Posttranscriptional regulation of MMP-9 by HuR contributes to IL-1ß-induced pterygium fibroblast migration and invasion.

Inflammation is considered to be critical in the pterygium progression and recurrence. However, the underlying molecular mechanism is not well understood. Herein, we investigated the potential role of RNA binding protein human antigen R (HuR) responsible for the impact of inflammation on pterygium development. The expression of HuR and matrix metallopeptidase-9 (MMP-9) in pterygium and normal conjunctiva was detected with immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The influence of interleukin-1ß (IL-1ß) on HuR expression and cellular distribution was determined with western blot and immunofluorescence. The pterygium fibroblast (PTF) migration was determined with scratch wound healing assay and Transwell migration assay. MMP-9 production was determined with qRT-PCR and gelatin zymography. The interaction between HuR and MMP-9 was investigated with RNP immunoprecipitation (IP) followed by RT-PCR and messenger RNA (mRNA) stability analysis. HuR and MMP-9 expression are elevated in pterygium, especially progressive pterygium compared with normal conjunctiva. IL-1ß could increase the expression and nucleus-cytoplasm shuttle of HuR in cultured PTFs. HuR mediated the stimulatory effect of IL-1ß on PTF migration and MMP-9 production. HuR bound to MMP-9 mRNA and in turn increased it stability. Our results suggest that posttranscriptional regulation of MMP-9 via stabilizing mRNA by HuR might contribute to the stimulatory effect of inflammatory factor IL-1ß on pterygium progression. These findings shed light on the pathogenesis of pterygium and provide a promising target for adjuvant treatment of pterygium.

Self-expandable metallic stent as a bridge to elective surgery versus emergency surgery for acute malignant colorectal obstruction.

BACKGROUD: The efficacy and safety of self-expandable metallic stents (SEMSs) as a bridge for patients with acute malignant colorectal obstructions (AMCOs) are still controversial. We conducted this study to evaluate the outcomes of patients with AMCOs treated by different strategies. METHODS: From January 2010 to March 2014, a total of 171 patients with AMCOs from Zhongshan Hospital were retrospectively enrolled in this study. One hundred twenty patients successfully received stent placement followed by one-stage laparoscopic or open resection in the stent group, and 51 patients received emergency operations in the emergency group. RESULTS: The operation duration and postoperative hospital stay were significantly shorter in the stent group (114.51 ± 28.65 vs. 160.39 ± 58.94 min, P < 0.001; 8.00 ± 3.97 vs. 12.59 ± 9.07 days, P = 0.001). The stent group also had significantly reduced intraoperative blood loss and the incidence of postoperative complications compared with the emergency group (61.00 ± 43.70 vs. 121.18 ± 85.90 ml, P < 0.001; 16.7 vs. 37.3%, P = 0.003). Kaplan-Meier survival curves showed that the median survival time in the stent group was significantly longer than that in the emergency group (53 vs. 41 months, P = 0.034). In subgroup analysis of stent group, the stent laparoscopy group had significantly decreased postoperative complications (P = 0.025), and similar long-term survival (P = 0.81). CONCLUSIONS: Stent placement as a bridge to surgery is a safe and feasible procedure and provides significant advantages in terms of short-term outcomes and favorable prognoses for patients with AMCOs. Laparoscopic surgery could be considered as an optimal treatment after stent placement.

High patatin like phospholipase domain containing 8 expression as a biomarker for poor prognosis of colorectal cancer.

BACKGROUND: Patatin like phospholipase domain containing 8 (PNPLA8) has been shown to play a significant role in various cancer entities. Previous studies have focused on its roles as an antioxidant and in lipid peroxidation. However, the role of PNPLA8 in colorectal cancer (CRC) progression is unclear. AIM: To explore the prognostic effects of PNPLA8 expression in CRC. METHODS: A retrospective cohort containing 751 consecutive CRC patients was enrolled. PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores. CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off values, which were calculated by X-tile software. The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis. The overall survival (OS) rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test. RESULTS: PNPLA8 expression was significantly associated with distant metastases in our cohort (P = 0.048). CRC patients with high PNPLA8 expression indicated poor OS (median OS = 35.3, P = 0.005). CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS. For patients with left-sided colon and rectal cancer, the survival curves of two PNPLA8-expression groups showed statistically significant differences. Multivariate analysis also confirmed that high PNPLA8 expression was an independent prognostic factor for overall survival (hazard ratio HR = 1.328, 95%CI: 1.016-1.734, P = 0.038). CONCLUSION: PNPLA8 is a novel independent prognostic factor for CRC. These findings suggest that PNPLA8 is a potential target in clinical CRC management.

Low ferroptosis score predicts chemotherapy responsiveness and immune-activation in colorectal cancer.

BACKGROUND: Existing studies for ferroptosis and prognosis in colorectal cancer (CRC) were limited. In this study, we aim to investigate the prognostic role of ferroptosis markers in patients with CRC and exploration of its micro-environmental distributions. METHODS: Immunohistochemical staining was performed for CRC patients' tissue microarray. Selection and prognostic validation of markers were based on mRNA data from the cancer genome atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed to indicate relative immune landmarks and hallmarks. Ferroptosis and immune contexture were examined by CIBERSORT. Survival outcomes were analyzed by Kaplan-Meier analysis and cox analysis. RESULTS: A panel of 42 genes was selected. Through mRNA expression difference and prognosis analysis, GPX4, NOX1 and ACSL4 were selected as candidate markers. By IHC, increased GPX4, decreased NOX1 and decreased FACL4 indicate poor prognosis and worse clinical characteristics. Ferroptosis score based on GPX4, NOX1 and ACSL4 was constructed and validated with high C-index. Low ferroptosis score can also demonstrate the better progression free survival and better adjuvant chemotherapy (ACT) responsiveness. Moreover, tumor with low ferroptosis score tend to be infiltrated with more CD4+ T cells, CD8+ T cells and less M1 macrophage. Finally, we found that IFN-γ was potentially the central molecule at the crossroad between ferroptosis and onco-immune response. CONCLUSION: Ferroptosis plays important role on CRC tumor progression, ACT response and prognosis. Ferroptosis contributes to immune-supportive responses and IFN-γ was the central molecule for this process.

Combined test of third lumbar skeletal muscle index and prognostic nutrition index improve prognosis prediction power in resected colorectal cancer liver metastasis.

BACKGROUND: In this paper, we aim to explore clinical value of skeletal muscle index (SMI) and prognostic nutrition index (PNI) on resected colorectal cancer liver metastasis (CRLM). RESULTS: Among the 539 patients, 355 were males. Baseline lower SMI was associated with smaller BMI, smaller PNI, smaller pre-albumin and longer hospitalization days (P<0.05). Patients with lower SMI and PNI had significantly shorter duration of PFS and OS (P<0.05). SMI can reflect the postoperative treatment response. Postoperative 6-month's and 12-month's SMI and PNI can indicate overall prognosis. When combined SMI and PNI, prognostic AUC of ROC curves improved significantly. CONCLUSION: Combined monitor of SMI and PNI can improve the power at predicting prognosis. Postoperative 6-month's record of SMI and PNI was more accurate and predictive for CRLM prognosis. METHOD: A total of 539 resected CRLM patients between January 2013 to December 2016 with complete clinical data were included. Computed tomography image was collected from each patient. Receiver-operating characteristic (ROC) curves were constructed; area under curves (AUC) were also determined. All clinical variables were analyzed in proper way.

Exploration of exact significance of lymph node ratio and construction of a novel stage in colon cancer with no distant metastasis.

AIM: Lymph node ratio (LNR) seems to be more precise than classic N stage in classifying cancer stage. Thus, we aim to construct a modified classification system based on LNR for colon cancer without distant metastasis. METHODS: This study enrolled two independent cohorts of patients. The primary cohort enrolled 2,152 patients from 2008 to 2013 in Zhongshan Hospital, Fudan University. The validation cohort consisted of 77,406 patients from the Surveillance, Epidemiology, and End Results (SEER) registry from 2004 to 2014. The inclusion criteria were: pathologically confirmed colon cancer, and American Joint Committee on Cancer (AJCC) stage I/II/III. The exclusion criteria included: incomplete follow-up information, rectal cancer, and multiple primary sites. The prognostic value of LNR for overall survival was evaluated. The cutoff value of LNR was determined by the X-tile. Predictive performance of modified classification was determined by the concordance index. RESULTS: After analysis, 0.05 and 0.50 were determined as the best threshold values of LNR. A value of <0.05, 0.05-0.50 and >0.50 was reclassified as the mN0, mN1 and mN2 stage. A modified classification based on mN0, mN1, and mN2 was further constructed for stage I/II/III colon cancer. C-index of the modified classification was statistically more precise than AJCC classification (0.687 versus 0.605, P<0.001). The same results can also be determined in the validation cohort (0.715 versus 0.640, P<0.001). Furthermore, a prognostic nomogram including independent factors was constructed. The constructed nomogram showed good performance according to the calibration curve. CONCLUSION: The clinical value of LNR level was preferable to classic N stage in colon cancer patients. Our proposed classification based on LNR and AJCC T category can effectively differentiate patients with varied survival outcomes.

Airborne particulate matter impairs corneal epithelial cells migration via disturbing FAK/RhoA signaling pathway and cytoskeleton organization.

BACKGROUND: Cornea is the outmost structure of the eye and exposed directly to the air pollution. However, little is known about the effect of PM2.5 on corneal epithelium, which is critical for maintenance of cornea homeostasis and visual function. OBJECTIVE: We investigated the influence of PM2.5 exposure on corneal epithelial migration and the possible mechanisms involved in the process. METHODS: We observed wound healing in mouse model of cornea abrasion, evaluated the migration and mobility of cultured corneal epithelial cells with wound scratch assay and Transwell migration assay, detected the phosphorylation and interaction of FAK/paxillin with immunofluorescence and immunoprecipitation, and determined the RhoA activity and actin reorganization, in response to PM2.5 exposure. RESULTS: Exposure to PM2.5 remarkably inhibited corneal epithelial cell migration both in mouse model of corneal abrasion and in cell culture model. We found the phosphorylation and interaction of FAK/paxillin, RhoA activity as well as actin reorganization were suppressed by PM2.5 exposure. Moreover, formation of ROS might play a role in the action of PM2.5. CONCLUSIONS: PM2.5 exposure could result in delay of corneal epithelium wound healing by inhibiting cell migration, thus more attention should be paid to the potential risk of corneal infection and effort should be made to protect eyes against impairment induced by PM2.5.

Aberrant expression of genes and proteins in pterygium and their implications in the pathogenesis.

Pterygium is a common ocular surface disease induced by a variety of factors. The exact pathogenesis of pterygium remains unclear. Numbers of genes and proteins are discovered in pterygium and they function differently in the occurrence and development of this disease. We searched the Web of Science and PubMed throughout history for literatures about the subject. The keywords we used contain pterygium, gene, protein, angiogenesis, fibrosis, proliferation, inflammation, pathogenesis and therapy. In this review, we summarize the aberrant expression of a range of genes and proteins in pterygium compared with normal conjunctiva or cornea, including growth factors, matrix metalloproteinases and tissue inhibitors of metalloproteinases, interleukins, tumor suppressor genes, proliferation related proteins, apoptosis related proteins, cell adhesion molecules, extracellular matrix proteins, heat shock proteins and tight junction proteins. We illustrate their possible mechanisms in the pathogenesis of pterygium as well as the related intervention based on them for pterygium therapy.

Anti-EGFR and anti-VEGF agents: important targeted therapies of colorectal liver metastases.

Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, "new" RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The results of the FIRE-III trial showed that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, P = 0.017) for evaluable population. With the balanced allocation of second-line treatment, the FIRE-III trial was expected to provide evidence for selecting following regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combination therapy with more than one targeted agent has been proven to provide no benefit, and even was reported to be harmful as first-line treatment by four large clinical trials. However, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents.