource usage and has proven an early advocate of green supply chains, results from this study can provide insights to other firms with similar operations and aims. The contributions of this research are twofold. First, its theoretical contribution consists of integrating previously separate strands of different theories into a holistic framework and exploring the causal relationships among decision factors. Second, its practical contribution lies in its establishment of a strategic path that provides firms a set of priorities when adopting green supply chains.
Colorectal cancer (CRC) is a common malignancy worldwide. CRC patients in the same stage often present with dramatically different clinical scenarios. Thus, robust prognostic biomarkers are urgently ...needed to guide therapies and improve treatment outcomes. The NKX6.1 gene has been identified as a hypermethylation marker in cervical cancer, functioning as a metastasis suppressor by regulating epithelial–mesenchymal transition. Here, we investigated whether hypermethylation of NKX6.1 might be a prognostic biomarker for CRC. By analyzing the methylation and expression of NKX6.1 in CRC tissues and CRC cell lines. We quantitatively examined the NKX6.1 methylation levels in 151 pairs of CRC tissues by using methylation‐specific polymerase chain reaction analysis and found that NKX6.1 was hypermethylated in 35 of 151 CRC tissues (23%). NKX6.1 gene expression was inversely correlated with the DNA methylation level in CRC cell lines in vitro. Then, we analyzed the association of NKX6.1 methylation with clinical characteristics of these CRC patients. Our data demonstrated that patients with NKX6.1 methylation presented poorer 5‐year overall survival (P = 0.0167) and disease‐free survival (P = 0.0083) than patients without NKX6.1 methylation after receiving adjuvant chemotherapy. Most importantly, these data revealed that stage II CRC patients with NKX6.1 methylation had poorer 5‐year disease‐free survival (P = 0.0322) than patients without NKX6.1 methylation after adjuvant chemotherapy. Our results demonstrate that methylation of NKX6.1 is a novel prognostic biomarker in CRC and that it may be used as a predictor of the response to chemotherapy.
The regulation of RagAGTP is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagAGTP, how GATOR1 is ...recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagAGTP hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions.
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•Skp2 mediates amino-acid-induced RagA ubiquitination and GATOR1 recruitment•Skp2 is a negative feedback regulator of amino-acid-dependent mTORC1 signaling•Skp2 promotes autophagy but inhibits cell size and cilia growth by mTORC1 repression
Jin et al. identify a critical molecular mechanism by which amino acids initiate a negative feedback loop for amino-acid-dependent mTORC1signaling. The findings demonstrate that mTORC1 signaling is properly restricted in the physiological condition under continuous amino acid stimulation, thus preventing mTORC1 hyperactivation and cellular functional disorders.
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