Leaf senescence is a developmental process designed for nutrient recycling and relocation to maximize growth competence and reproductive capacity of plants. Thus, plants integrate developmental and ...environmental signals to precisely control senescence. To genetically dissect the complex regulatory mechanism underlying leaf senescence, we identified an early leaf senescence mutant,
rse1
.
RSE1
encodes a putative glycosyltransferase. Loss-of-function mutations in
RSE1
resulted in precocious leaf yellowing and up-regulation of senescence marker genes, indicating enhanced leaf senescence. Transcriptome analysis revealed that salicylic acid (SA) and defense signaling cascades were up-regulated in
rse1
prior to the onset of leaf senescence. We found that SA accumulation was significantly increased in
rse1.
The
rse1
phenotypes are dependent on
SA-INDUCTION DEFICIENT 2
(
SID2
), supporting a role of SA in accelerated leaf senescence in
rse1
. Furthermore, RSE1 protein was localized to the cell wall, implying a possible link between the cell wall and RSE1 function. Together, we show that RSE1 negatively modulates leaf senescence through an
SID2
-dependent SA signaling pathway.
OBJECTIVE:We investigated microsatellite instability (MSI) status and programed cell death ligand 1 (PD-L1) expression as predictors of prognosis and responsiveness to chemotherapy for stage II/III ...gastric cancer.
BACKGROUND:The clinical implications of MSI status and PD-L1 expression in gastric cancer have not been well-elucidated.
METHODS:Tumor specimens and clinical information were collected from patients enrolled in the CLASSIC trial—a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. Five quasi-monomorphic mononucleotide markers were used to assess tumor MSI status. PD-L1 expressions of tumor and stromal immune cells were evaluated using immunohistochemistry.
RESULTS:Of 592 patients, 40 (6.8%) had MSI-high (MSI-H) tumors. Among 582 patients available for immunohistochemistry evaluation, PD-L1 was positive in tumor cells (tPD-L1) of 16 patients (2.7%) and stromal immune cells (sPD-L1) of 165 patients (28.4%). Multivariable analysis of disease-free survival (DFS) showed that MSI-H and sPD-L1-positivity were independent prognostic factors hazard ratio 0.301 (0.123–0.736), 0.714 (0.514–0.991); P = 0.008, 0.044), as were receiving chemotherapy, age, tumor grade, and TNM stage. Although adjuvant chemotherapy improved DFS in the microsatellite-stable (MSS) group (5-year DFS66.8% vs 54.1%; P = 0.002); no benefit was observed in the MSI-H group (5-year DFS83.9% vs 85.7%; P = 0.931). In the MSS group, sPD-L1-negative patients, but not sPD-L1-positive patients, had significant survival benefit from adjuvant chemotherapy compared with surgery only (5-year DFS66.1% vs 50.7%; P = 0.001).
CONCLUSION:MSI status and PD-L1 expression are clinically actionable biomarkers for stratifying patients and predicting benefit from adjuvant chemotherapy after D2 gastrectomy for stage II/III gastric cancer.
The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular ...targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.
The authors reveal the mechanisms of degradation of capacity, charge voltage, and discharge voltage of commercially‐available high‐nickel cathode material when it is cycled without a voltage margin ...by two different charge protocols: constant‐current charging and constant‐current, constant‐voltage charging. With repeated constant‐current charging, the cathode material changes to a non‐periodic cation‐mixed state, which causes a relatively low voltage degradation, whereas during constant‐current, constant‐voltage charging, the cathode material changes from a layered structure to a periodic cation‐mixed spinel‐like phase, with consequent severe voltage decay. This decay results from a reduction in the equilibrium electrode potential and an increase of overpotential which are aggravated in a periodic cation‐mixed state. The findings provide insights into the use of excess Li without charge‐voltage margin in high‐Ni cathode materials.
Constant voltage step at high voltage (4.3 V) entails periodic cation‐mixed states in high‐nickel cathode materials which leads to severe voltage decay. Thus, constant voltage step at high voltage should be avoided for high‐nickel cathode materials. More fundamentally, structural stability of high‐nickel cathode materials should be improved to alleviate lattice distortion induced by the phase transition between two hexagonal phases.
Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its ...clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin‐6/signal transducer and activator of transcription 3 (IL‐6/STAT3) signaling up‐regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL‐6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL‐6, with a concomitant decrease of hypoxia‐inducible factor 1 alpha (HIF‐1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF‐κB) p65 subunit to positively regulate the transcription of HIF‐1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF‐1α and CD133 expression were not observed in Toll‐like receptor 4/IL‐6 double‐knockout mice. Long‐term silencing of CD133 by a lentiviral‐based approach inhibited cancer cell‐cycle progression and suppressed in vivo tumorigenicity by down‐regulating expression of cytokinesis‐related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF‐1α proteins. Conclusion: IL‐6/STAT3 signaling induces expression of CD133 through functional cooperation with NF‐κB and HIF‐1α during liver carcinogenesis. Targeting STAT3‐mediated CD133 up‐regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment. (Hepatology 2015;62:1160‐1173)
Chromosomal instability (CIN) in cancer cells has been reported to activate the cGAS-STING innate immunity pathway via micronuclei formation, thus affecting tumor immunity and tumor progression. ...However, adverse effects of the cGAS/STING pathway as they relate to CIN have not yet been investigated. We addressed this issue using knockdown and add-back approaches to analyze each component of the cGAS/STING/TBK1/IRF3 pathway, and we monitored the extent of CIN by measuring micronuclei formation after release from nocodazole-induced mitotic arrest. Interestingly, knockdown of cGAS (cyclic GMP-AMP synthase) along with induction of mitotic arrest in HeLa and U2OS cancer cells clearly resulted in increased micronuclei formation and chromosome missegregation. Knockdown of STING (stimulator of interferon genes), TBK1 (TANK-binding kinase-1), or IRF3 (interferon regulatory factor-3) also resulted in increased micronuclei formation. Moreover, transfection with cGAMP, the product of cGAS enzymatic activity, as well as add-back of cGAS WT (but not catalytic-dead mutant cGAS), or WT or constitutively active STING (but not an inactive STING mutant) rescued the micronuclei phenotype, demonstrating that all components of the cGAS/STING/TBK1/IRF3 pathway play a role in preventing CIN. Moreover, p21 levels were decreased in cGAS-, STING-, TBK1-, and IRF3-knockdown cells, which was accompanied by the precocious G2/M transition of cells and the enhanced micronuclei phenotype. Overexpression of p21 or inhibition of CDK1 in cGAS-depleted cells reduced micronuclei formation and abrogated the precocious G2/M transition, indicating that the decrease in p21 and the subsequent precocious G2/M transition is the main mechanism underlying the induction of CIN through disruption of cGAS/STING signaling.
Macrophages release iron into the bloodstream via a membrane-bound iron export protein, ferroportin (FPN). The hepatic iron-regulatory hormone hepcidin controls FPN internalization and degradation in ...response to bacterial infection. Salmonella typhimurium can invade macrophages and proliferate in the Salmonella-containing vacuole (SCV). Hepcidin is reported to increase the mortality of Salmonella-infected animals by increasing the bacterial load in macrophages. Here we assess the iron levels and find that hepcidin increases iron content in the cytosol but decreases it in the SCV through FPN on the SCV membrane. Loss-of-FPN from the SCV via the action of hepcidin impairs the generation of bactericidal reactive oxygen species (ROS) as the iron content decreases. We conclude that FPN is required to provide sufficient iron to the SCV, where iron serves as a cofactor for the generation of antimicrobial ROS rather than as a nutrient for Salmonella.
This study investigated whether MSI status can be used as a prognostic biomarker and whether it is helpful for predicting which patients will benefit from 5‐FU based adjuvant chemotherapy. Between ...2005 and 2008, an MSI status examination was performed in 1,990 gastric cancer patients who had undergone curative gastrectomy for gastric adenocarcinoma. MSI was analyzed by PCR amplification with fluorescent dye‐labeled primers of mononucleotide markers (BAT25 and BAT26) and dinucleotide markers (D5S346, D2S123 and D17S250) specific to the microsatellite loci. Patients with MSI‐H tumors accounted for 8.5% (n = 170) of the total study population. They tended to be older and female and to have distal tumor location, lower tumor stage, intestinal type of Lauren classification and differentiated histological type. The disease‐free survival curves showed no significant differences between MSS/MSI‐L and MSI‐H patients at each stage of I, II, III and IV. In gastric cancer patients with stage II and III, 5‐FU‐based adjuvant chemotherapy showed better disease‐free survival in the MSS/MSI‐L group, but showed no benefits in the MSI‐H group. By multivariate analysis, patients with MSS/MSI‐L tumors benefited from 5‐FU‐based adjuvant chemotherapy in terms of tumor disease‐free survival. MSI status in gastric cancer is not itself a prognostic indicator. However, it appears to be a possible guidance for the use of 5‐FU‐based chemotherapy in stage II and III gastric cancers after R0 resection.
Background
Various parameters are used to predict perioperative surgical outcomes. However, no comprehensive studies in gastrectomy have been conducted. This study aimed to compare the performance of ...each parameter in patients with gastric cancer.
Methods
The medical records of 1032 gastric cancer patients who underwent curative gastrectomy between 2009 and 2015 were reviewed. Laboratory values and associated parameters (neutrophil count, lymphocyte count, platelet count, albumin level, Prognostic Nutritional Index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and Systemic Immune-Inflammation Index) as well as body weight-related data and associated parameters body mass index (BMI), percentage of weight loss, Nutritional Risk Screening 2002 assessment, the Malnutrition Universal Screening Tool, and the Nutritional Risk Index were measured and calculated. The study end points were major complications, operative mortality, prolonged hospital stay, overall survival (OS), and recurrence-free survival (RFS).
Results
Multivariable logistic regression analysis showed that male gender, total gastrectomy, advanced-stage gastric cancer, and low albumin level were risk factors for major complications. Old age, total gastrectomy, advanced-stage cancer, and high BMI were risk factors for operative mortality. Old age, open approach, and total gastrectomy were risk factors for prolonged hospital stay. Multivariable Cox proportional hazards models showed that old age, total gastrectomy, advanced-stage cancer, and high neutrophil count were unfavorable risk factors for OS. Old age, advanced-stage cancer, high neutrophil count, and high BMI were unfavorable risk factors for RFS.
Conclusions
Albumin level, BMI, and neutrophil count are the most useful parameters for predicting short- and long-term surgical outcomes. Compared with complex parameters, simple-to-measure parameters are better for predicting surgical outcomes for gastric cancer patients.
Although many studies have demonstrated the excellent potential of hard carbon as an anode in sodium ion batteries, the contribution of its active sites to the capacities of the sloping and plateau ...voltage regions is not yet clear. Herein, systematical investigation of the relationship between the active sites and sodium ion (Na+) storage in the sloping and plateau voltage regions was presented. In light of the physicochemical properties of the lignin-derived hard carbon (graphitization degree, interlayer spacing, micropore size distribution, and specific surface area), the results of Na+ ion diffusivity, and the change in these properties during Na+ ion insertion/extraction (as characterized by ex situ techniques), new mechanistic insights into Na+ ion storage were proposed. At the beginning of the sodiation process, Na+ ions were adsorbed on defect/edge sites; then partial micropore filling occurred in the sloping region above 0.1 V. In the plateau region below 0.1 V, Na+ ions were intercalated in the graphitic layers, and further adsorption in the micropores occurred near the cutoff potential. Furthermore, sodium clustering occurred below 0.1 V owing to the high concentration of Na+ ions in the micropores.
Proposed new sodium ion storage mechanism in hard carbon derived from lignin. At the beginning of the sodiation process, Na+ ions are adsorbed on defect/edge sites; then partial micropore filling occurs in the sloping region above 0.1 V. In the plateau region below 0.1 V, Na+ ions are intercalated in the graphitic layers, and further adsorption in the micropores occurs near the cutoff potential. Furthermore, sodium clustering occurs below 0.1 V owing to the high concentration of Na+ ions in micropores. Display omitted
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