Comprehensive evaluation of serum hepatic proteins in predicting prognosis among cancer patients with cachexia: an observational cohort study.

BACKGROUND: Hepatic proteins, including albumin, prealbumin, and transferrin have been confirmed to be prognostic predictors in various cancers. This study aimed to comprehensively assess the prognostic value of these three serum markers in patients with cancer cachexia. METHODS: This multicenter prospective cohort study included 1303 cancer cachexia patients, among whom 592 deaths occurred during a median follow-up of 20.23 months. The definition of cachexia was based on the 2011 international consensus. Concordance index (C-index) and receiver operating characteristic (ROC) curves were applied to compare the prognostic performance. The primary outcome was overall survival, which was calculated using the Kaplan-Meier method generated by log-rank test. A Cox proportional hazard regression model was used to identify independent predictors associated with survival. The secondary outcomes included 90-days mortality and quality of life (QoL). RESULTS: C-index and ROC curves showed that albumin had the most accurate predictive capacity for survival, followed by transferrin and prealbumin. Multivariate Cox analysis confirmed that low albumin (hazard ratio [HR] = 1.51, 95% confidence interval [95%CI] = 1.28-1.80, P < 0.001), prealbumin (HR = 1.42, 95%CI = 1.19-1.69, P < 0.001), and transferrin (HR = 1.50, 95%CI = 1.25-1.80, P < 0.001) were independent risk factors for long-term survival in cancer patients with cachexia. In subgroup analysis, the prognostic value of low albumin was significant in patients with upper gastrointestinal, hepatobiliary and pancreatic, and colorectal cancers; low prealbumin was significant in colorectal cancer; and low transferrin was significant in patients with upper gastrointestinal and colorectal cancer. All three hepatic proteins were valuable as prognostic predictors for patients with advanced (Stage III and IV) cancer with cachexia. The risks of 90-days mortality and impaired QoL were higher in cachexia patients with low albumin, prealbumin, and transferrin levels. CONCLUSION: Low albumin, prealbumin, and transferrin levels were all independent prognostic factors affecting patients with cancer cachexia, especially in patients in the advanced stages. These results highlight the value of routinely checking serum hepatic proteins in clinical practice to predict the prognosis of patients with cancer cachexia.

Development and validation of an inflammatory biomarkers model to predict gastric cancer prognosis: a multi-center cohort study in China.

BACKGROUND: Inflammatory factors have increasingly become a more cost-effective prognostic indicator for gastric cancer (GC). The goal of this study was to develop a prognostic score system for gastric cancer patients based on inflammatory indicators. METHODS: Patients' baseline characteristics and anthropometric measures were used as predictors, and independently screened by multiple machine learning(ML) algorithms. We constructed risk scores to predict overall survival in the training cohort and tested risk scores in the validation. The predictors selected by the model were used in multivariate Cox regression analysis and developed a nomogram to predict the individual survival of GC patients. RESULTS: A 13-variable adaptive boost machine (ADA) model mainly comprising tumor stage and inflammation indices was selected in a wide variety of machine learning models. The ADA model performed well in predicting survival in the validation set (AUC = 0.751; 95% CI: 0.698, 0.803). Patients in the study were split into two sets - "high-risk" and "low-risk" based on 0.42, the cut-off value of the risk score. We plotted the survival curves using Kaplan-Meier analysis. CONCLUSION: The proposed model performed well in predicting the prognosis of GC patients and could help clinicians apply management strategies for better prognostic outcomes for patients.

Humoral immune response to tumor-associated antigen Ubiquilin 1 (UBQLN1) and its tumor-promoting potential in lung cancer.

BACKGROUND: This study aims to investigate the expression of UBQLN1 in lung cancer (LC) tissue and the diagnostic capability of autoantibody to UBQLN1 (anti-UBQLN1) in the detection of LC and the discrimination of pulmonary nodules (PNs). METHODS: Sera from 798 participants were used to discover and validate the level of autoantibodies via HuProt microarray and Enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was applied to establish model. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the diagnostic potential. Immunohistochemistry was performed to detect UBQLN1 expression in 88 LC tissues and 88 para-tumor tissues. qRT-PCR and western blotting were performed to detect the expression of UBQLN1 at the mRNA and protein levels, respectively. Trans-well assay and cell counting kit-8 (CCK-8) was used to investigate the function of UBQLN1. RESULTS: Anti-UBQLN1 was identified with the highest fold change by protein microarray. The level of anti-UBQLN1 in LC patients was obviously higher than that in NC or patients with benign lung disease of validation cohort 1 (P<0.05). The area under the curve (AUC) of anti-UBQLN1 was 0.610 (95%CI: 0.508-0.713) while reached at 0.822 (95%CI: 0.784-0.897) when combining anti-UBQLN1 with CEA, CYFRA21-1, CA125 and three CT indicators (vascular notch sign, lobulation sign and mediastinal lymph node enlargement) in the discrimination of PNs. UBQLN1 protein was overexpressed in lung adenocarcinoma (LUAD) tissues compared to para-tumor tissues. UBQLN1 knockdown remarkably inhibited the migration, invasion and proliferation of LUAD cell lines. CONCLUSIONS: Anti-UBQLN1 might be a potential biomarker for the diagnosis of LC and the discrimination of PNs.

De novo transcriptome assembly and molecular response mechanism analysis of a diatom Cyclotella meneghiniana Kützing exposed to cadmium.

Cadmium is a persistent heavy metal commonly found in aquatic ecosystems and has a strong toxic effect on organisms. The sensitivity of phytoplankton to environmental changes and its role as an indicator of aquatic ecosystem health have been well-established. However, the mechanisms by which phytoplankton respond to cadmium remain incompletely understood. In this study, we chose the typical planktonic diatom Cyclotella meneghiniana Kützing, by integrating physiological-biochemical data and transcriptome analysis, to reveal the molecular mechanisms of C. meneghiniana responing to cadmium. Under cadmium stress, the cell density and chlorophyll-a content of C. meneghiniana significantly decreased, while MDA content and SOD activity gradually increased. At 72 h of cadmium stress, we found that at this time point, cell abundance and physiological variation were very significant, therefore we selected 72 h for subsequent analysis. To better understand the cadmium stress response mechanisms of C. meneghiniana, a de novo transcriptome method was used to analyse C. meneghiniana under cadmium stress for 72 h, and 1704 (M vs. CK) and 4788 (H vs. CK) differentially expressed genes were found. Our results showed that the changes in gene expression were closely correlated to the physiological-biochemical changes. Although cadmium stress could promote the nitrogen metabolism pathway, ROS scavenging system, and photosynthesis. While, C. meneghiniana under medium and high concentrations of cadmium can also limit various intracellular metabolic pathways, such as the MAPK pathway and phosphatidylinositol metabolic pathway, and the degree of inhibition increases with the increase of stress concentration. In present study, the complete molecular mechanism of the planktonic diatom response to cadmium has been established, which provided important information for further studies on heavy metal pollutants and the multiple functional genes responsible for cadmium sensitivity and tolerance in planktonic diatoms.

Matrine suppresses hepatocellular carcinoma tumorigenesis by modulating circ_0055976/miR-1179/lactate dehydrogenase A axis.

BACKGROUND: Matrine has been identified to have anticancer activity in hepatocellular carcinoma (HCC). Circ_0055976 was highly expressed in HCC. Here, we investigated the function and relationship of Matrine and circ_0055976 in HCC tumorigenesis. METHODS: Cell proliferation and invasion were detected using Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine (EdU), colony formation and transwell assays, respectively. Cell aerobic glycolysis was evaluated by detecting glucose consumption, lactate production, and the ratios of ATP/ADP. Levels of genes and proteins were detected by quantitative real-time polymerase chain reaction and Western blotting. The target relationship between miR-1179 and circ_0055976 or lactate dehydrogenase A (LDHA) was analyzed by dual-luciferase reporter assay. The mouse xenograft model was established to conduct the in vivo assay. RESULTS: Matrine suppressed HCC cell proliferation, invasion and anaerobic glycolysis in vitro. Circ_0055976 was highly expressed in HCC tissues and cells, and was reduced by Matrine treatment. Moreover, overexpression of circ_0055976 reversed the anticancer effects of Matrine in HCC cells. Mechanistically, circ_0055976/miR-1179/LDHA formed an axis. Circ_0055976 knockdown or miR-1179 overexpression impaired HCC cell proliferation, invasion, and anaerobic glycolysis, which were reversed by miR-1179 inhibition or LDHA overexpression. Meanwhile, forced expression of LDHA abolished the regulatory effects of Matrine on HCC cells. In the clinic, Matrine impeded HCC tumor growth in vivo, and this effect was boosted after circ_0055976 silencing. CONCLUSION: Matrine suppressed HCC cell proliferation, invasion, and anaerobic glycolysis via circ_0055976/miR-1179/LDHA axis, providing a new insight into the clinical application of Matrine in HCC treatment.

Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.

Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.

Autoantibody signatures discovered by HuProt protein microarray to enhance the diagnosis of lung cancer.

This study aims to discover novel autoantibodies against tumor-associated antigens (TAAs) and establish diagnostic models for assisting in the diagnosis of lung cancer and discrimination of pulmonary nodules (PNs). Ten autoantibodies to TAAbs (TAAbs) were discovered by means of protein microarray and their serum level was also higher in 212 LC patients than that in 212 NC of validation cohort 1 (P < 0.05). The model 1 comprising 4 TAAbs and CEA reached an AUC of 0.813 (95%CI: 0.762-0.864) for diagnosing LC from normal individuals. Five TAAbs existed a significant difference between 105 malignant pulmonary nodules (MPNs) and 105 benign pulmonary nodules (BPNs) patients in validation cohort 2 (P < 0.05). Model 2 could distinguish MPNs from BPNs with an AUC of 0.845. High-throughput protein microarray is an efficient approach in discovering novel TAAbs which could be used as biomarkers in lung cancer diagnosis.

Habitually Skipping Breakfast Is Associated with the Risk of Gastrointestinal Cancers: Evidence from the Kailuan Cohort Study.

BACKGROUND: Habitually skipping breakfast may promote the initiation and progression of gastrointestinal (GI) cancers, which have never been systematically explored in large-scale prospective studies. METHODS: We prospectively examined the effects of breakfast frequency on the occurrence of GI cancers among 62,746 participants. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of GI cancers were calculated by Cox regression. The CAUSALMED procedure was used to perform the mediation analyses. RESULTS: During a median follow-up of 5.61 (5.18 ~ 6.08) years, 369 incident GI cancer cases were identified. Participants who consumed 1-2 times breakfasts per week exhibited an increased risk of stomach (HR = 3.45, 95% CI: 1.06-11.20) and liver cancer (HR = 3.42, 95% CI: 1.22-9.53). Participants who did not eat breakfast had an elevated risk of esophageal (HR = 2.72, 95% CI: 1.05-7.03), colorectal (HR = 2.32, 95% CI: 1.34-4.01), liver (HR = 2.41, 95% CI: 1.23-4.71), gallbladder, and extrahepatic bile duct cancer (HR = 5.43, 95% CI: 1.34-21.93). In the mediation effect analyses, BMI, CRP, and TyG (fasting triglyceride-glucose) index did not mediate the association between breakfast frequency and the risk of GI cancer incidence (all P for mediation effect > 0.05). CONCLUSIONS: Habitually skipping breakfast was associated with a greater risk of GI cancers including esophageal, gastric, colorectal, liver, gallbladder, and extrahepatic bile duct cancer. TRIAL REGISTRATION: Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050.

Malnutrition diagnosed by GLIM criteria better predicts long-term outcomes for patients with non-Hodgkin's lymphoma: A prospective multicenter cohort study.

Since Global Leadership Initiative on Malnutrition (GLIM) method was proposed, few studies have applied these new criteria to hematological tumors. In this study, we explored the prevalence of malnutrition according to the GLIM criteria and scored Patient-Generated Subjective Global Assessment (sPG-SGA) and their association with 1-year, 3-year and 5-year mortality among patients with non-Hodgkin's lymphoma (NHL). Malnutrition of all patients were assessed by GLIM criteria and sPG-SGA. Relationship between the malnutrition based on GLIM criteria or sPG-SGA and mortality was investigated by Cox regression analyses. The performance of GLIM criteria was evaluated by assessing the sensitivity, specificity, k-value, receiver operating characteristic (ROC) curve and time-dependent ROC. Of 963 patients with NHL, the prevalence of malnutrition was 38.8% with GLIM criteria, 65.3% with GLIM-omitted NRS-2002 and 53.2% with sPG-SGA. In comparison with sPG-SGA, the sensitivity of GLIM criteria was 61.7%, the specificity was 84.8%, and the agreement was moderate (k = 0.48, p < 0.001). Malnutrition based on GLIM criteria could also predict 3-year and 5-year mortality after adjusting for confounders, except for sPG-SGA (HR = 1.816, 95%CI = 1.274-2.589, p = 0.001 for 3-year mortality; HR = 1.707, 95%CI = 1.223-2.382, p = 0.002 for 5-year mortality). For patients with NHL, GLIM criteria could be applied as an effective replacement to sPG-SGA for nutrition assessment and mortality prediction, especially for predicting long-term prognostic outcomes.

Association of Phase Angle with Overall Survival in Patients with Cancer: A Prospective Multicenter Cohort Study.

Low phase angle (PhA) is related with poor clinical status of cancer patients. The objective of this study was to establish sex- and age-specific cutoff points and examine the association between PhA and overall survival (OS) in Chinese cancer patients. This cohort study included data on 1,814 patients with cancer from December 2013 to October 2020. The association between low PhA and overall survival was analyzed using the Kaplan-Meier method and Cox regression model. Among 1,814 participants, there were 993 (54.70%) male and 821 (45.30%) female patients. The optimal cutoff points of low PhA were 4.8°, 4.2°, 4.4°, and 3.8° for the young male, elderly male, young female, and elderly female, respectively. Low PhA was independently associated with poorer OS in young female, elderly female and male (HR: 1.59, 95% CI: 1.08-2.34; HR: 1.65, 95% CI: 1.03-2.67; HR: 2.00, 95% CI: 1.45-2.75). In addition, low PhA was demonstrated to be an adverse prognostic factor in patients with lung cancer, colorectal cancer, and esophagus cancer (HR: 1.85, 95% CI: 1.39-2.47; HR: 2.05, 95% CI: 1.13-3.70; HR: 2.92, 95% CI: 1.49-5.71). Based on cutoff points, low PhA was associated with worse prognosis in patients with cancer.

Nutritional status and its correlation to prognosis of nasopharyngeal carcinoma patients in different ages in China: a multicenter cohort study.

Nasopharyngeal carcinoma (NPC) patients usually presented malnutrition under chemoradiotherapy (CRT)/radiotherapy (RT). Few studies stratified by age to investigate the association of nutritional status with overall survival (OS) in NPC patients. This study aimed to explore the nutritional parameters related prognosis of NPC patients in different age. The total 1365 NPC patients were classified into young (18~45), middle-aged (46~60), and old groups (> 60). PG-SGA scores, NRS-2002 scores, Karnofsky performance status scores, anthropometric, and blood indicators (albumin, prealbumin, transferrin, C-reactive protein, hemoglobin, and total lymphocyte) were assessed. Cox regression analysis was performed to evaluate the association between risk factors of nutritional status and the overall survival in different age group of NPC patients. Kaplan-Meier (KM) survival analysis was used to estimate the effect of nutritional indexes on prognosis. The abnormal rate of albumin, prealbumin, hemoglobin, hand grip strength, and calf circumference increased with age. The malnutrition occurred in all age group and low calf circumference (HR, 4.427, 1.167-16.791) was an independent death risk in young adults. Distant metastasis (HR, 4.754, 2.737-8.260), low albumin (HR, 3.530, 1.708-7.296), hand grip strength (HR, 1.901, 1.160-3.115), and the nutritional intervention requirement (NRS-2002 ≥ 3) (HR, 2.802, 1.211-6.483) was significantly correlated with poor OS in NPC patients with middled age adults. Distant metastasis (HR, 2.546, 1.497-4.330), low albumin (HR, 1.824, 0.949-3.507), low hemoglobin (HR, 1.757, 1.015-3.044), low hand grip strength (HR, 1.771, 1.112-2.818), and low calf circumference (HR, 1.951, 1.074-3.545) were associated with increased risk of death in the elderly. KM analysis indicated that over 60 years, distant metastasis, low albumin, low hand grip strength, low calf circumference, and malnutritional risk (NRS-2002 ≥ 3) were correlated to prognosis of NPC patients. Low calf circumference could be a prognosis not only in elderly but also in young adults of NPC patients, whereas low albumin and distant metastasis were the prognostic factors in middle-aged and elderly patients. Patients aged over 60 years exhibited poorer OS compared with young and middle-aged adults.

A comprehensive analysis of the association between anemia and systemic inflammation in older patients with cancer.

PURPOSE: Our study aimed to comprehensively analyze the association between anemia and systemic inflammation in older patients with cancer. METHODS: This multicenter prospective cohort study included 4955 older patients with cancer between 2013 and 2020. Logistic regression analysis was performed to investigate risk factors of anemia, reporting odds ratios (ORs), and 95% confidence intervals (CIs). Comprehensive survival analyses, including Kaplan-Meier curve, Cox proportional risk model, and subgroup analysis, were performed. RESULTS: The participants' median age was 70.0 (interquartile range [IQR]=67.0-74.0) years, with 3293 (66.5%) males and 1662 (33.5%) females. There were 1717 (34.7%) older patients with cancer diagnosed with anemia. High neutrophil-to-lymphocyte ratio (NLR) was an independent risk factor associated with anemia (adjusted OR=1.97, 95%CI=1.73-2.24, P<0.001). In older patients with cancer and different anemia levels, the median overall survival was significantly shorter in those with a high NLR. In multivariate Cox analysis, high NLR served as a negative factor, independently affecting survival. The anemia-inflammation prognostic grading system showed a significant survival discriminative performance in older patients with cancer. After adjusting for confounders, high grades were independent risk factors for survival (grade 2: hazard ratio [HR] = 1.38, 95%CI = 1.26-1.52, P<0.001; grade 3: HR=1.82 95%CI = 1.59-2.09, P<0.001). This grading system was beneficial in determining survival in patients with lung, digestive tract, and urogenital cancers. CONCLUSIONS: Increased systemic inflammation is an independent risk factor for anemia. A high inflammatory status is also associated with poor survival in older cancer patients at different anemia levels. The anemia-inflammation grading system is beneficial for determining the prognosis in older patients with cancer.

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling.

Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.

Hepatitis B virus infection and the risk of gastrointestinal cancers among Chinese population: A prospective cohort study.

Our study aims to explore the relationship between chronic hepatitis B virus (HBV) infection and the risk of gastrointestinal (GI) cancers including liver, gastric, gallbladder or extrahepatic bile duct, pancreatic, small intestine, esophageal and colorectal cancer in the Kailuan Cohort study. We prospectively examined the relationship between HBV infection and new-onset GI cancers among 93 402 participants. Cox proportional hazards regression models, subgroup analyses and competing risk analyses were used to evaluate the association between HBV infection and the risk of new-onset GI cancers. During a median follow-up of 13.02 years, 1791 incident GI cancer cases were diagnosed. Compared to HBsAg seronegative participants, a significant positive association between HBV infection and GI cancers was observed in the multivariate-adjusted models (HR 5.59, 95% CI: 4.84-6.45). In the site-specific analyses, participants with HBsAg seropositive exhibited an increased risk of liver cancer (HR = 21.56, 95% CI: 17.32-26.85), gallbladder or extrahepatic bile duct cancer (HR = 14.89, 95% CI: 10.36-21.41), colorectal cancer (HR = 1.75, 95% CI: 1.15-2.96) and pancreatic cancer (HR = 1.86, 95% CI: 1.10-3.99). After taking death as the competing risk event, the associations of HBV infection with the risk of these cancers were attenuated but remained significant both in the cause-specific hazards models, the subdistribution proportional hazards models and sensitivity analyses. Our study suggests that HBV infection is associated with the elevated risk of liver cancer and extrahepatic cancer including gallbladder or extrahepatic bile duct, pancreatic and colorectal cancer among adults in Northern China.

C-reactive protein trajectories and the risk of all cancer types: A prospective cohort study.

A single CRP measurement is insufficient to examine the association of long-term patterns of CRP concentration with cancer risk. We prospectively examined the relationship between CRP trajectory patterns and new-onset cancers among 52 276 participants. Latent mixture modeling was used to identify CRP trajectories. Cox proportional hazards regression models were used to evaluate the association between CRP trajectory patterns and the risk of overall and specific-site cancer. Four CRP trajectories patterns were identified: low-stable pattern (n = 43 258), moderate-increasing pattern (n = 2591), increasing-decreasing pattern (n = 2068) and elevated-decreasing pattern (n = 4359). Relative to the low-stable pattern, the moderate-increasing trajectory pattern was associated with an elevated risk of overall, lung, breast, leukemia, bladder, stomach, colorectal, liver, gallbladder or extrahepatic bile duct cancer and leukemia. Participants in the increasing-decreasing trajectory pattern were associated with an elevated risk of overall, lung, breast, bladder, pancreatic and liver cancer. The increasing-decreasing trajectory pattern was also associated with decreased risk of colorectal cancer in the multivariate analyses. Elevated-decreasing trajectory pattern was associated with increased risk of leukemia and decreased risk of esophageal and colorectal cancer. CRP trajectories play an important role in the occurrence of cancers, especially in the lung, breast, bladder, stomach, colorectal, liver, gallbladder and extrahepatic bile duct cancer and leukemia.

Transcriptome analysis of the winter wheat Dn1 in response to cold stress.

BACKGROUND: Heilongjiang Province has a long and cold winter season (the minimum temperature can reach -30 ℃), and few winter wheat varieties can safely overwinter. Dongnongdongmai1 (Dn1) is the first winter wheat variety that can safely overwinter in Heilongjiang Province. This variety fills the gap for winter wheat cultivation in the frigid region of China and greatly increases the land utilization rate. To understand the molecular mechanism of the cold response, we conducted RNA-sequencing analysis of Dn1 under cold stress. RESULTS: Approximately 120,000 genes were detected in Dn1 under cold stress. The numbers of differentially expressed genes (DEGs) in the six comparison groups (0 ℃ vs. 5 ℃, -5 ℃ vs. 5 ℃, -10 ℃ vs. 5 ℃, -15 ℃ vs. 5 ℃, -20 ℃ vs. 5 ℃ and -25 ℃ vs. 5 ℃) were 11,313, 8313, 15,636, 13,671, 14,294 and 13,979, respectively. Gene Ontology functional annotation suggested that the DEGs under cold stress mainly had "binding", "protein kinase" and "catalytic" activities and were involved in "oxidation-reduction", "protein phosphorylation" and "carbohydrate metabolic" processes. Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the DEGs performed important functions in cold signal transduction and carbohydrate metabolism. In addition, major transcription factors (AP2/ERF, bZIP, NAC, WRKY, bHLH and MYB) participating in the Dn1 cold stress response were activated by low temperature. CONCLUSION: This is the first study to explore the Dn1 transcriptome under cold stress. Our study comprehensively analysed the key genes involved in cold signal transduction and carbohydrate metabolism in Dn1 under cold stress. The results obtained by transcriptome analysis could help to further explore the cold resistance mechanism of Dn1 and provide basis for breeding of cold-resistant crops.

IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia.

High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS' function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

Lymphocyte to C-reactive protein ratio could better predict the prognosis of patients with stage IV cancer.

BACKGROUND: Systemic inflammation is currently regarded as a hallmark of cancer. This study aimed to accurately clarify the prognostic value of various inflammatory markers in patients with stage IV cancer. METHODS: This study assessed 2,424 patients with cancer diagnosed with cancer in tumor, node, metastasis (TNM) stage IV. After evaluating the predictive value of 13 inflammatory indicators for patient prognosis using the C index, the lymphocyte C-reactive protein ratio (LCR) was selected to elucidate the prognostic and predictive values in patients with stage IV cancer. Kaplan-Meier and Cox proportional hazards regression models were used to analyze long-term survival. RESULTS: A total of 1,457 men (60.1%) and 967 women (39.9%) diagnosed with TNM stage IV cancer were enrolled. A ratio of 2,814 was defined as the optimal cut-off value for the LCR. The LCR was the most accurate prognosis predictor for patients with stage IV cancer among the 13 inflammatory nutritional markers evaluated. The multivariate-adjusted restricted cubic spline plot suggested that LCR had an L-shaped dose-response association with all-cause mortality risk. Patients with lower LCR levels tended to present with worse prognoses. Kaplan-Meier curves and log-rank test results showed that the high LCR groups (LCR ≥ 2,814) exhibited a better prognosis, whereas patients with stage IV cancer of different sex and tumor types (for example, gastrointestinal tumor, non-gastrointestinal tumor, and lung cancer) had a worse survival time. CONCLUSION: The LCR score can be regarded as a stable and useful biomarker to predict prognosis in patients with TNM stage IV compared to other evaluated inflammation indicators.

The combination of metabolic syndrome and inflammation increased the risk of colorectal cancer.

BACKGROUND: Inflammation and metabolic syndrome (MetS) may act synergistically and possibly accelerate the initiation and progression of colorectal cancer (CRC). We prospectively examined the joint effect of MetS and inflammation on the risk of CRC. METHODS: We studied 92,770 individuals from the Kailuan study. MetS was defined based on the presence of three or more of the following components. (1) high glucose: FPG > 5.6 mmol/L; (2) high blood pressure: SBP ≥ 130 mmHg or DBP ≥ 85 mmHg; (3) high triglycerides: triglycerides > 1.69 mmol/L; (4) low HDL-C: HDL-C < 1.04 mmol/L in men or 1.29 mmol/L in women; and (5) visceral adiposity: waist circumference ≥ 85 cm in men or 80 cm in women. Inflammation was defined as hs-CRP ≥ 3 mg/L. We divided participants into four groups for the primary exposure according to the presence/absence of inflammation and presence/absence of MetS. Cox proportional hazards regression models were used to evaluate the association of MetS and/or inflammation with the risk of CRC. RESULTS: Compared with metabolically healthy noninflammatory individuals, inflammatory participants without MetS and inflammatory participants with MetS were associated with a 1.3-fold and 4.18-fold increased risk of CRC with corresponding HRs (95% CI) of 1.34 (1.09, 1.64) and 4.18 (3.11, 5.62), respectively. The combination of MetS and inflammation was associated with the highest risk of CRC in all subgroups, especially among participants who were female, in younger age, and obese. Sensitivity analyses further validated our primary findings. CONCLUSIONS: We found the combination of MetS and inflammation could significantly increase the risk of CRC. Including CRP in the diagnosis of MetS may help to identify additional high-risk participants who should be targeted for early diagnosis and prevention of CRC. Trial registration Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, http:// www.chictr.org.cn/showprojen.aspx?proj=8050.

Comprehensive comparison of the prognostic value of systemic inflammation biomarkers for cancer cachexia: a multicenter prospective study.

AIMS: Systemic inflammation plays an important role in cancer cachexia. However, among the systemic inflammatory biomarkers, it is unclear which has optimal prognostic value for cancer cachexia. METHODS: The Kaplan-Meier method was used and the log-rank analysis was performed to estimate survival differences between groups. Cox proportional hazard regression analyses were conducted to assess independent risk factors for all-cause mortality. RESULTS: The C-reactive protein-to-albumin ratio (CAR) was the optimal prognostic assessment tool for patients with cancer cachexia, with 1-, 3-, and 5-year predictive powers of 0.650, 0.658, and 0.605, respectively. Patients with a high CAR had significantly lower survival rates than those with a low CAR. Moreover, CAR can differentiate the prognoses of patients with the same pathological stage. Cox proportional risk regression analyses showed that a high CAR was an independent risk factor for cancer cachexia. For every standard deviation increase in CAR, the risk of poor prognosis for patients with cancer cachexia was increased by 20% (hazard ratio = 1.200, 95% confidence interval = 1.132-1.273, P < 0.001). CONCLUSIONS: CAR is an effective representative of systemic inflammation and a powerful factor for predicting the life function and clinical outcome of patients with cancer cachexia.