Panpan Liu

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan-Meier plotter

DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan–Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients.

Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells

Programmed cell death ligand 1 (PD‐L1) is a negative regulator of the immune response that enables tumor cells to escape T‐cell immunity. Although PD‐L1 expression in cancer cells has been extensively studied, the expression of PD‐L1 in stromal cells and its clinical significance remain largely unknown. Here, we show that bone marrow stromal cells express a low level of PD‐L1 and that this molecule is significantly upregulated by key drugs used in the treatment of lymphoma at clinically relevant concentrations. Mechanistically, chemotherapeutic drugs induce PD‐L1 expression in stromal cells through upregulation of granulocyte macrophage colony‐stimulating factor and activation of the extracellular signal‐regulated kinase (ERK) 1/2 signaling pathway. Suppression of ERK by a chemical inhibitor or genetic silencing of ERK2 expression prevents drug‐induced PD‐L1 expression. PD‐L1 expression is upregulated in the bone marrow stromal cells of mice treated with doxorubicin and in drug‐treated bone marrow specimens from lymphoma patients. Drug‐induced PD‐L1 expression in stromal cells can cause significant impairment of T‐cell functions. Overall, our study reveals a previously unrecognized mechanism by which chemotherapy induces tumor immune evasion by upregulation of PD‐L1 in bone marrow stromal cells, and provides new evidence for the combination of chemotherapy and anti‐PD‐L1/PD‐1 as an effective strategy for treatment of lymphoma and other cancers.

High Pretreatment D-Dimer Levels Correlate with Adverse Clinical Features and Predict Poor Survival in Patients with Natural Killer/T-Cell Lymphoma.

Pretreatment plasma D-dimer levels have been reported to predict survival in several types of malignancies. The aim of this study was to evaluate the prognostic value of D-dimer levels in patients with newly diagnosed natural killer/T-cell lymphoma (NKTCL). The cut-off value of D-dimer to predict survival was set as 1.2 μg/mL based on the receiver operating curve analysis. Patients with a D-dimer level ≥ 1.2 μg/mL had significantly more adverse clinical features, including poor performance status, advanced stage diseases, B symptoms, elevated serum lactic dehydrogenase levels, involvement of regional lymph nodes, more extranodal diseases, and higher International Prognostic Index and natural killer/T-cell lymphoma prognostic index scores. A D-dimer level ≥ 1.2 μg/mL was significantly associated with inferior 3-year overall survival (OS, 13.0 vs. 68.5%, P < 0.001). In the multivariate analysis, a D-dimer level ≥ 1.2 μg/mL remained an independent predictor for worse OS (HR: 3.13, 95% CI: 1.47–6.68, P = 0.003) after adjusting for other confounding prognostic factors. Among patients with Ann Arbor stage I-II diseases, those with a D-dimer level ≥ 1.2 μg/mL had a significantly worse survival than those with a D-dimer level < 1.2 μg/mL (3 year-OS: 76.2 vs. 22.2%, P < 0.001). Survival of early-stage patients with a high D-dimer level was similar to that of the advanced-stage patients. In conclusion, pretreatment plasma D-dimer level may serve as a simple but effective predictor of prognosis in patients with NKTCL.

Albumin-to-Alkaline phosphatase ratio: A novel prognostic index of overall survival in cisplatin-based chemotherapy-treated patients with metastatic nasopharyngeal Carcinoma

The Albumin-to-Alkaline Phosphatase Ratio (AAPR) has been recently revealed as a prognostic index for hepatocellular carcinoma, whereas its role in metastatic nasopharyngeal cancer (NPC) remains unclear. The aim of this study was to evaluate the clinical value of AAPR in patients with metastatic NPC. We retrospectively reviewed 209 metastatic NPC patients treated with cisplatin-based regimens. Survival data were calculated using the Kaplan-Meier method and were compared using the log-rank test. Univariate and multivariate survival analyses were conducted using the Cox proportional hazards regression methodology. The optimal cutoff level of AAPR for assessing overall survival (OS) was 0.447, which was determined by R software. An AAPR less than 0.447 was significantly associated with a higher lactate dehydrogenase (LDH) level (273 vs. 185 U/L, P = 0.004), a higher EBV DNA viral load (5.59×105 vs. 3.49×104 copies/ml, P = 0.001), and more liver and bone metastases (P = 0.005 and P = 0.001, respectively). Additionally, patients with an AAPR < 0.447 had a shorter overall survival and progression-free survival (hazard ratio: 3.269, 95% confidence interval: 1.710-6.248; HR: 2.295, 95% confidence interval: 1.217-4.331, respectively) than those with an AAPR ≥ 0.447. Our study suggested that the AAPR might be a novel prognostic factor in metastatic NPC patients treated with cisplatin-based regimens. However, a prospective study to validate its prognostic value is needed, and the mechanisms underlying the low AAPR and poor survival in metastatic NPC need to be further investigated.

Association between extranodal natural killer/T-cell lymphoma and hepatitis B viral infection: a case-control study

Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a rare subtype of lymphoma that is often associated with poor clinical prognosis. Several studies have shown that hepatitis B virus (HBV) infection may be associated with increased risk of B-cell non-Hodgkin lymphoma; however, because of the rarity of ENKTL, little is known about its association with HBV. Our study aimed to assess whether HBV infection was associated with increased odds of ENKTL. We conducted a hospital-based case-control study including 417 ENKTL cases and 488 age- and sex-matched subjects with nonmalignant diseases unrelated to HBV infection. Multivariable unconditional logistic regression analyses were performed to estimate adjusted odds ratios [AOR] and their corresponding 95% confidence intervals (CI). The results of the multivariable analysis showed that after adjustment for a set of known risk factors, patients previously infected with HBV (HBsAg-seronegative/anti-HBc-seropositive) and naturally immune to HBV (anti-HBs-seropositive/anti-HBc-seropositive) were at significantly greater odds of being diagnosed with ENKTL (AOR, 1.497; 95% CI 1.098-2.042, P=0.033 and AOR, 1.871; 95% CI 1.302-2.689, P=0.001, respectively). After adjusting for other factors, significantly greater odds of being diagnosed with ENKTL were observed among cases who reported ever drinking alcohol (AOR, 1.675; 95% CI 1.054-2.660, P=0.029). The odds of ENKTL diagnosis were not significantly associated with ABO blood type, cigarette smoking status or family history of cancer. The results of our study suggest that patients previously infected with HBV and naturally immune to HBV were at greater odds of being diagnosed with ENKTL.

The Ratio of C-Reactive Protein/Albumin is a Novel Inflammatory Predictor of Overall Survival in Cisplatin-Based Treated Patients with Metastatic Nasopharyngeal Carcinoma

The C-reactive protein/albumin (CRP/Alb) ratio has been recently identified as a prognostic factor in various cancers, whereas its role remains unclear in metastatic nasopharyngeal carcinoma (NPC). The current study retrospectively analyzed 148 patients with metastatic NPC who underwent cisplatin-based chemotherapy and further evaluated the prognostic value of the CRP/Alb ratio and its association with clinical characteristics in these patients. The optimal cut-off value was 0.189 for the CRP/Alb ratio. The high CRP/Alb ratio was significantly associated with elevated NLR, platelet-to-lymphocyte ratio (PLR), and EBV-DNA levels and decreased haemoglobin level (all p < 0.05). The results of multivariate analysis showed that the CRP/Alb ratio was an independent prognostic factor of overall survival. Patients with a high CRP/Alb ratio (≥0.189) had a 1.867 times (p = 0.024, 95% CI = 1.085–3.210) greater risk of mortality compared with those with a low CRP/Alb ratio (<0.189). In addition, combining the CRP/Alb ratio with GPS could accurately discriminate the prognosis of our patients. Our results suggested that the CRP/Alb ratio is a feasible and inexpensive tool for predicting survival outcomes and is a valuable coadjutant for the GPS to further identify differences in survivals of patients with metastatic NPC.

A comparison of R-EPOCH and R-CHOP as a first-line regimen in de novo DLBCL patients with high Ki-67 expression in a single institution

Diffuse large B-cell lymphoma (DLBCL) patients with high Ki-67 expression receive limited benefits from R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. This study aims to compare the R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and R-CHOP regimens as first-line therapy in DLBCL patients with high Ki-67 expression. Data from 44 untreated DLBCL patients with high Ki-67 expression receiving R-EPOCH therapy were matched with those from 132 untreated DLBCL patients with high Ki-67 expression receiving R-CHOP therapy based on the International Prognostic Index (IPI: age, Ann Arbor stage, performance status, LDH level, number of extranodal sites), gender, and Ki-67 expression. In the R-EPOCH group, 42/44 patients were eligible for response evaluation. A total of 35 patients (83.3%) achieved complete remission (CR); 6 patients (14.3%) achieved partial remission (PR); and one patient (2.4%) exhibited progressive disease (PD) after 2 cycles of therapy. Patients in the R-EPOCH group presented better survival outcomes than those in the R-CHOP group (3-year overall survival [OS]: 89.9% vs. 70.2%, p = 0.041; 3-year progression-free survival [PFS]: 86.6% vs. 59.7%, p = 0.024). The survival superiority of the R-EPOCH over the R-CHOP regimen persisted when considering only patients of low-to-intermediate IPI risk, but it was not observed in those of high IPI risk. Our data suggest that R-EPOCH could be superior to R-CHOP as a first-line regimen in DLBCL patients with high Ki-67 expression, especially in those of low-to-intermediate IPI risk.

Heterocyclic Iodoniums for the Assembly of Oxygen-Bridged Polycyclic Heteroarenes with Water as the Oxygen Source

A diverse set of novel heterocyclic iodoniums was synthesized for the first time. The reactions of these unique iodoniums with environmentally benign water as the oxygen source provided structurally complex oxygen-incorporated heteropolycycles that are essential motifs in natural products and biologically active compounds. The transformation only required low-cost copper acetate. Further derivatization of the obtained polycycles expanded the structural diversity, which is important in the building of chemical libraries for drug discovery.

Trends in Survival of Patients with Primary Gastric Diffuse Large B-Cell Lymphoma: An Analysis of 7051 Cases in the SEER Database

Treatment modalities for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) have changed significantly during the past decades. However, limited information on the trends of clinical outcome of PG-DLBCL patients has been reported. Here, we conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database to compare the survival trends of PG-DLBCL patients from 1973 to 2014. Patients were divided into 2 eras based on the year of diagnosis in relation to immunotherapy with the anti-CD20 antibody rituximab that was approved in 1997 and became a widely used drug in 2000. There was a significant improvement in survival among PG-DLBCL patients diagnosed in the 2001–2014 era (n = 4186) compared to patients diagnosed in the 1973–2000 era (n = 2865), with the 5-year overall survival rates of 53% and 47%, respectively (p = 0.001). Multivariable analysis revealed that the 2001–2014 era (HR = 0.892, p = 0.001) was associated with lower mortality and that patients of older age, Black race, advanced stage, and male gender were associated with poor prognosis. Although outcome of PG-DLBCL has significantly improved over time, more effective therapies are needed for older patients to further improve their survival.

Expressions and prognostic values of the E2F transcription factors in human breast carcinoma

E2F transcription factors (E2Fs) are a family of transcription factors involved in cell proliferation, differentiation, and apoptosis. Their important roles in the development and metastasis of breast carcinoma (BC) have been discovered by previous in vitro and in vivo studies. Yet, expressions and distinct prognostic values of these eight E2Fs in human BC remain unclear in many respects. In this study, we aimed to reveal their roles in BC through analyzing the transcription and survival data of the E2Fs in BC patients from four online databases including ONCOMINE, Breast Cancer Gene-Expression Miner v4.1, cBioPortal for Cancer Genomics, and Kaplan–Meier Plotter. We found the overexpression of E2Fs in BC tissues compared with normal breast tissues, except for E2F4. Higher expression levels of E2Fs, except for E2F4 and E2F6, were associated with higher levels of Scarff–Bloom–Richardson grade of BC. Alterations of E2Fs were found to be significantly correlated with poorer overall survival of BC patients. Through plotting the survival curve in the Kaplan–Meier Plotter, it was found that higher mRNA levels of E2F1, E2F3, E2F7, and E2F8 were associated with poorer relapse-free survival in all BC patients, indicating that they are potential targets for individualized treatments of BC patients. Conversely, higher mRNA expression level of E2F4 predicted better RFS in BC patients, suggesting E2F4 as a new biomarker for BC prognosis. Considering currently available limited evidence, further studies need to be performed to investigate the roles of E2Fs in BC.