The prognostic model and immune landscape based on cancer-associated fibroblast features for patients with locally advanced rectal cancer.

Background: This study aimed to construct a nomogram based on CAF features to predict the cancer-specific survival (CSS) rates of locally advanced rectal cancer (LARC) patients. Methods: The EPIC algorithm was employed to calculate the proportion of CAFs. based on the differentially expressed genes between the high and low CAF proportion subgroups, prognostic genes were identified via LASSO and Cox regression analyses. They were then used to construct a prognostic risk signature. Moreover, the GSE39582 and GGSE38832 datasets were used for external validation. Lastly, the level of immune infiltration was evaluated using ssGSEA, ESTIMATE, CIBERSORTx, and TIMER. Results: A higher level of CAF infiltration was associated with a worse prognosis. Additionally, the number of metastasized lymph nodes and distant metastases, as well as the level of immune infiltration were higher in the high CAF proportion subgroup. Five prognostic genes (SMOC2, TUBAL3, C2CD4A, MAP1B, BMP8A) were identified and subsequently incorporated into the prognostic risk signature to predict the 1-, 3-, and 5-year CSS rates in the training and validation sets. Differences in survival rates were also determined in the external validation cohort. Furthermore, independent prognostic factors, including TNM stage and risk score, were combined to established a nomogram. Notably, our results revealed that the proportions of macrophages and neutrophils and the levels of cytokines secreted by M2 macrophages were higher in the high-risk subgroup. Finally, the prognostic genes were significantly associated with the level of immune cell infiltration. Conclusion: Herein, a nomogram based on CAF features was developed to predict the CSS rate of LARC patients. The risk model was capable of reflecting differences in the level of immune cell infiltration.

Integrated bioinformatics analysis for conducting a prognostic model and identifying immunotherapeutic targets in gastric cancer.

BACKGROUND: Gastric cancer is the third leading cause of death from cancer worldwide and has a poor prognosis. Practical risk scores and prognostic models for gastric cancer are lacking. While immunotherapy has succeeded in some cancers, few gastric cancer patients benefit from immunotherapy. Immune genes and the tumor microenvironment (TME) are essential for cancer progression and immunotherapy response. However, the roles of immune genes and the tumor microenvironment in immunotherapy remain unclear. The study aimed to construct a prognostic prediction model and identify immunotherapeutic targets for gastric cancer (GC) patients by exploring immune genes and the tumor microenvironment. RESULTS: An immune-related risk score (IRRS) model, including APOH, RNASE2, F2R, DEFB126, CXCL6, and CXCL3 genes, was constructed for risk stratification. Patients in the low-risk group, which was characterized by elevated tumor mutation burden (TMB) have higher survival rate. The risk level was remarkably correlated with tumor-infiltrating immune cells (TIICs), the immune checkpoint molecule expression, and immunophenoscore (IPS). CXCL3 and CXCL6 were significantly upregulated in gastric cancer tissues compared with normal tissues using the UALCAN database and RT-qPCR. The nomogram showed good calibration and moderate discrimination in predicting overall survival (OS) at 1-, 3-, and 5- year for gastric cancer patients using risk-level and clinical characteristics. CONCLUSION: Our findings provided a risk stratification and prognosis prediction tool for gastric cancer patients and further the research into immunotherapy in gastric cancer.

Long-term exposure to ambient air pollutants and their interaction with physical activity on insomnia: A prospective cohort study.

Exposure to air pollution or lack of physical activity (PA) increases the risk of insomnia. However, evidence on joint exposure to air pollutants is limited, and the interaction of joint air pollutants and PA on insomnia is unknown. This prospective cohort study included 40,315 participants with related data from the UK Biobank, which recruited participants from 2006 to 2010. Insomnia was assessed by self-reported symptoms. The annual average air pollutant concentrations of particulate matter (PM2.5, PM10), nitrogen oxides (NO2, NOX), sulfur dioxide (SO2) and carbon monoxide (CO) were calculated based on participants' addresses. We applied a weighted Cox regression model to evaluate the correlation between air pollutants and insomnia and newly proposed an air pollution score to assess joint air pollutants effect using a weighted concentration summation after obtaining the weights of each pollutant in the Weighted-quantile sum regression. With a median follow-up of 8.7 years, 8511 participants developed insomnia. For each 10 µg/m³ increase in NO2, NOX, PM10, SO2, the average hazard ratios (AHRs) and 95% confidence interval (CI) of insomnia were 1.10 (1.06, 1.14), 1.06 (1.04, 1.08), 1.35 (1.25, 1.45) and 2.58 (2.31, 2.89), respectively; For each 5 µg/m³ increase in PM2.5 and each 1 mg/m³ increase in CO, the corresponding AHRs (95%CI) were 1.27 (1.21, 1.34) and 1.83 (1.10, 3.04), respectively. The AHR (95%CI) for insomnia associated with per interquartile range (IQR) increase in air pollution scores were 1.20 (1.15, 1.23). In addition, potential interactions were examined by setting cross-product terms of air pollution score with PA in the models. We observed an interaction between air pollution scores and PA (P = 0.032). The associations between joint air pollutants and insomnia were attenuated among participants with higher PA. Our study provides evidence on developing strategies for improving healthy sleep by promoting PA and reducing air pollution.

Lifestyle trajectories and ischaemic heart diseases: a prospective cohort study in UK Biobank.

AIMS: To evaluate the associations of baseline and long-term trajectories of lifestyle with incident ischaemic heart diseases (IHDs). METHODS AND RESULTS: 29 164 participants in the UK Biobank who had at least one follow-up assessment and were free of IHD at the last follow-up assessment were included. We constructed a weighted unhealthy lifestyle score though summing five lifestyle factors [smoking, physical activity, diet, body mass index, and sleep duration]. Lifestyle assessed at baseline (2006-09), the first follow-up assessment (2012-13), and the second follow-up assessment (since 2014) were used to derive the trajectories of each individual. The joint categories were created through cross-classifying the three baseline lifestyle categories (ideal, intermediate, and poor) by the three lifestyle trajectory categories (improve, maintain, and decline). During a median follow-up period of 4.2 years, 868 IHD events were recorded. The hazard ratio (HR) of incident IHD associated with per unit increase in unhealthy lifestyle trajectory was 1.08 [95% confidence interval (CI): 0.99-1.17]. Subgroup analyses indicated such association was stronger among individuals with hypertension (HR: 1.13, 95% CI: 1.03-1.24), diabetes (HR: 1.23, 95% CI: 0.96-1.58), or hyperlipidaemia (HR: 1.09, 95% CI: 0.97-1.22). Compared with participants consistently adhering to an ideal lifestyle (ideal-maintain), the HRs of incident IHD were 1.30 (1.07-1.58) for intermediate-maintain, 1.52 (1.23-1.88) for poor-maintain, 1.25 (0.93-1.68) for intermedia-improve, 1.48 (1.17-1.88) for poor-improve, 1.46 (1.08-1.99) for intermedia-decline, and 1.77 (1.21-2.59) for poor-decline. CONCLUSIONS: A declined lifestyle trajectory increased the risk of incident IHD, irrespective of baseline lifestyle levels. Individuals with hypertension, diabetes, or hyperlipidaemia were more predisposed to the influence of lifestyle change.

It is known that an unhealthy lifestyle at baseline was associated with an increased risk of cardiovascular diseases (CVDs), but the risk attributed to the lifestyle changes (or trajectories) over the long term has not been well quantified. Meanwhile, the effects of lifestyle, either in baseline level or trajectories, on different CVD subtypes such as ischaemic heart diseases (IHDs) and stroke varied. Thus, this study used the data from UK Biobank to construct a weighted unhealthy lifestyle score and to evaluate the prospective associations of baseline and long-term trajectories of the unhealthy lifestyle score with the risk of incident IHD. A total of 352 251 and 29 164 participants were included in the unhealthy lifestyle construction and lifestyle trajectory analysis, respectively. We found a poorer lifestyle at baseline was significantly associated with an increased risk of incident IHD in a linear dose­response fashion. Besides, a declined lifestyle trajectory was associated with an increased risk of incident IHD, irrespective of baseline lifestyle levels, and such an association was stronger among individuals with hypertension, diabetes, or hyperlipidaemia. Compared with the maintainers, risks of incident IHD attenuated when individuals improved their lifestyle and strengthened when declined their lifestyle.A declined lifestyle trajectory increased the risk of incident IHD, irrespective of baseline lifestyle levels. Such association was stronger among participants with hypertension, diabetes, or hyperlipidaemia.Compared with the maintainers of lifestyle, risks of incident IHD attenuated when individuals improved their lifestyle and strengthened when declined their lifestyle.

Clinical characteristics and quality of life in patients with inflammatory bowel disease-associated anemia in Southeast China.

BACKGROUND/AIMS: Clinical characteristics of inflammatory bowel disease (IBD) with anemia have not been fully elucidated. This study aimed to investigate the frequency of, risk factors for, and management of anemia in IBD patients and to evaluate the quality of life (QOL) in IBD patients with anemia. METHODS: We included two patient cohorts. In cohort 1, clinical data from 697 IBD patients were retrospectively collected. In cohort 2, the Short Form-36 Health Survey (SF-36) and Fatigue Scale-14 (FS-14) questionnaires for IBD patients were completed to evaluate the QOL. RESULTS: Anemia was present in 35.6% of IBD patients [38.2% of Crohn's disease (CD) patients vs. 29.3% of ulcerative colitis (UC) patients, P = 0.025]. Elevated platelet (PLT) count (CD: OR, 1.004; 95% CI, 1.001-1.007; P = 0.007; UC: OR, 1.010; 95% CI, 1.004-1.016; P = 0.001), elevated erythrocyte sedimentation rate (ESR) (CD: OR, 1.024; 95% CI, 1.012-1.036; P < 0.001; UC: OR, 1.025; 95% CI, 1.001-1.051; P = 0.044), and lower albumin levels (CD: OR, 0.801; 95% CI, 0.749-0.857; P < 0.001; UC: OR, 0.789; 95% CI, 0.720-0.864; P < 0.001) were associated with anemia. Among the IBD patients with anemia, only 25.8% received treatment for anemia. IBD patients with anemia had significantly lower SF-36 scores (P = 0.011) and higher FS-14 scores (P = 0.026) than those without anemia. CONCLUSION: Anemia is common in IBD patients. Elevated PLT count and ESR are risk factors for anemia in IBD patients. Anemia may negatively impact IBD patients' QOL, but few anemia patients receive treatment for anemia.

Rice ubiquitin-conjugating enzyme OsUBC26 is essential for immunity to the blast fungus Magnaporthe oryzae.

The functions of ubiquitin-conjugating enzymes (E2) in plant immunity are not well understood. In this study, OsUBC26, a rice ubiquitin-conjugating enzyme, was characterized in the defence against Magnaporthe oryzae. The expression of OsUBC26 was induced by M. oryzae inoculation and methyl jasmonate treatment. Both RNA interference lines and CRISPR/Cas9 null mutants of OsUBC26 reduced rice resistance to M. oryzae. WRKY45 was down-regulated in OsUBC26 null mutants. In vitro E2 activity assay indicated that OsUBC26 is an active ubiquitin-conjugating enzyme. Yeast two-hybrid assays using OsUBC26 as bait identified the RING-type E3 ligase UCIP2 as an interacting protein. Coimmunoprecipitation assays confirmed the interaction between OsUBC26 and UCIP2. The CRISPR/Cas9 mutants of UCIP2 also showed compromised resistance to M. oryzae. Yeast two-hybrid screening using UCIP2 as bait revealed that APIP6 is a binding partner of UCIP2. Moreover, OsUBC26 working with APIP6 ubiquitinateds AvrPiz-t, an avirulence effector of M. oryzae, and OsUBC26 null mutation impaired the proteasome degradation of AvrPiz-t in rice cells. In summary, OsUBC26 plays important roles in rice disease resistance by regulating WRKY45 expression and working with E3 ligases such as APIP6 to counteract the effector protein AvrPiz-t from M. oryzae.