High fibrinogen-albumin ratio index (FARI) predicts poor survival in head and neck squamous cell carcinoma patients treated with surgical resection.

PURPOSE: The aim of the present study was to investigate the predictive value of the fibrinogen/albumin ratio index (FARI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the prognosis of patients with operable head and neck squamous cell carcinoma (HNSCC). METHODS: A cohort of 155 operable HNSCC patients were enrolled. Laboratory and clinical data were extracted from the patients' electronic medical record. The optimal cut-off values were determined by receiver operating characteristic (ROC) curves analysis. Clinicopathological characteristics of patients were compared via Chi-square test. Survival curves were analyzed by Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses via the Cox hazards regression analysis. RESULTS: The median follow-up time was 31.7 months. An increased level of NLR was associated with later T stages, later N stages, and more advanced clinical stages(all P < 0.05). On univariate analyses, FARI, NLR, PLR, and N stage were correlated with progression-free survival (PFS) (all P < 0.05) as well as overall survival (OS) (all P < 0.05). And the clinical stage was only relevant to OS (P = 0.007). Multivariate Cox regression analysis revealed that FARI (HR 3.486, 95% CI 2.086-5.825, P < 0.001; HR 4.474, 95% CI 2.442-8.199, P < 0.001), NLR (HR 3.163, 95% CI 1.810-5.528, P < 0.001; HR 3.690, 95% CI 1.955-6.963, P < 0.001), and N stage (HR 1.718, 95% CI 1.058-2.789, P = 0.029; HR 1.777, 95% CI 1.024-3.084, P = 0.041) were independent prognostic factors for PFS and OS. CONCLUSION: Our findings indicate that FARI and NLR are effective and convenient markers for predicting prognosis in operable HNSCC patients.

BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells.

BRCA1-associated basal-like breast cancer originates from luminal progenitor cells. Breast epithelial cells from cancer-free BRCA1 mutation carriers are defective in luminal differentiation. However, how BRCA1 deficiency leads to lineage-specific differentiation defect is not clear. BRCA1 is implicated in resolving R-loops, DNA-RNA hybrid structures associated with genome instability and transcriptional regulation. We recently showed that R-loops are preferentially accumulated in breast luminal epithelial cells of BRCA1 mutation carriers. Here, we interrogate the impact of a BRCA1 mutation-associated R-loop located in a putative transcriptional enhancer upstream of the ERα-encoding ESR1 gene. Genetic ablation confirms the relevance of this R-loop-containing region to enhancer-promoter interactions and transcriptional activation of the corresponding neighboring genes, including ESR1, CCDC170 and RMND1. BRCA1 knockdown in ERα+ luminal breast cancer cells increases intensity of this R-loop and reduces transcription of its neighboring genes. The deleterious effect of BRCA1 depletion on transcription is mitigated by ectopic expression of R-loop-removing RNase H1. Furthermore, RNase H1 overexpression in primary breast cells from BRCA1 mutation carriers results in a shift from luminal progenitor cells to mature luminal cells. Our findings suggest that BRCA1-dependent R-loop mitigation contributes to luminal cell-specific transcription and differentiation, which could in turn suppress BRCA1-associated tumorigenesis.

Insights into Capacity Fading Mechanism and Coating Modification of High-Nickel Cathodes in Lithium-Ion Batteries.

Developments in electric vehicles and mobile electronic devices are promoting the demand for lithium-ion batteries with higher capacity and longer lifetime. The performances of lithium-ion batteries are crucially affected by cathode materials, among which ternary cathode materials are the most competitive option with the advantages of high capacity, safety, and cost-effectiveness. However, although high-nickel ternary cathode materials can achieve relatively high specific capacity, they generally have unsatisfactory stability during long-term cycling. In this study, the microscopic mechanisms of the cathode failure and the principle of coating modification in lithium-ion batteries have been comprehensively examined. It has been revealed that the irreversible capacity fading is mainly attributed to the interface chemical reaction, which reduces the transition-metal valence states and generates undesired disordered rock-salt phases. This structural phase transformation at the interface induces the dissolution of transition metals and results in irreversible capacity loss of the cathode. To restrain the occurrence of this process, a LiNbO3 coating-modified single-crystal LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode material has been prepared. The electrochemical properties as well as the microstructural evolution of the cathode-electrolyte interface during cycling of both the uncoated and coated samples have been comprehensively characterized and compared through impedance spectroscopy testing, SEM-EDX, STEM, and EELS characterization. Additionally, molecular dynamics simulation results confirmed that LiNbO3 coating can effectively inhibit the dissolution of transition metals while providing stable lithium-ion channels. The experimental results also indicate that the coating modification can effectively improve the cycling stability of the NCM811, with the capacity retention rate for 500 cycles increasing from 19% to 70%. This study is helpful to deepen the understanding of the capacity fading mechanisms, and the coating method is effective at maintaining the structural stability and improving the cycle life of lithium-ion batteries.

High fibrinogen-albumin ratio index predicts poor prognosis for lung adenocarcinoma patients undergoing epidermal growth factor receptor-tyrosine kinase inhibitor treatments.

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) have become the preferred therapy as first-line treatment of non-small cell lung cancer patients harboring sensitizing EGFR mutations. However, the prognostic indicators are limited. The present study aimed to assess the prognostic value of immune-inflammation factors, fibrinogen-albumin ratio index (FARI), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) in EGFR-Mutant lung adenocarcinoma patients receiving first-generation EGFR-TKIs treatment.194 patients were included in this retrospective analysis. FARI was calculated as fibrinogen / albumin. Receiver operating characteristic curve was used to evaluate the optimal cut-off value for FARI, NLR, and PLR to progression free survival (PFS). Univariate and multivariate survival analysis were performed to identify factors correlated with PFS and overall survival (OS).Applying cut-offs of ≥0.08 (FARI), ≥3.28 (NLR), and ≥273.85 (PLR), higher FARI or NLR was associated with worse Eastern Cooperative Oncology Group performance status (ECOG PS) (P = .018, .002, respectively), and there were more males in high NLR group (P = .043). In univariate analysis, ECOG PS status, NLR, PLR, and FARI were significantly associated with PFS (P = .017, .004, <.001, .001, respectively) as well as OS (P < .001, = .001, .002, .023, respectively). In multivariate analysis, PLR (hazard ratios [HR] 1.692; 95% CI 1.054-2.715; P = .029) and FARI (HR 1.496; 95% CI 1.031-2.172; P = .034) were independent prognostic factors for PFS. While only ECOG PS status (HR 2.052; 95% CI 1.272-3.310; P = .003) was independently correlated with OS.FARI is independently associated with PFS in EGFR-Mutant lung adenocarcinoma patients receiving first-line EGFR-TKIs treatment.

Gene-Specific Genetic Complementation between Brca1 and Cobra1 During Mouse Mammary Gland Development.

Germ-line mutations in breast cancer susceptibility gene, BRCA1, result in familial predisposition to breast and ovarian cancers. The BRCA1 protein has multiple functional domains that interact with a variety of proteins in multiple cellular processes. Understanding the biological consequences of BRCA1 interactions with its binding partners is important for elucidating its tissue-specific tumor suppression function. The Cofactor of BRCA1 (COBRA1) is a BRCA1-binding protein that, as a component of negative elongation factor (NELF), regulates RNA polymerase II pausing during transcription elongation. We recently identified a genetic interaction between mouse Brca1 and Cobra1 that antagonistically regulates mammary gland development. However, it remains unclear which of the myriad functions of Brca1 are required for its genetic interaction with Cobra1. Here, we show that, unlike deletion of Brca1 exon 11, separation-of-function mutations that abrogate either the E3 ligase activity of its RING domain or the phospho-recognition property of its BRCT domain are not sufficient to rescue the mammary developmental defects in Cobra1 knockout mice. Furthermore, deletion of mouse Palb2, another breast cancer susceptibility gene with functional similarities to BRCA1, does not rescue Cobra1 knockout-associated mammary defects. Thus, the Brca1/Cobra1 genetic interaction is both domain- and gene-specific in the context of mammary gland development.

Author Correction: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

This corrects the article DOI: 10.1038/ncomms15908.

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

Translational Initiation at a Non-AUG Start Codon for Human and Mouse Negative Elongation Factor-B.

Negative elongation factor (NELF), a four-subunit protein complex in metazoan, plays an important role in regulating promoter-proximal pausing of RNA polymerase II (RNAPII). Genetic studies demonstrate that the B subunit of mouse NELF (NELF-B) is critical for embryonic development and homeostasis in adult tissue. We report here that both human and mouse NELF-B proteins are translated from a non-AUG codon upstream of the annotated AUG. This non-AUG codon sequence is conserved in mammalian NELF-B but not NELF-B orthologs of lower metazoan. The full-length and a truncated NELF-B that starts at the first AUG codon both interact with the other three NELF subunits. Furthermore, these two forms of NELF-B have a similar impact on the transcriptomics and proliferation of mouse embryonic fibroblasts. These results strongly suggest that additional amino acid sequence upstream of the annotated AUG is dispensable for the essential NELF function in supporting cell growth in vitro. The majority of mouse adult tissues surveyed express the full-length NELF-B protein, and some contain a truncated NELF-B protein with the same apparent size as the AUG-initiated version. This result raises the distinct possibility that translational initiation of mouse NELF-B is regulated in a tissue-dependent manner.