A Modified NAR Scoring Model Incorporating Immune Infiltration Characteristics to Better Predict Long-Term Survival Following Neoadjuvant Radiotherapy in Rectal Cancer.

(1) Background: The neoadjuvant rectal (NAR) score has been developed as a prognostic tool for survival in locally advanced rectal cancer (LARC). However, the NAR score only incorporates weighted cT, ypT, and ypN categories. This long-term follow-up study aims to modify a novel prognostic scoring model and identify a short-term endpoint for survival. (2) Methods: The prognostic factors for overall survival (OS) were explored through univariate and multivariate analyses. Based on Cox regression modeling, nomogram plots were constructed. Area under the curve (AUC) and concordance indices were used to evaluate the performance of the nomogram. Receiver operating characteristic (ROC) analysis was conducted to compare the efficiency of the nomogram with other prognostic factors. (3) Results: After a long-term follow-up, the 5-year OS was 67.1%. The mean NAR score was 20.4 ± 16.3. Multivariate analysis indicated that CD8+ T-cell, lymphovascular invasion, and the NAR score were independent predictors of OS. The modified NAR scoring model, incorporating immune infiltration characteristics, exhibited a high C-index of 0.739 for 5-year OS, significantly outperforming any individual factor. Moreover, the predictive value of the nomogram was superior to the AJCC stage and pathological complete regression at 3-year, 5-year, and 10-year time points, respectively. Over time, the model's predictions of long-term survival remained consistent and improved in accuracy. (4) Conclusions: The modified NAR scoring model, incorporating immune infiltration characteristics, demonstrates high accuracy and consistency in predicting OS.

Systemic administration of STING agonist promotes myeloid cells maturation and antitumor immunity through regulating hematopoietic stem and progenitor cell fate.

STING is a pivotal mediator of effective innate and adaptive anti-tumor immunity; however, intratumoral administration of STING agonists have shown limited therapeutic benefit in clinical trials. The systemic effect of the intravenous delivery of STING agonists in cancer is not well-defined. Here, we demonstrated that systemic administration of STING agonist inhibited melanoma growth, improved inflammatory effector cell infiltration, and induced bone marrow mobilization and extramedullary hematopoiesis, causing widespread changes in immune components in the peripheral blood. The systemically administered STING agonist promoted HSC expansion and influenced lineage fate commitment, which was manifested as the differentiation of HSPCs was skewed toward myeloid cells at the expense of B-cell lymphopoiesis and erythropoiesis. Transcriptome analysis revealed upregulation of myeloid lineage differentiation-related and type I interferon-related genes. This myeloid-biased differentiation promoted the production and maturation of myeloid cells toward an activated phenotype. Furthermore, depletion of Gr-1+ myeloid cells attenuated the anti-tumor immunity of STING agonist. Our findings reveal the anti-tumor mechanism of systemic administration of STING agonist that involves modulating HSPC differentiation and promoting myeloid cells maturation. Our study may help explain the limited clinical activity of STING agonists administered intratumorally.

Efficacy and safety of paxlovid (nirmatrelvir/ritonavir) in the treatment of COVID-19: An updated meta-analysis and trial sequential analysis.

Our study is aimed to access the efficacy and safety outcomes for coronavirus disease 2019 (COVID-19) patients treated with Paxlovid. According to inclusion and exclusion criteria, databases were used to retrieve articles from 1 January 2020 to 1 January 2023. Article screening, quality evaluation and data extraction were completed and cross-checked. The meta-analysis and trial sequential analysis (TSA) were conducted using RevMan, StataMP, and TSA software. A total of 42 original articles were included. Overall meta-analysis results showed that for death, hospitalisation, death or hospitalisation, emergency department (ED) visit, intensive care unit (ICU) admission, and extra oxygen requirement outcomes, every odds ratio (OR) was <1 and p < 0.05. For rebound outcome, the OR was >1 and p > 0.05. For adverse events (AEs) outcome, the OR was >1 and p < 0.05. In conclusion, Paxlovid effectively reduced the risks of death, hospitalisation, death or hospitalisation, ED visit, ICU admission, and extra oxygen requirement. There was no significant statistical difference considering rebound, but people should pay attention to possible AEs. However, for rebound and AEs outcomes, observations in certain subgroups suggested conclusions contrary to the overall meta-analysis. Trial sequential analysis indicated these two outcomes have a risk of false negative or false positive conclusions, so additional original studies are needed for further validation.

A modified melanoma-molGPA scoring model: assessment of survival after and efficacy of different radiotherapy modalities in patients with melanoma brain metastases.

PURPOSE: Patients with malignant melanoma brain metastases (MBMs) have poor prognoses. For MBMs, the Melanoma-molGPA is the most widely used predictive score, but its predictive value remains uncertain in patients fully treated with radiotherapy. We identified MBMs prognostic factors and modified the prognostic scoring model. METHODS: We retrospectively analyzed patients diagnosed with MBMs between December 2010 and November 2021 for prognostic factors influencing overall survival (OS) by univariate and multivariate analyses. Nomogram plots were based on Cox regression modeling. We evaluated overall survival (OS) using Kaplan-Meier survival curves and log-rank tests. RESULTS: The median OS (mOS) was 7.9 months. On multivariate analysis, BRAF mutation status (p < 0.001), number of brain metastases (BM) (p < 0.001), presence of liver metastases (p < 0.001), brain metastases with a midline shift (p = 0.003), Karnofsky Performance Score (p = 0.02), and lymphocyte-to-monocyte ratio (p < 0.0001) were independent OS predictors. These were incorporated into a modified risk-stratification model. Overall, whole-brain radiotherapy (WBRT) did not significantly affect mOS (mOS, 6.89 vs. 8.83 months; p = 0.07). After risk stratification using our model, WBRT resulted in no significant survival benefit in the low-risk group (mOS 10.07 vs. 13.1 months; p = 0.71) but significantly worse prognosis in the high-risk group (mOS, 2.37 vs. 6.92 months; p = 0.026). CONCLUSION: We propose a modified model that accurately distinguishes the prognosis of patients with MBMs and guides decision-making for radiotherapy. Based on this novel model, WBRT should be cautiously selected for high-risk patients.

A novel anoikis-related gene prognostic signature and its correlation with the immune microenvironment in colorectal cancer.

Background: Anoikis is a type of apoptosis associated with cell detachment. Resistance to anoikis is a focal point of tumor metastasis. This study aimed to explore the relationship among anoikis-related genes (ARGs), immune infiltration, and prognosis in colorectal cancer (CRC). Methods: The transcriptome profile and clinical data on patients with CRC were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Patients were divided into two clusters based on the expression of ARGs. Differences between the two ARG molecular subtypes were analyzed in terms of prognosis, functional enrichment, gene mutation frequency, and immune cell infiltration. An ARG-related prognostic signature for predicting overall survival in patients with CRC was developed and validated using absolute value convergence and selection operator (LASSO) regression analysis. The correlation between the signature risk score and clinicopathological features, immune cell infiltration, immune typing, and immunotherapy response was analyzed. The risk score combined with clinicopathological characteristics was used to construct a nomogram to assess CRC patients' prognosis. Results: Overall, 151 ARGs were differentially expressed in CRC. Two ARG subtypes, namely, ARG-high and ARG-low groups, were identified and correlated with CRC prognosis. The gene mutation frequency and immune, stromal, and ESTIMATE scores of the ARG-high group were higher than those of the ARG-low group. Moreover, CD8, natural killer cells, M1 macrophages, human leukocyte antigen (HLA), and immune checkpoint-related genes were significantly increased in the ARG-high group. An optimized 25-gene CRC prognostic signature was successfully constructed, and its prognostic predictive ability was validated. The high-risk score was correlated with T, N, M, and TNM stages. Risk scores were negatively correlated with dendritic cells, eosinophils, and CD4 cells, and significantly positively correlated with regulatory T cells. Patients in the high-risk group were more likely to exhibit immune unresponsiveness. Finally, the nomogram model was constructed and showed good prognostic predictive power. Conclusion: ARGs are associated with clinicopathological features and the prognosis of CRC, and play important roles in the immune microenvironment. Herein, we underpinned the usefulness of ARGs in CRC to develop more effective immunotherapy techniques.

Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy.

BACKGROUND: Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis. METHODS: The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining. RESULTS: We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF, N/KRAS, and NF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+ T-cell infiltration in PMME than in NEMM. CONCLUSIONS: PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.

Pathogen effector AvrSr35 triggers Sr35 resistosome assembly via a direct recognition mechanism.

Nucleotide-binding, leucine-rich repeat receptors (NLRs) perceive pathogen effectors to trigger plant immunity. The direct recognition mechanism of pathogen effectors by coiled-coil NLRs (CNLs) remains unclear. We demonstrate that the Triticum monococcum CNL Sr35 directly recognizes the pathogen effector AvrSr35 from Puccinia graminis f. sp. tritici and report a cryo-electron microscopy structure of Sr35 resistosome and a crystal structure of AvrSr35. We show that AvrSr35 forms homodimers that are disassociated into monomers upon direct recognition by the leucine-rich repeat domain of Sr35, which induces Sr35 resistosome assembly and the subsequent immune response. The first 20 amino-terminal residues of Sr35 are indispensable for immune signaling but not for plasma membrane association. Our findings reveal the direct recognition and activation mechanism of a plant CNL and provide insights into biochemical function of Sr35 resistosome.

Proliferation Marker Ki67 as a Stratification Index of Adjuvant Chemotherapy for Resectable Mucosal Melanoma.

Background: Adjuvant chemotherapy has been shown to produce a favorable prognosis for patients with resectable mucosal melanoma (MM), resulting in the need for stratification to optimally select patients to benefit from adjuvant therapy. This study analyzed Ki67 as a potential stratification index for adjuvant chemotherapy in resectable MM. Methods: Patients with resected MM who received subsequent adjuvant therapy in Beijing Cancer Hospital between 2010 and 2018 were retrospectively enrolled and analyzed. Relapse-free survival (RFS) and melanoma-specific survival (MSS) curves were used to perform the survival comparisons across different subgroups. Results: From Jan 2010 to Dec 2018, 1106 MM patients were screened from a database of 4706 patients and 175 of these patients were finally enrolled. A total of 100 patients received temozolomide (TMZ)-based adjuvant chemotherapy and 75 patients received high-dose interferon-α2b (HDI) adjuvant therapy. Compared with HDI, patients who received TMZ-based adjuvant chemotherapy had significantly superior RFS (21.0 vs. 9.6 months, P = 0.002). For patients with low Ki67 expression (<30%), the two regimens showed no significant difference for impact on RFS (33.9 vs. 22.7 months, P = 0.329). However, for patients with high Ki67 expression (≥30%), TMZ-based adjuvant chemotherapy achieved favorable RFS compared with HDI (18.0 vs. 6.7 months, P < 0.001) and tended to improve MSS compared to HDI (41.4 vs. 25.1 months, P = 0.067). Conclusion: Compared with HDI, adjuvant chemotherapy may be more relevant for patients with Ki67 ≥ 30%. Ki67 may serve as a potential index to distinguish populations benefiting from adjuvant chemotherapy in resectable MM, and may provide a basis for stratification in the selection of adjuvant regimens.

Association of TLR3 gene 1377C/T (rs3775290) and TLR7 gene C/G (rs3853839) polymorphism with hand, foot, and mouth disease caused by human enterovirus 71 infection susceptibility and severity in the Chinese Han population: A meta-analysis of case-control studies.

BACKGROUND: Several case-control studies have been conducted on the relationship between rs3775290 C/T and rs3853839 C/G single nucleotide polymorphisms of the Toll-like receptor (TLR) gene and hand, foot, and mouth disease (HFMD) susceptibility and severity. This meta-analysis aimed to offer a systemic review of HFMD susceptibility and severity among the Chinese Han population associated with the C/T (rs3775290) polymorphism of the TLR3 gene or C/G (rs3853839) polymorphism of the TLR7 gene. METHODS: A computer search was conducted using PubMed, Web of Science, Embase, CNKI, CBM, VIP, and WanFang databases. The time ranges were from database establishment to 30/7/2021. Articles selected according to the inclusion and exclusion criteria underwent data extraction and methodological quality evaluation. RevMan 5.4 and Stata 16.0 were adopted for meta-analysis, and the incorporated odds ratio (OR) values and 95% confidence intervals (CIs) were calculated. Sensitivity and publication bias assessments were performed. RESULTS: 8 articles with 9 studies were selected. Among them, there were 858 cases and 577 controls in TLR3 rs3775290 studies as well as 2151 cases and 1554 controls in TLR7 rs3853839 studies. Regarding rs3775290 of TLR3, susceptibilities of the severe type of T-possessing individuals were larger than those of C-possessing individuals [OR = 1.34, 95%CI (1.10, 1.64), P = .004]. The susceptibility of individuals with the severe TT genotype was 1.61 times that of individuals with the CC genotype [95%CI (1.07, 2.43), P=0.02], while susceptibility to HFMD was not influenced by the genotype. In terms of the rs3853839 of the TLR7 gene, C allele carriers have a higher risk of developing HFMD than G allele carriers. The susceptibility to HFMD in CC+CG individuals was 1.24 times than that in GG individuals [95%CI (1.07, 1.43), P = .004]. However, no relationship was found between this polymorphism and severity of the severe type. No significant publication bias was observed in this study. CONCLUSIONS: rs3775290 (C/T) of TLR3 is associated with susceptibility to the severe type, whereas rs3853839 (C/G) of TLR7 is associated with susceptibility to HFMD. However, owing to the limited quantity and quality of the research, the aforementioned conclusions are yet to be justified by more high-quality research.

Gallic Acid Alleviates Visceral Pain and Depression via Inhibition of P2X7 Receptor.

Chronic visceral pain can occur in many disorders, the most common of which is irritable bowel syndrome (IBS). Moreover, depression is a frequent comorbidity of chronic visceral pain. The P2X7 receptor is crucial in inflammatory processes and is closely connected to developing pain and depression. Gallic acid, a phenolic acid that can be extracted from traditional Chinese medicine, has been demonstrated to be anti-inflammatory and anti-depressive. In this study, we investigated whether gallic acid could alleviate comorbid visceral pain and depression by reducing the expression of the P2X7 receptor. To this end, the pain thresholds of rats with comorbid visceral pain and depression were gauged using the abdominal withdraw reflex score, whereas the depression level of each rat was quantified using the sucrose preference test, the forced swimming test, and the open field test. The expressions of the P2X7 receptor in the hippocampus, spinal cord, and dorsal root ganglion (DRG) were assessed by Western blotting and quantitative real-time PCR. Furthermore, the distributions of the P2X7 receptor and glial fibrillary acidic protein (GFAP) in the hippocampus and DRG were investigated in immunofluorescent experiments. The expressions of p-ERK1/2 and ERK1/2 were determined using Western blotting. The enzyme-linked immunosorbent assay was utilized to measure the concentrations of IL-1ß, TNF-α, and IL-10 in the serum. Our results demonstrate that gallic acid was able to alleviate both pain and depression in the rats under study. Gallic acid also reduced the expressions of the P2X7 receptor and p-ERK1/2 in the hippocampi, spinal cords, and DRGs of these rats. Moreover, gallic acid treatment decreased the serum concentrations of IL-1ß and TNF-α, while raising IL-10 levels in these rats. Thus, gallic acid may be an effective novel candidate for the treatment of comorbid visceral pain and depression by inhibiting the expressions of the P2X7 receptor in the hippocampus, spinal cord, and DRG.

Association of PTPN22 SNP1858 (rs2476601) and Gene SNP1123 (rs2488457) Polymorphism With Primary Immune Thrombocytopenia Susceptibility: A Meta-Analysis of Case-Control Studies and Trial Sequential Analysis.

Objective: Systematic review of the association of protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene 1858 and 1123 sites single nucleotide polymorphism (SNP) with the susceptibility of primary immune thrombocytopenia (ITP). Method: Database searched includes PubMed, Embase, Web of Science, CNKI, CBM, VIP and WanFang Data. The retrieval period is from the establishment of the database to 30 June 2021. After screening articles according to inclusion and exclusion criteria, the data were extracted and methodological quality of the included studies was evaluated. Meta-analysis was performed using RevMan 5.4 and Stata 16.0 software. The combined OR value and its 95%CI were calculated. Sensitivity analysis and publication bias assessment were performed. Trial sequential analysis (TSA) was performed using TSA 0.9.5.10 Beta software. Results: A total of 10 studies with 10 articles were included, with a total of 932 cases and 2,112 controls. The results of meta-analysis showed that for SNP1858, the susceptibility of TT genotype to ITP was 5.01 times higher than CC genotype [95%CI (1.81, 13.86), p = 0.002]. For SNP1123, G allele carriers were more susceptible to ITP than C allele carriers [OR = 1.23, 95%CI (1.05, 1.45), p = 0.01], and GG genotype carriers were 1.51 times more susceptible to ITP than CC genotype carriers [95%CI (1.11, 2.06), p = 0.009]. Although the results are statistically significant, the results of sensitivity analysis showed certain limitations of stability, and the TSA analysis still indicated the possibility of false positive. No significant publication bias was observed. Conclusion: PTPN22 gene SNP1858 (rs2476601) and SNP1123 (rs2488457) polymorphisms are associated with susceptibility to primary immune thrombocytopenia. Due to the limitation of the number and quality of the included studies, the above conclusions need to be verified by more high-quality studies.

EZH2 Inhibitor Enhances the STING Agonist‒Induced Antitumor Immunity in Melanoma.

STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. Recently, multiple clinical trials of STING agonists have been conducted in hematological malignancies and solid tumors. However, STING is commonly suppressed in melanoma through mechanisms that remain unclear. We found that STING expression was epigenetically suppressed by H3K27me3 in melanoma, and EZH2 inhibitor could induce an H3K27 shift from trimethylation to acetylation, resulting in increased expression of STING. Furthermore, a combination of STING agonist and EZH2 inhibitor upregulated major histocompatibility complex class I expression and chemokine production. Whole-transcriptome analysis showed that IFN-1‒related genes were significantly upregulated in the combination treatment group. In addition, the combination treatment synergistically reduced tumor growth and increased CD8+ T-cell infiltration in a poorly immunogenic melanoma mouse model B16-F10. These results showed, to our knowledge, a previously unreported mechanism underlying the epigenetic regulation of STING expression in melanoma; a combination of STING agonists and EZH2 inhibitors can boost the antitumor immune response and would be a promising treatment option for patients with melanoma who are refractory to current immunotherapies.

Patterns of supraclavicular area failure after mastectomy in breast cancer patients: implications for target volume delineation.

PURPOSE: To characterize the pattern of post-mastectomy supraclavicular lymph node (LN) metastases in patients with breast cancer (BC) and to provide insights for individualized clinical target volume delineation for radiotherapy. METHODS: We retrospectively analyzed 88 patients with BC who developed post-mastectomy regional LN metastases. The affected regional LNs were categorized as the ipsilateral medial supraclavicular LN area (IMSC-LN), ipsilateral lateral supraclavicular LN area (ILSC-LN), ipsilateral infraclavicular LN area (IIC-LN), and ≥2 groups in the ipsilateral clavicular LN area (MMIC-LN). Clinical characteristics were included in a multivariate analysis to identify risk factors for clavicular LN metastases. RESULTS: The ILSC-LNs (68.2%) were the most common metastatic site. IMSC-LN metastases showed a significant association with estrogen-receptor (ER) negative status, left-sided BC, and positive axillary LNs. Tumor size ≥2.4 cm and Her2 type were predictors of ILSC-LN metastases. Additionally, tumor size ≥2.4 cm, and level I ipsilateral axillary metastases were associated with MMIC-LN metastasis. CONCLUSION: ILSC-LN was the most frequently affected group of supraclavicular lymph nodes. ER-negative status, left-sided BC, tumor size, and positive ipsilateral axillary LNs are potentially associated with the pattern of supraclavicular LN metastatic involvement.

High Biologically Effective Dose Radiotherapy for Brain Metastases May Improve Survival and Decrease Risk for Local Relapse Among Patients With Small-Cell Lung Cancer: A Propensity-Matching Analysis.

To evaluate whether high biologically effective dose (BED) radiotherapy improves local control and survival outcomes for patients with brain metastases (BMs) from small-cell lung cancer (SCLC) and to determine possible prognostic factors. From January 1998 to June 2018, 250 patients with BM from SCLC were retrospectively analyzed. The Cutoff Finder program was used to classify patients by BED. Overall survival (OS) and BM progression-free survival (BM-PFS) were analyzed using the Kaplan-Meier method and log-rank test. A Cox regression model was used to calculate the hazard ratio and 95% CI for prognostic factors for OS among the study population and propensity score (PS)-matched patients. A BED of 47.4 was taken as the optimal cutoff value. Both OS and BM-PFS were significantly improved in the high-BED (>47.4 Gy) than in the low-BED (≤47.4 Gy) group (median OS: 17.5 months vs 9.5 months, P < .001, median BM-PFS: 14.4 months vs 8.3 months, P < .001). Biologically effective dose (P < .001), Eastern Cooperative Oncology Group performance status (P = .047), smoking (P = .005), and pleural effusion (P = .004) were independent prognostic factors for OS. Propensity score matching with a ratio of 1:2 resulted in 57 patients in the high-BED group and 106 patients in the low-BED group. In the PS-matched cohort, OS and BM-PFS were significantly prolonged in the high-BED group compared with the low-BED group (P < .001). Biologically effective dose >47.4 Gy improves survival among patients with BM from SCLC. Eastern Cooperative Oncology Group score, smoking, and pleural effusion independently affect OS of SCLC patients with BM.

Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although multiple efforts have been made to understand the development of HCC, morbidity, and mortality rates remain high. In this study, we aimed to discover the mRNAs and long non-coding RNAs (lncRNAs) that contribute to the progression of HCC. We constructed a lncRNA-related competitive endogenous RNA (ceRNA) network to elucidate the molecular regulatory mechanism underlying HCC. METHODS: A microarray dataset (GSE54238) containing information about both mRNAs and lncRNAs was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and lncRNAs (DElncRNAs) in tumor tissues and non-cancerous tissues were identified using the limma package of the R software. The miRNAs that are targeted by DElncRNAs were predicted using miRcode, while the target mRNAs of miRNAs were retrieved from miRDB, miRTarBas, and TargetScan. Functional annotation and pathway enrichment of DEGs were performed using the EnrichNet website. We constructed a protein-protein interaction (PPI) network of DEGs using STRING, and identified the hub genes using Cytoscape. Survival analysis of the hub genes and DElncRNAs was performed using the gene expression profiling interactive analysis database. The expression of molecules with prognostic values was validated on the UALCAN database. The hepatic expression of hub genes was examined using the Human Protein Atlas. The hub genes and DElncRNAs with prognostic values as well as the predictive miRNAs were selected to construct the ceRNA networks. RESULTS: We found that 10 hub genes (KPNA2, MCM7, CKS2, KIF23, HMGB2, ZWINT, E2F1, MCM4, H2AFX, and EZH2) and four lncRNAs (FAM182B, SNHG6, SNHG1, and SNHG3) with prognostic values were overexpressed in the hepatic tumor samples. We also constructed a network containing 10 lncRNA-miRNA-mRNA pathways, which might be responsible for regulating the biological mechanisms underlying HCC. CONCLUSION: We found that the 10 significantly overexpressed hub genes and four lncRNAs were negatively correlated with the prognosis of HCC. Further, we suggest that lncRNA SNHG1 and the SNHG3-related ceRNAs can be potential research targets for exploring the molecular mechanisms of HCC.

Role of postoperative radiotherapy in pT3N0 rectal cancer: A risk-stratification system based on population analyses.

The impact of adjuvant radiotherapy in pT3N0 rectal cancer is controversial. We aimed to determine the risk factors for cancer-specific survival (CSS) among these patients and to develop a risk-stratification system to identify which of these patients would benefit from adjuvant radiotherapy. In this review of the Surveillance, Epidemiology, and End Results database (2010-2014), we analyzed the data of pT3N0 rectal cancer patients who had not undergone neoadjuvant radiotherapy. Prognostic factors were identified using the Cox proportional hazards model, and risk scores were derived according to the ß regression coefficient. A total of 1021 patients were identified from the database search. The overall 5-year CSS was 86.31%. Multivariate analysis showed that age (P < 0.001), tumor differentiation (P = 0.044), number of nodes resected (P = 0.032), marital status (P = 0.005), and radiotherapy (P = 0.006) were independent prognostic factors for CSS. A risk-stratification system composed of age, tumor differentiation, and number of nodes resected was generated. Low-risk patients had better CSS than high-risk patients (92.13% vs 72.55%, P < 0.001). The addition of radiotherapy to surgery doubled the CSS among the high-risk patients (42.06% vs 91.26%, P = 0.001) but produced no survival benefit among the low-risk patients (93.36% vs 96.38%, P = 0.182). Our risk-stratification model based on age, tumor differentiation, and number of nodes resected predicted the outcomes of pT3N0 rectal cancer patients. This model could help identify patients who may benefit from adjuvant radiotherapy.

Association of markers of systemic and local inflammation with prognosis of patients with rectal cancer who received neoadjuvant radiotherapy.

PURPOSE: The inflammatory status of patients with cancer appears to affect cancer progression and patient prognosis. We examined the characteristics of cancer-associated systemic and local inflammation and its impact on the overall survival (OS) of patients with locally advanced rectal cancer (LARC) who received neoadjuvant radiotherapy (nRT). PATIENTS AND METHODS: Seventy-six consecutive LARC patients who received nRT from February 2012 to September 2015 were retrospectively analyzed. The peripheral neutrophil-to-lymphocyte ratio (NLR) was determined at diagnosis, and the CD8+ T-cell count was determined from surgical specimens. Factors associated with OS were identified by univariate and multivariate Cox regression. RESULTS: The median follow-up time was 23.0 months (range: 2-59), and the overall 5-year OS rate was 68.6% (95% CI =46.06-91.14). Patients with a high NLR (≥2.0) and a low CD8+ T-cell count (<9%) had a significantly worse 5-year OS than those with a low NLR and a high CD8+ T-cell count (P=0.005). NLR was also associated with lymphovascular invasion (P=0.014) and T stage (P=0.047), and the CD8+ T-cell count was associated with mucinous adenocarcinoma (P=0.005) and T stage (P=0.049). An NLR <2.0 was associated with pathological complete regression after nRT (P=0.039). Multivariate Cox regression indicated that NLR (P=0.025), CD8+ T-cell count (P=0.018), age (P=0.020), lymphovascular invasion (P=0.038), and T stage (P=0.011) were independently associated with OS. CONCLUSION: A high NLR and a low CD8+ T-cell count were significantly associated with poor survival in our population of patients with LARC. Measurement of markers of systemic and local inflammation might help to predict the prognosis of patients with LARC after nRT.

Role of postoperative radiotherapy in dermatofibrosarcoma protuberans: a propensity score-matched analysis.

OBJECTIVE: This study aimed to evaluate the role of postoperative radiotherapy (RT) in dermatofibrosarcoma protuberans (DFSP) and identify the prognostic factors influencing the disease-free survival (DFS). METHODS: A total of 184 patients with DFSP were analyzed from 2000 to 2016. The regression model was used to examine the prognostic factors for DFS. Baseline covariates were balanced using a propensity score model. The role of RT was assessed by comparing the DFS of the surgery + RT group with that of the surgery group. RESULTS: The median follow-up was 58 months (range, 6-203 months). The 5-year DFS rate was 89.8%. The univariate analysis showed that age ≥ 50 years, presence of fibrosarcoma, margins < 2 cm, and tumor size ≥5 cm were associated with worse DFS (P = 0.002, P <  0.001, P = 0.030, and P = 0.032, respectively). The multivariate Cox regression model revealed that age, margin width, lesion number, and histological subtype independently affected DFS. The Ki-67 expression was related to age and histological subtype. Patients with Ki-67 ≥ 17% showed a worse DFS than those with Ki-67 < 17% (35.8% vs 87.8%, P = 0.002). In the matched cohort, DFS was significantly higher in the S + RT group than in the S group (5-year DFS, 88.1% vs 56.2%, P = 0.044). CONCLUSIONS: Age, margin width, lesion number, and histological subtype were independent risk factors for DFS in patients with DFSP. The high expression of Ki-67 could predict a poor prognosis. Postoperative RT could improve DFS for patients with DFSP.

Prolyl hydroxylase domain 3 influences the radiotherapy efficacy of pancreatic cancer cells by targeting hypoxia-inducible factor-1α.

PURPOSE: Pancreatic cancer is characterized by a hypoxic microenvironment and resistance to most currently available treatment modalities. Prolyl hydroxylase domain 3 (PHD3) is a rate-limiting enzyme that regulates the degradation of hypoxia-inducible factors (HIFs) and is deregulated in pancreatic cancer cells. Whether such alteration of PHD3 expression contributes to the sustained growth and radioresistance of pancreatic cancer cells remains largely unknown. MATERIALS AND METHODS: PHD3 was overexpressed in pancreatic cancer Mia-paca2 cells via lentiviral expression. Cell cycle progression and apoptosis were assayed by flow cytometry. HIF-1α, EGFR, and PHD3 protein expression was assessed by Western blotting. Cell survival was determined in a colony formation assay. RESULTS: PHD3 overexpression suppressed HIF-1α protein expression and EGFR phosphorylation and enhanced the 2 Gy irradiation-mediated reductions in HIF-1α and phosphorylated (p)-EGFR under either normoxic or hypoxic conditions. PHD3 overexpression inhibited the growth and colony formation of Mia-paca2 cells in response to irradiation under either normoxic or hypoxic conditions. PHD3 overexpression exacerbated irradiation-induced apoptosis, with a greater effect under hypoxia than normoxia. Cell cycle distribution analysis demonstrated that PHD3 overexpression resulted in further shortened S phase and lengthened G2/M phase in response to irradiation. CONCLUSION: PHD3 expression may contribute to the radiotherapy efficacy of pancreatic cancer cells and serve as a novel biomarker for improving radiotherapy efficacy in pancreatic cancer.

Prognostic value of vascular endothelial growth factor receptor 1 and class III ß-tubulin in survival for non-metastatic rectal cancer.

AIM: To assess the long-term prognostic value of vascular endothelial growth factor receptor 1 (VEGFR1) and class III ß-tubulin (TUBB3) mRNA expression in non-metastatic rectal cancer. METHODS: A total of 75 consecutive patients with non-metastatic rectal cancer from March 2004 to November 2008 were analyzed retrospectively at our institute. The mRNA expressions of VEGFR1 and TUBB3 were detected by multiplex branched DNA liquid-chip technology. The Cutoff Finder application was applied to determine cutoff point of mRNA expression. SPSS software version 22.0 was used for analysis. RESULTS: The median follow-up was 102.7 mo (range, 6-153.6). The χ2 and Fisher's exact tests showed that VEGFR1 expression was related to lymph node metastasis (P = 0.013), while no relationships between TUBB3 and clinicopathological features were observed. Univariate analysis showed that T stage, lymph node metastasis, tumor differentiation, VEGFR1 and TUBB3 mRNA expression were correlated to overall survival (OS) (P = 0.048, P = 0.003, P = 0.052, P = 0.003 and P = 0.015, respectively). Also, lymph node metastasis and VEGFR1 expression independently influenced OS by multivariate analysis (P = 0.027 and P = 0.033). VEGFR1 expression was positively correlated with TUBB3 (P = 0.024). The patients with low expression of both TUBB3 and VEGFR1 presented a better OS (P = 0.003). In addition, the receiver operating characteristic analysis suggested that the combination of lymph node metastasis and VEGFR1 had a more favorable prognostic value (P < 0.001). CONCLUSION: VEGFR1 expression and lymph node metastasis independently and jointly affect survival. Moreover, low expression of VEGFR1 and TUBB3 presented a better OS in patients with non-metastatic rectal cancer, which might serve as a potential prognostic factor.