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Background: TP53 Arg72Pro (SNP rs1042522) is associated with risk of non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL. However, the relationship between this SNP and prognosis of DLBCL in Asians is unknown., Methods: Genotyping of TP53 Arg72Pro was done in 425 Chinese DLBCL patients. Two hundred and eighty-nine patients were treated with R-CHOP, and 136 patients received CHOP or CHOP-like as frontline regimen. Three hundred and ninety-six patients were assessable for the efficacy., Results: Patients with Arg/Arg and Arg/Pro at codon 72 of TP53 had a higher complete response rate (61% vs. 44%, P = 0.007) than those with Pro/Pro. In the subgroup treated with CHOP or CHOP-like therapy, patients with Arg/Arg and Arg/Pro showed a higher 5-year overall survival (OS) rate than those with Pro/Pro (68.8% vs. 23.2%, P = 0.001). Multivariate Cox regression analysis revealed TP53 Arg72 as a favorable prognostic factor in this group. However, the combination of rituximab with CHOP significantly increased the 5-year OS rate of patients with Pro/Pro to 63%., Conclusion: This study revealed TP53 Arg72 as a favorable prognostic factor for Chinese DLBCL patients treated with CHOP or CHOP-like as frontline therapy.

Deregulation of microRNAs (miRNAs) is a typical feature of human hepatocellular carcinoma (HCC). However, the in vivo relevance of miRNAs along hepatocarcinogenesis remains largely unknown. Here, we show that liver tumors induced in mice by c-Myc overexpression or AKT/Ras co-expression exhibit distinct miRNA expression profiles. Among the downregulated miRNAs, eight (miR-101, miR-107, miR-122, miR-29, miR-365, miR-375, miR-378, and miR-802) were selected and their tumor suppressor activity was determined by overexpressing each of them together with c-Myc or AKT/Ras oncogenes in mouse livers via hydrodynamic transfection. The tumor suppressor activity of these microRNAs was extremely heterogeneous in c-Myc and AKT/Ras mice: while miR-378 had no tumor suppressor activity, miR-107, mir-122, miR-29, miR-365 and miR-802 exhibited weak to moderate tumor suppressor potential. Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis. Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development. Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes. Finally, our findings support a strong tumor suppressor activity of miR-101 in liver cancer models regardless of the driver oncogenes involved, thus representing a promising therapeutic target in human HCC.

Background. In recent years, the incidence and mortality of colorectal cancer (CRC) are increasing, and the 5-year survival rate of advanced metastatic CRC is poor. Small mothers against decapentaplegic (SMAD) superfamily are intracellular signal transduction proteins associated with the development and prognosis of a variety of tumors. At present, no study has systematically analysed the relationship between SMADs and CRC. Methods. Here, R3.6.3 was used to analyse the expression of SMADs in pan-cancer and CRC. Protein expression of SMADs were analysed by Human Protein Atlas (HPA). Gene expression profiling interactive analysis (GEPIA) was used to evaluate the correlation between SMADs and tumor stage in CRC. The effect of R language and GEPIA on prognosis was analysed. Mutation rates of SMADs in CRC were determined by cBioPortal, and potentially related genes were predicted using GeneMANIA. R analysis was used to correlate immune cell infiltration in CRC. Results. Both SMAD1 and SMAD2 were found to be weakly expressed in CRC and correlated with the immune invasion level. SMAD1 was correlated with patient prognosis, and SMAD2 was correlated with tumor stage. SMAD3, SMAD4, and SMAD7 were all expressed at low levels in CRC and associated with a variety of immune cells. SMAD3 and SMAD4 proteins were also expressed at low levels, and SMAD4 had the highest mutation rate. SMAD5 and SMAD6 were overexpressed in CRC, and SMAD6 was also associated with patient overall survival (OS) and CD8+ T cells, macrophages, and neutrophils. Conclusions. Our results reveal innovative and strong evidence that SMADs can be used as biomarkers for the treatment and prognosis of CRC. [ABSTRACT FROM AUTHOR]

Background: Smoking is well-recognized as a risk factor for heart failure (HF). However, few studies have evaluated the prospective association of cigarette smoking and smoking cessation with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) as distinct phenotypes.Objectives: The aim of this study was to quantify the association of cigarette smoking and smoking cessation with the incidence of HFpEF and HFrEF.Methods: In 9,345 ARIC (Atherosclerosis Risk In Communities) study White and Black participants without history of HF at baseline in 2005 (age range 61-81 years), we quantified the associations of several established cigarette smoking parameters (smoking status, pack-years, intensity, duration, and years since cessation) with physician-adjudicated incident acute decompensated HF using multivariable Cox models.Results: Over a median follow-up of 13.0 years, there were 1,215 incident HF cases. Compared with never smokers, current cigarette smoking was similarly associated with HFpEF and HFrEF, with adjusted HRs ∼2. There was a dose-response relationship for pack-years of smoking and HF. A more extended period of smoking cessation was associated with a lower risk of HF, but significantly elevated risk persisted up to a few decades for HFpEF and HFrEF.Conclusions: All cigarette smoking parameters consistently showed significant and similar associations with HFpEF and HFrEF. Smoking cessation significantly reduced the risk of HF, but excess HF risk persisted for a few decades. Our results strengthened the evidence that smoking is an important modifiable risk factor for HF and highlighted the importance of smoking prevention and cessation for the prevention of HF, including HFpEF. [ABSTRACT FROM AUTHOR]

The utility of circulating tumor DNA (ctDNA) in classifying the cell origin of diffuse large B-cell lymphoma (DLBCL) has not been explored in the Chinese population. In this study, we aimed to investigate the genetic characteristics of DLBCL based on both tumor and ctDNA sequencing and to assess the predictive value of ctDNA in DLBCL. A targeted sequencing panel of 413 genes was applied to tumor biopsies and paired plasma samples obtained from 30 patients with DLBCL before therapeutic intervention (pretreatment). The concordance between plasma genotyping classification and traditional cell-of-origin classification using tumor tissue was 80.0% (20/25). Patients with higher baseline plasma ctDNA levels had poorer survival compared to those with lower ctDNA levels (2-year progression survival rate: 40.0% vs. 80.0%, p = 0.011; 5-year overall survival rate: 30.5% vs. 70.0%, p = 0.004). Collectively, our results demonstrated that pretreatment ctDNA analysis could assist origin determination and prognosis prediction clinically. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods: Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. Results: Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion: TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. [ABSTRACT FROM AUTHOR]

Aberrant expression of microRNAs may affect tumorigenesis and progression by regulating their target genes. This study aimed to construct a risk model for predicting the prognosis of patients with lung adenocarcinoma (LUAD) based on differentially expressed microRNA-regulated target genes. The miRNA sequencing data, RNA sequencing data, and patients' LUAD clinical data were downloaded from the The Cancer Genome Atlas (TCGA) database. Differentially expressed miRNAs and genes were screened out by combining differential analysis with LASSO regression analysis to further screen out miRNAs associated with patients' prognosis, and target gene prediction was performed for these miRNAs using a target gene database. Overlapping gene screening was performed for target genes and differentially expressed genes. LASSO regression analysis and survival analysis were then used to identify key genes. Risk score equations for prognostic models were established using multifactorial COX regression analysis to construct survival prognostic models, and the accuracy of the models was evaluated using subject working characteristic curves. The groups were divided into high- and low-risk groups according to the median risk score, and the correlation with the clinicopathological characteristics of the patients was observed. A total of 123 up-regulated miRNAs and 22 down-regulated miRNAs were obtained in this study. Five prognosis-related miRNAs were screened using LASSO regression analysis and Kaplan-Meier method validation, and their target genes were screened with the overlap of differentially expressed genes before multifactorial COX analysis finally resulted in an 11-gene risk model for predicting patient prognosis. The area under the ROC curve proved that the model has high accuracy. The 11-gene risk-prediction model constructed in this study may be an effective predictor of prognosis. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors in China, and its prognosis remains poor. Autophagy is an evolutionarily conserved catabolic process involved in the occurrence and development of ESCC. In this study, we described the expression profile of autophagy-related genes (ARGs) in ESCC and developed a prognostic prediction model for ESCC patients based on the expression pattern of ARGs. We used four ESCC cohorts, GSE53624 (119 samples) set as the discovery cohort, The Cancer Genome Atlas (TCGA) ESCC set (95 samples) as the validation cohort, 155 ESCC cohort, and Oncomine cohort were used to screen and verify differentially expressed ARGs. We identified 34 differentially expressed genes out of 222 ARGs. In the discovery cohort, we divided ESCC patients into three groups that showed significant differences in prognosis. Then, we analyzed the prognosis of 34 differentially expressed ARGs. Three genes [poly (ADP-ribose) polymerase 1 (PARP1), integrin alpha-6 (ITGA6), and Fas-associated death domain (FADD)] were ultimately obtained through random forest feature selection and were constructed as an ARG-related prognostic model. This model was further validated in TCGA ESCC set. Cox regression analysis confirmed that the three-gene signature was an independent prognostic factor for ESCC patients. This signature effectively stratified patients in both discovery and validation cohorts by overall survival (P = 5.162E-8 and P = 0.052, respectively). We also constructed a clinical nomogram with a concordance index of 0.713 to predict the survival possibility of ESCC patients by integrating clinical characteristics and the ARG signature. The calibration curves substantiated fine concordance between nomogram prediction and actual observation. In conclusion, we constructed a new ARG-related prognostic model, which shows the potential to improve the ability of individualized prognosis prediction in ESCC. [ABSTRACT FROM AUTHOR]

Introduction: Angiogenesis is a key factor in promoting tumor growth, invasion and metastasis. In this study we aimed to investigate the prognostic value of angiogenesis-related genes (ARGs) in gastric cancer (GC).Methods: mRNA sequencing data with clinical information of GC were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The differentially expressed ARGs between normal and tumor tissues were analyzed by limma package, and then prognosis‑associated genes were screened using Cox regression analysis. Nine angiogenesis genes were identified as crucially related to the overall survival (OS) of patients through least absolute shrinkage and selection operator (LASSO) regression. The prognostic model and corresponding nomograms were establish based on 9 ARGs and verified in in both TCGA and GEO GC cohorts respectively.Results: Eighty-five differentially expressed ARGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that ARGs-related signaling pathway genes were highly related to tumor angiogenesis development. Kaplan-Meier analysis revealed that patients in the high-risk group had worse OS rates compared with the low-risk group in training cohort and validation cohort. In addition, RS had a good prognostic effect on GC patients with different clinical features, especially those with advanced GC. Besides, the calibration curves verified fine concordance between the nomogram prediction model and actual observation.Conclusions: We developed a nine gene signature related to the angiogenesis that can predict overall survival for GC. It's assumed to be a valuable prognosis model with high efficiency, providing new perspectives in targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Distant metastasis (DM) is relatively rare in superficial gastric cancer (SGC), especially in patients without lymph node metastasis. This study aimed to explore the main clinical risk factors for DM in patients with superficial gastric cancer‐no lymph node metastasis (SGC‐NLNM) and the prognostic factors for patients with DM. Methods: Records of patients with SGC‐NLNM between 2004 and 2015 were collected from the public Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariate logistic regressions were performed to analyze the clinical risk factors for DM. The Kaplan–Meier method and Cox regression model were used to identify prognostic factors for patients with DM. A nomogram was built based on multivariate logistic regression and evaluated by the C‐index, the calibration, and the area under the receiver operating characteristic curve (AUC). Results: We developed and validated a nomogram to predict DM in patients with SGC‐NLNM, showing that race, age, primary site, depth, size, and grade were independent risk factors. The built nomogram had a good discriminatory performance, with a C‐index of 0.836 (95% confidence interval [CI]: 0.813–0.859). Calibration plots showed that the predicted DM probability was identical to the actual observations in both the training and validation sets. AUC was 0.846 (95% CI: 0.820–0.871) and 0.801 (95% CI: 0.751–0.850) in the training and validation sets, respectively. The results of the survival analysis revealed that surgery (hazard ratio [HR] = 0.249; 95% CI, 0.125–0.495), chemotherapy (HR = 0.473; 95% CI, 0.353–0.633), and grade (HR = 1.374; 95% CI, 1.018–1.854) were independent prognostic factors associated with cancer‐specific survival (CSS), but radiotherapy was not (log‐rank test, p = 0.676). Conclusions: We constructed a sensitive and discriminative nomogram to identify high‐risk patients with SGC‐NLNM who may harbor dissemination at initial diagnosis. The tumor size and primary site were the largest contributors to DM prediction. Compared with radiotherapy, aggressive surgery, and chemotherapy may be better options for patients with DM. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the expression of IL‐35 and the lymphatic vessel density (LVD) and microvessel density (MVD) in the pathological tissues from patients with non‐small cell lung cancer (NSCLC) and to analyze their correlation with other common clinical prognostic factors, as well as patients' overall survival and progression‐free survival. We analyzed the pathological characteristics of 130 patients with NSCLC and determined the IL‐35 expression, MVD, and LVD changes in the pathological tissues by immunohistochemistry. The results showed that IL‐35 expression was significantly correlated with tumor differentiation, lymph node metastasis, T staging, LVD, and MVD (P < 0.05) but was not associated with age, sex, smoking, and other factors. Univariate analysis of risk models showed that age, lymph node metastasis, T stage, and high IL‐35 expression, LVD, and MVD were significantly associated with NSCLC prognosis (P < 0.05), whereas sex, smoking, and high differentiation were not correlated with prognosis. Multivariate analysis of the proportional risk model showed that the IL‐35 expression, lymph node metastasis, high LVD, and high MVD were significantly correlated with NSCLC prognosis (P < 0.05). In conclusion, IL‐35, MVD, and LVD may be independent prognostic markers. In addition, IL‐35 might represent a promising clinical drug target for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating immune cells (TIICs) play essential roles in cancer development and progression. However, the association of TIICs with prognosis in colorectal cancer (CRC) patients remains elusive. Infiltration of TIICs was assessed using ssGSEA and CIBERSORT tools. The association of TIICs with prognosis was analyzed in 1,802 CRC data downloaded from the GEO (https://www.ncbi.nlm.nih.gov/geo/) and TCGA (https://portal.gdc.cancer.gov/) databases. Three populations of TIICs, including CD66b+ tumor-associated neutrophils (TANs), FoxP3+ Tregs, and CD163+ tumor-associated macrophages (TAMs) were selected for immunohistochemistry (IHC) validation analysis in 1,008 CRC biopsies, and their influence on clinical features and prognosis of CRC patients was analyzed. Prognostic models were constructed based on the training cohort (359 patients). The models were further tested and verified in testing (249 patients) and validation cohorts (400 patients). Based on ssGSEA and CIBERSORT analysis, the correlation between TIICs and CRC prognosis was inconsistent in different datasets. Moreover, the results with disease-free survival (DFS) and overall survival (OS) data in the same dataset also differed. The high abundance of TIICs found by ssGSEA or CIBERSORT tools can be used for prognostic evaluation effectively. IHC results showed that TANs, Tregs, TAMs were significantly correlated with prognosis in CRC patients and were independent prognostic factors (P DFS ≤ 0.001; P OS ≤ 0.023). The prognostic predictive models were constructed based on the numbers of TANs, Tregs, TAMs (C-indexDFS&OS = 0.86; AICDFS = 448.43; AICOS = 184.30) and they were more reliable than traditional indicators for evaluating prognosis in CRC patients. Besides, TIICs may affect the response to chemotherapy. In conclusion, TIICs were correlated with clinical features and prognosis in patients with CRC and thus can be used as markers. [ABSTRACT FROM AUTHOR]

Lysosomal protein transmembrane 4β (LAPTM4B) is an oncogene that is overexpressed in a number of various types of human cancer. There are two known alleles of LAPTM4B: LAPTM4B*1 and LAPTM4B*2. The present study assessed the association between LAPTM4B polymorphisms and the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its prognosis. LAPTM4B genotypes were determined using polymerase chain reaction analysis in 164 DLBCL and 350 healthy control cases. The association between LAPTM4B polymorphisms and the risk of DLBCL was analyzed using unconditional logistic regression. Differences in patient survival were calculated using Kaplan-Meier analysis. The present study indicated no significant differences (P>0.05) in the frequency of LAPTM4B*2 alleles between DLBCL cases (26.5%) and controls (24.1%). The risk of DLBCL was slightly increased in cases with the LAPTM4B*1/2 genotype [odds ratio (OR)=1.160; 95% confidence interval (CI)=0.781-1.724] or the LAPTM4B*2/2 genotype (OR=1.446; 95% CI=0.648-3.227) compared with those with the LAPTM4B*1/1 genotype. There was no significant association between the presence of the LAPTM4B*2 allele and overall survival (OS) and disease-free survival (DFS) in patients with DLBCL (P=0.399 and 0.520, respectively). However, there was a tendency for patients with LAPTM4B*2 and International Prognostic Index (IPI) score 3-5 to have longer OS and DFS (P=0.126 and 0.109, respectively). These findings suggest that genetic polymorphisms of LAPTM4B is not a risk factor for the development of DLBCL, but the LAPTM4B*2 allele may a better prognostic indicator in patients with IPI score 3-5 in DLBCL. [ABSTRACT FROM AUTHOR]

Interstitial pneumonia (IP) is a lethal complication in lymphoma patients undergoing chemotherapy. A total of 2212 consecutive patients diagnosed with lymphoma between 2009 and 2014 were enrolled in the present study. IP was defined as diffuse pulmonary interstitial infiltrate found on computed tomography scans. IP was observed in 106 patients. Of these, 23 patients were excluded from the study. Finally, 83 patients with IP were included in this study. The incidence of IP was 3.9% (7/287) in Hodgkin lymphoma and 2.4% (76/1925) in non-Hodgkin lymphoma (P = 0.210). The median number of chemotherapy cycles before IP was 3. The median time from the cessation of chemotherapy to IP was 17 days. Eighty-two (98.8%) patients recovered after the treatment with glucocorticoids. Sixty-six (79.5%) patients had a delay in chemotherapy, and 14 (16.9%) patients had premature termination of chemotherapy. Sixty-nine patients were re-treated with chemotherapy after remission from IP, of which 22 (31.9%) experienced IP recurrence. The incidence of IP recurrence was significantly higher in patients re-treated with a similar regimen than in those re-treated with an alternative regimen (65.4 vs. 11.6%, P < 0.001). In a multivariate Cox regression analysis, B symptoms and a history of drug allergies were identified as risk factors for IP. In conclusion, IP is a life-threatening complication in lymphoma patients. Glucocorticoid therapy with continuous monitoring of chest radiographic changes may be a favourable strategy for treating IP. However, IP may recur, especially in patients re-treated with a similar chemotherapy regimen. [ABSTRACT FROM AUTHOR]

Background: TP53 Arg72Pro (SNP rs1042522) is associated with risk of non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL. However, the relationship between this SNP and prognosis of DLBCL in Asians is unknown.Methods: Genotyping of TP53 Arg72Pro was done in 425 Chinese DLBCL patients. Two hundred and eighty-nine patients were treated with R-CHOP, and 136 patients received CHOP or CHOP-like as frontline regimen. Three hundred and ninety-six patients were assessable for the efficacy.Results: Patients with Arg/Arg and Arg/Pro at codon 72 of TP53 had a higher complete response rate (61% vs. 44%, P = 0.007) than those with Pro/Pro. In the subgroup treated with CHOP or CHOP-like therapy, patients with Arg/Arg and Arg/Pro showed a higher 5-year overall survival (OS) rate than those with Pro/Pro (68.8% vs. 23.2%, P = 0.001). Multivariate Cox regression analysis revealed TP53 Arg72 as a favorable prognostic factor in this group. However, the combination of rituximab with CHOP significantly increased the 5-year OS rate of patients with Pro/Pro to 63%.Conclusion: This study revealed TP53 Arg72 as a favorable prognostic factor for Chinese DLBCL patients treated with CHOP or CHOP-like as frontline therapy. [ABSTRACT FROM AUTHOR]

Background: The epithelial-mesenchymal transition (EMT) plays a pivotal role in various physiological processes, such as embryonic development, tissue morphogenesis, and wound healing. EMT also plays an important role in cancer invasion, metastasis, and chemoresistance. Additionally, EMT is partially responsible for chemoresistance in colorectal cancer (CRC). The aim of this research is to develop an EMT-based prognostic signature in CRC.Methods: RNA-seq and microarray data, together with clinical information, were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. A total of 244 differentially expressed EMT-related genes (ERGs) were obtained by comparing the expression between normal and tumor tissues. An EMT-related signature of 11 genes was identified as crucially related to the overall survival (OS) of patients through univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and Cox regression analysis. Finally, we established a clinical nomogram to predict the survival possibility of CRC patients by integrating clinical characteristics and the EMT-related gene signature.Results: Two hundred and forty-four differentially expressed ERGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that EMT-related signaling pathway genes were highly related to CRC. Kaplan-Meier analysis revealed that the 11-EMT signature could significantly distinguish high- and low-risk patients in both TCGA and GEO CRC cohorts. In addition, the calibration curves verified fine concordance between the nomogram prediction model and actual observation.Conclusion: We developed a novel EMT-related gene signature for the prognosis prediction of CRC patients, which could improve the individualized outcome prediction in CRC. [ABSTRACT FROM AUTHOR]