Hepatic-associated vascular morphological assessment to predict overt hepatic encephalopathy before TIPS: a multicenter study.

BACKGROUND: To provide patients the chance of accepting curative transjugular intrahepatic portosystemic shunt (TIPS) rather than palliative treatments for portal hypertension-related variceal bleeding and ascites, we aimed to assess hepatic-associated vascular morphological change to improve the predictive accuracy of overt hepatic encephalopathy (HE) risks. METHODS: In this multicenter study, 621 patients undergoing TIPS were subdivided into training (413 cases from 3 hospitals) and external validation datasets (208 cases from another 3 hospitals). In addition to traditional clinical factors, we assessed hepatic-associated vascular morphological changes using maximum diameter (including absolute and ratio values). Three predictive models (clinical, hepatic-associated vascular, and combined) were constructed using logistic regression. Their discrimination and calibration were compared to test the necessity of hepatic-associated vascular assessment and identify the optimal model. Furthermore, to verify the improved performance of ModelC-V, we compared it with four previous models, both in discrimination and calibration. RESULTS: The combined model outperformed the clinical and hepatic-associated vascular models (training: 0.814, 0.754, 0.727; validation: 0.781, 0.679, 0.776; p < 0.050) and had the best calibration. Compared to previous models, ModelC-V showed superior performance in discrimination. The high-, middle-, and low-risk populations displayed significantly different overt HE incidence (p < 0.001). Despite the limited ability of pre-TIPS ammonia to predict overt HE risks, the combined model displayed a satisfactory ability to predict overt HE risks, both in the low- and high-ammonia subgroups. CONCLUSION: Hepatic-associated vascular assessment improved the predictive accuracy of overt HE, ensuring curative chances by TIPS for suitable patients and providing insights for cirrhosis-related studies.

Body Compositions Correlate With Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt: A Multicentre Cohort Study.

BACKGROUND: The relationship between body composition and the risk of overt hepatic encephalopathy (OHE) following transjugular intrahepatic portosystemic shunt (TIPS) needs to be investigated. METHODS: Overall, 571 patients from 5 medical centers were included. To assess body compositions, we evaluated skeletal muscle indices, adipose tissue indices, sarcopenia, and myosteatosis at the third lumbar vertebral level. Univariate and Multivariate logistic regression analyses were performed to identify independent risk factors for post-TIPS OHE. An integrated score was then constructed using stepwise multiple regression analyses, with a cut-off value selected using the best Youden index. Finally, the Akaike information criterion (AIC) was performed to compare the integrated score and independent risk factors on their ability in predicting post-TIPS OHE. RESULTS: Sarcopenia and all skeletal muscle indices had limited associations with post-TIPS OHE. The index of the subcutaneous adipose tissue (SATI) (P=0.005; OR: 1.034, 95% CI: 1.010-1.058) and myosteatosis (297 cases, 52.01%, 125 with OHE, 42.09%; P=0.003; OR: 1.973; 95% CI: 1.262-3.084) were both ascertained as independent risk factors for post-TIPS OHE. The integrated score (ScoreALL=1.5760 + 0.0107 * SATI + 0.8579 * myosteatosis) was established with a cutoff value of -0.935. The akaike information criterion (AIC) of ScoreALL, SATI, and myosteatosis was 655.28, 691.18, and 686.60, respectively. CONCLUSIONS: SATI and myosteatosis are independent risk factors for post-TIPS OHE. However, the integrated score was more significantly associated with post-TIPS OHE than other skeletal muscle and adipose tissue factors.

Generation of aroma in three-line hybrid rice through CRISPR/Cas9 editing of BETAINE ALDEHYDE DEHYDROGENASE2 (OsBADH2).

Aroma or fragrance in rice is a genetically controlled trait; Its high appreciation by consumers increases the rice market price. Previous studies have revealed that the rice aroma is controlled by a specific gene called BETAINE ALDEHYDE DEHYDROGENASE (OsBADH2), and mutation of this gene leads to the accumulation of an aromatic substance 2-acetyl-1-pyrroline (2-AP). The use of genetic engineering to produce aroma in commercial and cultivated hybrids is a contemporary need for molecular breeding. The current study reports the generation of aroma in the three-line hybrid restorer line Shu-Hui-313 (SH313). We created knock-out (KO) lines of OsBADH2 through the CRISPR/Cas9. The analysis of KO lines revealed a significantly increased content of 2AP in the grains compared with the control. However, other phenotypic traits (plant height, seed setting rate, and 1000-grain weight) were significantly decreased. These KO lines were crossed with a non-aromatic three-line hybrid rice male sterile line (Rong-7-A) to produce Rong-7-You-626 (R7Y626), R7Y627 and R7Y628. The measurement of 2-AP revealed significantly increased contents in these cross combinations. We compared the content of 2-AP in tissues at the booting stage. Data revealed that young spike stalk base contained the highest content of 2-AP and can be used for identification (by simple chewing) of aromatic lines under field conditions. In conclusion, our dataset offers a genetic source and illustrates the generation of aroma in non-aromatic hybrids, and outlines a straightforward identification under field conditions.

Multi-Omics Characteristics of Ferroptosis Associated with Colon Adenocarcinoma Typing and Survival.

BACKGROUND: Ferroptosis, an iron-dependent form of cell death, plays a crucial role in the progression of various cancers, including colon adenocarcinoma (COAD). However, the multi-omics signatures relevant to ferroptosis regulation in COAD diagnosis remain to be elucidated. METHODS: The transcriptomic, miRNAomic, and methylomic profiles of COAD patients were acquired from the Cancer Genome Atlas (TCGA). Ferroptosis activity in these patients was determined, represented by a ferroptosis score (FS), using single-sample gene set enrichment analysis (ssGSEA) based on the expression of ferroptosis-related genes. RESULTS: Results showed that the COAD patients with high-FS displayed favorable survival outcomes and heightened drug sensitivity. They also exhibited an up-regulation of genes involved in immune-related pathways (e.g., tumor necrosis factor signaling pathway), suggesting a correlation between immunity and ferroptosis in COAD progression. Furthermore, three survival prediction models were established based on 10 CpGs, 12 long non-coding RNAs (lncRNAs), and 14 microRNAs (miRNAs), respectively. These models demonstrated high accuracy in predicting COAD survival, achieving areas under the curve (AUC) >0.7. The variables used in the three models also showed strong correlations at different omics levels and were effective at discriminating between high-FS and low-FS COAD patients (AUC >0.7). CONCLUSIONS: This study identified different DNA methylation (DNAm), lncRNA, and miRNA characteristics between COAD patients with high and low ferroptosis activity. Furthermore, ferroptosis-related multi-omics signatures were established for COAD prognosis and classification. These insights present new opportunities for improving the efficacy of COAD therapy.

A modified model for predicting mortality after transjugular intrahepatic portosystemic shunt: A multicentre study.

BACKGROUND AND AIMS: The transjugular intrahepatic portosystemic shunt has controversial survival benefits; thus, patient screening should be performed preoperatively. In this study, we aimed to develop a model to predict post-transjugular intrahepatic portosystemic shunt mortality to aid clinical decision making. METHODS: A total of 811 patients undergoing transjugular intrahepatic portosystemic shunt from five hospitals were divided into the training and external validation data sets. A modified prediction model of post-transjugular intrahepatic portosystemic shunt mortality (ModelMT ) was built after performing logistic regression. To verify the improved performance of ModelMT , we compared it with seven previous models, both in discrimination and calibration. Furthermore, patients were stratified into low-, medium-, high- and extremely high-risk subgroups. RESULTS: ModelMT demonstrated a satisfying predictive efficiency in both discrimination and calibration, with an area under the curve of .875 in the training set and .852 in the validation set. Compared to previous models (ALBI, BILI-PLT, MELD-Na, MOTS, FIPS, MELD, CLIF-C AD), ModelMT showed superior performance in discrimination by statistical difference in the Delong test, net reclassification improvement and integrated discrimination improvement (all p < .050). Similar results were observed in calibration. Low-, medium-, high- and extremely high-risk groups were defined by scores of ≤160, 160-180, 180-200 and >200, respectively. To facilitate future clinical application, we also built an applet for ModelMT . CONCLUSIONS: We successfully developed a predictive model with improved performance to assist in decision making for transjugular intrahepatic portosystemic shunt according to survival benefits.

HCC1, a Polygalacturonase, Regulates Chlorophyll Degradation via the Ethylene Synthesis Pathway.

Chlorophyll degradation is an important physiological process and is essential for plant growth and development. However, how chlorophyll degradation is controlled at the cellular and molecular level remains largely elusive. Pectin is a main component of the primary cell wall, and polygalacturonases (PGs) is a group of pectin-hydrolases that cleaves the pectin backbone and release oligogalacturonide. Whether and how PGs affect chlorophyll degradation metabolism and its association with ethylene (ETH) have not been reported before. Here, we report a novel function of PG in a mutant 'high chlorophyll content1' hcc1, which displayed a decrease in growth and yield. Our morphological, biochemical and genetic analyses of hcc1, knockout lines and complementation lines confirm the function of HCC1 in chlorophyll degradation. In hcc1, the PG activity, ETH content and D-galacturonic acid (D-GA) was significantly decreased and showed an increase in the thickness of the cell wall. Exogenous application of ETH and D-GA can increase ETH content and induce the expression of HCC1, which further can successfully induce the chlorophyll degradation in hcc1. Together, our data demonstrated a novel function of HCC1 in chlorophyll degradation via the ETH pathway.

Model containing sarcopenia and visceral adiposity can better predict the prognosis of hepatocellular carcinoma: a multicenter study.

AIM: This study aimed to explore whether the addition of sarcopenia and visceral adiposity could improve the accuracy of model predicting progression-free survival (PFS) in hepatocellular carcinoma (HCC). METHODS: In total, 394 patients with HCC from five hospitals were divided into the training and external validation datasets. Patients were initially treated by liver resection or transarterial chemoembolization. We evaluated adipose and skeletal muscle using preoperative computed tomography imaging and then constructed three predictive models, including metabolic (ModelMA), clinical-imaging (ModelCI), and combined (ModelMA-CI) models. Their discrimination, calibration, and decision curves were compared, to identify the best model. Nomogram and subgroup analysis was performed for the best model. RESULTS: ModelMA-CI containing sarcopenia and visceral adiposity had good discrimination and calibrations (integrate area under the curve for PFS was 0.708 in the training dataset and 0.706 in the validation dataset). ModelMA-CI had better accuracy than ModelCI and ModelMA. The performance of ModelMA-CI was not affected by treatments or disease stages. The high-risk subgroup (scored > 198) had a significantly shorter PFS (p < 0.001) and poorer OS (p < 0.001). CONCLUSIONS: The addition of sarcopenia and visceral adiposity improved accuracy in predicting PFS in HCC, which may provide additional insights in prognosis for HCC in subsequent studies.

3D automatic liver and spleen assessment in predicting overt hepatic encephalopathy before TIPS: a multi-center study.

BACKGROUND: Overt hepatic encephalopathy (HE) should be predicted preoperatively to identify suitable candidates for transjugular intrahepatic portosystemic shunt (TIPS) instead of first-line treatment. This study aimed to construct a 3D assessment-based model to predict post-TIPS overt HE. METHODS: In this multi-center cohort study, 487 patients who underwent TIPS were subdivided into a training dataset (390 cases from three hospitals) and an external validation dataset (97 cases from another two hospitals). Candidate factors included clinical, vascular, and 2D and 3D data. Combining the least absolute shrinkage and operator method, support vector machine, and probability calibration by isotonic regression, we constructed four predictive models: clinical, 2D, 3D, and combined models. Their discrimination and calibration were compared to identify the optimal model, with subgroup analysis performed. RESULTS: The 3D model showed better discrimination than did the 2D model (training: 0.719 vs. 0.691; validation: 0.730 vs. 0.622). The model combining clinical and 3D factors outperformed the clinical and 3D models (training: 0.802 vs. 0.735 vs. 0.719; validation: 0.816 vs. 0.723 vs. 0.730; all p < 0.050). Moreover, the combined model had the best calibration. The performance of the best model was not affected by the total bilirubin level, Child-Pugh score, ammonia level, or the indication for TIPS. CONCLUSION: 3D assessment of the liver and the spleen provided additional information to predict overt HE, improving the chance of TIPS for suitable patients. 3D assessment could also be used in similar studies related to cirrhosis.

Establishment and verification of prognostic model and ceRNA network analysis for colorectal cancer liver metastasis.

OBJECTS: Colorectal cancer (CRC) is one of the most common cancers in the world. Approximately two-thirds of patients with CRC will develop colorectal cancer liver metastases (CRLM) at some point in time. In this study, we aimed to construct a prognostic model of CRLM and its competing endogenous RNA (ceRNA) network. METHODS: RNA-seq of CRC, CRLM and normal samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Limma was used to obtain differential expression genes (DEGs) between CRLM and CRC from sequencing data and GSE22834, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses were performed, respectively. Univariate Cox regression analysis and lasso Cox regression models were performed to screen prognostic gene features and construct prognostic models. Functional enrichment, estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, single-sample gene set enrichment analysis, and ceRNA network construction were applied to explore potential mechanisms. RESULTS: An 8-gene prognostic model was constructed by screening 112 DEGs from TCGA and GSE22834. CRC patients in the TCGA and GSE29621 cohorts were stratified into either a high-risk group or a low-risk group. Patients with CRC in the high-risk group had a significantly poorer prognosis compared to in the low-risk group. The risk score was identified as an independent predictor of prognosis. Functional analysis revealed that the risk score was closly correlated with various immune cells and immune-related signaling pathways. And a prognostic gene-associated ceRNA network was constructed that obtained 3 prognosis gene, 14 microRNAs (miRNAs) and 7 long noncoding RNAs (lncRNAs). CONCLUSIONS: In conclusion, a prognostic model for CRLM identification was proposed, which could independently identify high-risk patients with low survival, suggesting a relationship between local immune status and prognosis of CRLM. Moreover, the key prognostic genes-related ceRNA network were established for the CRC investigation. Based on the differentially expressed genes between CRLM and CRC, the prognosis model of CRC patients was constructed.

Protein homeostasis in aging and cancer.

Aging is a major risk factor for cancer development. As dysfunction in protein homeostasis, or proteostasis, is a universal hallmark of both the aging process and cancer, a comprehensive understanding of the proteostasis system and its roles in aging and cancer will shed new light on how we can improve health and quality of life for older individuals. In this review, we summarize the regulatory mechanisms of proteostasis and discuss the relationship between proteostasis and aging and age-related diseases, including cancer. Furthermore, we highlight the clinical application value of proteostasis maintenance in delaying the aging process and promoting long-term health.

Saikosaponin A enhances Docetaxel efficacy by selectively inducing death of dormant prostate cancer cells through excessive autophagy.

Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.

A putative SUBTILISIN-LIKE SERINE PROTEASE 1 (SUBSrP1) regulates anther cuticle biosynthesis and panicle development in rice.

INTRODUCTION: Panicle abortion is a severe physiological defect and causes a reduction in grain yield. OBJECTIVES: In this study, we aim to provide the characterization and functional analysis of a mutant apa1331 (apical panicle abortion1331). METHODS: The isolated mutant from an EMS-mutagenized population was subjected to SSR analysis and Mutmap assay for candidate gene mapping. We performed phenotypic analysis, anthers cross-sections morphology, wax and cutin profiling, biochemical assays and phylogenetic analysis for characterization and evaluation of apa1331. We used CRISPR/Cas9 disruption for functional validation of its candidate gene. Furthermore, comparative RNA-seq and relative expression analysis were performed to get further insights into mechanistic role of the candidate gene. RESULTS: The anthers from the apical spikelets of apa1331 were degenerated, pollen-less and showed defects in cuticle formation. Transverse sections of apa1331 anthers showed defects in post-meiotic microspore development at stage 8-9. Gas Chromatography showed a significant reduction of wax and cutin in anthers of apa1331 compared to Wildtype (WT). Quantification of H2O2 and MDA has indicated the excessive ROS (reactive oxygen species) in apa1331. Trypan blue staining and TUNEL assay revealed cell death and excessive DNA fragmentation in apa1331. Map-based cloning and Mutmap analysis revealed that LOC_Os04g40720, encoding a putative SUBTILISIN-LIKE SERINE PROTEASE (OsSUBSrP1), harbored an SNP (A > G) in apa1331. Phenotypic defects were only seen in apical spikelets due to highest expression of OsSUBSrP1 in upper panicle portion. CRISPR-mediated knock-out lines of OsSUBSrP1 displayed spikelet abortion comparable to apa1331. Global gene expression analysis revealed a significant downregulation of wax and cutin biosynthesis genes. CONCLUSIONS: Our study reports the novel role of SUBSrP1 in anther cuticle biosynthesis by ROS-mediated programmed cell death in rice.

Investigation of flavonoid components and their associated antioxidant capacity in different pigmented rice varieties.

Black and red rice are flavonoid-rich and nutritious. However, comprehensive information of flavonoid components in different pigmented rice varieties remain unclear. Here, we analyze the differences in flavonoid components in black, red, and white rice by ultra-high-performance liquid chromatography (UPLC) and metabolome analysis. Cyanidin-3-glucoside (Cy-3-G), peonidin-3-glucoside (Pe-3-G), quercetin, dihydromyricetin, naringin, and taxifolin contents were significantly high in black rice. By contrast, catechin and epicatechin contents were substantial in red rice. Cy-3-G was the main anthocyanin and its content was more than four times that of Pe-3-G in black rice varieties. Trifolin hardly showed specificity and exhibited a high content in all rice varieties. The antioxidant capacity of the red and black rice varieties was significantly higher than that of white rice. Moreover, in black and red rice, quercetin and catechin respectively exhibited the strongest antioxidant capacity and a good contribution toward the total flavonoid content, and mean time, white rice possessed antioxidant capacity main derived from quercetin and trifolin. Besides, the study also found that there was slightly inconsistent results between UPLC and metabolome, because certain components with trace by metabolome were not detected by UPLC, but their combination could play a complementary role in the exploration of metabolic components to confirm the ingredients.

Enhanced Effects of Iron on Mycelial Growth, Metabolism and In Vitro Antioxidant Activity of Polysaccharides from Lentinula edodes.

The polysaccharides found in Lentinula edodes have a variety of medicinal properties, such as anti-tumor and anti-viral effects, but their content in L. edodes sporophores is very low. In this study, Fe2+ was added to the liquid fermentation medium of L. edodes to analyze its effects on mycelial growth, polysaccharide and enzyme production, gene expression, and the activities of enzymes involved in polysaccharide biosynthesis, and in vitro antioxidation of polysaccharides. The results showed that when 200 mg/L of Fe2+ was added, with 7 days of shaking at 150 rpm and 3 days of static culture, the biomass reached its highest value (0.28 mg/50 mL) 50 days after the addition of Fe2+. Besides, Fe2+ addition also enhanced intracellular polysaccharide (IPS) and exopolysaccharide (EPS) productions, the levels of which were 2.98- and 1.79-fold higher than the control. The activities of the enzymes involved in polysaccharides biosynthesis, including phosphoglucomutase (PGM), phosphoglucose isomerase (PGI), and UDPG-pyrophosphorylase (UGP) were also increased under Fe2+ addition. Maximum PGI activity reached 1525.20 U/mg 30 days after Fe2+ addition, whereas PGM and UGP activities reached 3607.05 U/mg and 3823.27 U/mg 60 days after Fe2+ addition, respectively. The Pearson correlation coefficient showed a strong correlation (p < 0.01) between IPS production and PGM and UGP activities. The corresponding coding genes of the three enzymes were also upregulated. When evaluating the in vitro antioxidant activities of polysaccharides, EPS from all Fe2+-treated cultures exhibited significantly better capacity (p < 0.05) for scavenging -OH radicals. The results of the two-way ANOVA indicated that the abilities of polysaccharides to scavenge O2− radicals were significantly (p < 0.01) affected by Fe2+ concentration and incubation time. These results indicated that the addition of iron provided a good way to achieve desirable biomass, polysaccharide production, and the in vitro antioxidation of polysaccharides from L. edodes.

Rice ß-Glucosidase 4 (Os1ßGlu4) Regulates the Hull Pigmentation via Accumulation of Salicylic Acid.

Salicylic acid (SA) is a stress hormone synthesized in phenylalanine ammonia-lyase (PAL) and the branching acid pathway. SA has two interconvertible forms in plants: SAG (SA O-ß-glucoside) and SA (free form). The molecular mechanism of conversion of SA to SAG had been reported previously. However, which genes regulate SAG to SA remained unknown. Here, we report a cytoplasmic ß-glucosidase (ß-Glu) which participates in the SA pathway and is involved in the brown hull pigmentation in rice grain. In the current study, an EMS-generated mutant brown hull 1 (bh1) displayed decreased contents of SA in hulls, a lower photosynthesis rate, and high-temperature sensitivity compared to the wild type (WT). A plaque-like phenotype (brown pigmentation) was present on the hulls of bh1, which causes a significant decrease in the seed setting rate. Genetic analysis revealed a mutation in LOC_Os01g67220, which encodes a cytoplasmic Os1ßGlu4. The knock-out lines displayed the phenotype of brown pigmentation on hulls and decreased seed setting rate comparable with bh1. Overexpression and complementation lines of Os1ßGlu4 restored the phenotype of hulls and normal seed setting rate comparable with WT. Subcellular localization revealed that the protein of Os1ßGlu4 was localized in the cytoplasm. In contrast to WT, bh1 could not hydrolyze SAG into SA in vivo. Together, our results revealed the novel role of Os1ßGlu4 in the accumulation of flavonoids in hulls by regulating the level of free SA in the cellular pool.

Phytohormones and Transcriptome Analyses Revealed the Dynamics Involved in Spikelet Abortion and Inflorescence Development in Rice.

Panicle degeneration, sometimes known as abortion, causes heavy losses in grain yield. However, the mechanism of naturally occurring panicle abortion is still elusive. In a previous study, we characterized a mutant, apical panicle abortion1331 (apa1331), exhibiting abortion in apical spikelets starting from the 6 cm stage of panicle development. In this study, we have quantified the five phytohormones, gibberellins (GA), auxins (IAA), abscisic acid (ABA), cytokinins (CTK), and brassinosteroids (BR), in the lower, middle, and upper parts of apa1331 and compared these with those exhibited in its wild type (WT). In apa331, the lower and middle parts of the panicle showed contrasting concentrations of all studied phytohormones, but highly significant changes in IAA and ABA, compared to the upper part of the panicle. A comparative transcriptome of apa1331 and WT apical spikelets was performed to explore genes causing the physiological basis of spikelet abortion. The differential expression analysis revealed a significant downregulation and upregulation of 1587 and 978 genes, respectively. Hierarchical clustering of differentially expressed genes (DEGs) revealed the correlation of gene ontology (GO) terms associated with antioxidant activity, peroxidase activity, and oxidoreductase activity. KEGG pathway analysis using parametric gene set enrichment analysis (PGSEA) revealed the downregulation of the biological processes, including cell wall polysaccharides and fatty acids derivatives, in apa1331 compared to its WT. Based on fold change (FC) value and high variation in expression during late inflorescence, early inflorescence, and antherdevelopment, we predicted a list of novel genes, which presumably can be the potential targets of inflorescence development. Our study not only provides novel insights into the role of the physiological dynamics involved in panicle abortion, but also highlights the potential targets involved in reproductive development.

Development and external validation of prognostic nomograms for liver disease-free and overall survival in locally advanced rectal cancer with neoadjuvant therapy: a post cohort study based on the FOWARC trial.

Background: There is still a lack of nomograms that can accurately predict liver metastasis and poor prognosis after neoadjuvant therapy for locally advanced rectal cancer (LARC). Effective nomograms may help clinicians better identify LARC patients with potential high-risk risks, so as to carry out more targeted monitoring, treatment and follow-up. Methods: The nomograms were based on the FOWARC trial (NCT01211210), which included 302 LARC patients who underwent neoadjuvant treatment before surgery at the Sixth Affiliated Hospital of Sun Yat-sen University from 2011 to 2014. The predictive accuracy and discriminative ability of the nomograms were determined by the concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling and a prospective study on 100 patients in 2017. Results: The 3-year liver disease-free survival (LDFS) rate after neoadjuvant treatment for LARC was 91.65% (training cohort 92.22%, validation cohort 90.01%). Factors associated with LDFS were hepatitis B virus (HBV) infection, anemia, lymph node number, postoperative T stage and tumor nodule, which were all included in the nomogram for LDFS. The C-indies of the nomogram for LDFS were 0.828 and 0.845 in the training and validation cohorts. The 3-year overall survival (OS) rate was 94.14% (training cohort 94.13%, validation cohort 94.05%). Factors in the nomogram for OS were mesorectal fascia involvement (MRF), postoperative N stage, pathological differentiation, tumor nodule and neural invasion. The C-indies of the nomogram for predicting OS were 0.73 and 0.774 in the training and validation cohorts. The calibration curve for the survival probability showed good agreement between the nomogram predictions and the actual observations. Conclusions: The nomograms established in this study can effectively predict LDFS and has good clinical application potential for OS in LARC patients treated with neoadjuvant therapy.

Crosstalk between the Circadian Clock and Histone Methylation.

The circadian clock and histone modifications could form a feedback loop in Arabidopsis; whether a similar regulatory mechanism exists in rice is still unknown. Previously, we reported that SDG724 and OsLHY are two rice heading date regulators in rice. SDG724 encodes a histone H3K36 methyltransferase, and OsLHY is a vital circadian rhythm transcription factor. Both could be involved in transcription regulatory mechanisms and could affect gene expression in various pathways. To explore the crosstalk between the circadian clock and histone methylation in rice, we studied the relationship between OsLHY and SDG724 via the transcriptome analysis of their single and double mutants, oslhy, sdg724, and oslhysdg724. Screening of overlapped DEGs and KEGG pathways between OsLHY and SDG724 revealed that they could control many overlapped pathways indirectly. Furthermore, we identified three candidate targets (OsGI, OsCCT38, and OsPRR95) of OsLHY and one candidate target (OsCRY1a) of SDG724 in the clock pathway. Our results showed a regulatory relationship between OsLHY and SDG724, which paved the way for revealing the interaction between the circadian clock and histone H3K36 methylation.