Circulating PD-L1 is associated with T cell infiltration and predicts prognosis in patients with CRLM following hepatic resection.

BACKGROUND: Exosomal PD-L1 (exoPD-L1) could induce immunosuppression functionally, thus impairing patients' survival in melanoma, NSCLC, and gastric cancer. However, no evidence demonstrates the feasibility of circulating exoPD-L1 and soluble PD-L1 (sPD-L1) as biomarkers for prognosis and early recurrence in colorectal liver metastasis (CRLM) patients following hepatectomy or their association with T cell infiltration at liver metastases. METHODS: In cohort 1, exoPD-L1 and sPD-L1 were preoperatively tested using ELISA. CD3, CD8, granzyme B (GB) and PD1 expressed at liver metastases were evaluated using immunohistochemistry. In cohort 2, exoPD-L1 and sPD-L1 were detected at baseline, before hepatectomy, after hepatectomy, and after disease progression. RESULTS: In cohort 1, higher preoperative exoPD-L1 or sPD-L1 significantly impaired RFS (exoPD-L1, P = 0.0043; sPD-L1, P = 0.0041) and OS (exoPD-L1, P = 0.0034; sPD-L1, P = 0.0061). Furthermore, preoperative exoPD-L1 was negatively correlated with CD3 + T-lymphocytes infiltrated at tumor center (CT), and GB and PD1 were expressed at tumor invasive margin (IM). Preoperative sPD-L1 was negatively correlated with CD3 + and CD8 + T-lymphocytes' infiltration at IM and CT, GB and PD1 expression at IM. In cohort 2, exoPD-L1 and sPD-L1 levels decreased following hepatectomy but increased when tumor progressed. Moreover, higher postoperative exoPD-L1 and sPD-L1 or a small reduction in exoPD-L1 and sPD-L1 levels after hepatectomy suggested higher early recurrence rate. CONCLUSIONS: Both preoperative exoPD-L1 and sPD-L1 had promising prognostic values and were associated with T cell infiltration at liver metastases in CRLM patients following hepatectomy. Dynamically tracking exoPD-L1 and sPD-L1 levels could monitor disease status and detect early recurrence.

Effective of metastasis-directed therapy for de novo metastatic nasopharyngeal carcinoma: A propensity score matched analysis.

OBJECTIVE: Our objective was to establish a prognostic model for patients with de novo metastatic nasopharyngeal carcinoma (NPC) who received chemotherapy followed by locoregional radiotherapy (LRRT) to identify candidates for metastasis-directed therapy (MDT). METHODS: De novo metastatic NPC patients who received chemotherapy followed by LRRT were enrolled. Propensity score matching (PSM) method was used to compare overall survival (OS) for patients receiving LRRT alone and MDT plus LRRT. We developed a predictive model to predict survival and estimate the outcome of stratified therapy and identify suitable candidates for MDT. RESULTS: A total of 107 patients received MDT plus LRRT and 178 received LRRT alone were enrolled. PSM analysis identified 107 patients in each cohort and showed that MDT plus LRRT was associated with a significant survival benefit (HR: 0.640; 95% CI, 0.29-0.956; p = 0.027). Based on five independent prognostic factors, including metastases number, serum lactate dehydrogenase, liver metastasis, C-reactive protein, and tumor response, a prognostic model was established. All patients were stratified according to the prognostic score obtained by the prognostic model. In the low-risk group, MDT plus LRRT group revealed a significant improvement for OS compared with LRRT alone group (5-year OS, 69.9% vs. 57.8%, p = 0.020). However, no significant difference was observed between MDT plus LRRT group and LRRT alone in the high-risk group (p = 0.75). CONCLUSION: MDT plus LRRT was associated with improved OS in patients with de novo metastatic NPC, especially low-risk patients identified with a newly developed prognostic model.

Efficacy and Safety of Anti-PD1/PDL1 in Advanced Biliary Tract Cancer: A Systematic Review and Meta-Analysis.

Background: Anti-programmed cell death protein 1 and its ligand (anti-PD1/PDL1) have been proposed as a promising therapeutic option for advanced biliary tract cancer (aBTC). Given the scarce quantitative analyses of anti-PD1/PDL1 in aBTC, we thus did a meta-analysis to assess the benefits and risks of this emerging treatment strategy in patients with aBTC. Methods: PubMed, Embase, the Cochrane Library, Web of Science, and meeting resources were searched for relevant studies. The main endpoints were median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), any-grade adverse events (AEs), and grade 3-4 AEs. Results: Twenty-eight studies with 1,338 participants were included. The best curative effect was found in the anti-PD1/PDL1 combined with anti-CTLA4 and chemotherapy group (mPFS: 12.4 months; mOS: 16.0 months; ORR: 45.1%; DCR: 95.0%), followed by the anti-PD1/PDL1 plus chemotherapy group (mPFS: 8.2 months; mOS: 14.8 months; ORR: 36.3%; DCR: 84.6%), the anti-PD1/PDL1 plus antiangiogenesis group (mPFS: 4.9 months; mOS: 10.2 months; ORR: 17.5%; DCR: 68.7%), the anti-PD1/PDL1 plus anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) group (mPFS: 2.9 months; mOS: 8.3 months; ORR: 9.9%; DCR: 36.8%), and the anti-PD1/PDL1 monotherapy group (mPFS: 2.5 months; mOS: 7.6 months; ORR: 6.8%; DCR: 34.7%). Compared with anti-PD1-containing regimens, anti-PDL1-containing regimens achieved preferable mPFS (11.1 vs. 3.8 months), mOS (12.2 vs. 9.8 months), and ORR (23.7% vs. 17.4%), despite a similar DCR (61.1% vs. 61.3%). The mPFS, mOS, ORR, and DCR were 10.6 months, 15.8 months, 42.3%, and 88.6% of first-line anti-PD1/PDL1 and 3.0 months, 9.1 months, 11.6%, and 51.1% of second-line therapy or beyond, respectively. There were 80.6% and 34.0% of the patients suffering any-grade AEs and grade 3-4 AEs. Anti-PD1/PDL1 monotherapy might be considered as a safer alternative than combination regimens. Meanwhile, obvious toxicities in the first-line setting could not be neglected. Conclusions: Anti-PD1/PDL1 showed encouraging efficacy and acceptable safety profile in aBTC and, thus, could be an alternative treatment.

An Injectable Epigenetic Autophagic Modulatory Hydrogel for Boosting Umbilical Cord Blood NK Cell Therapy Prevents Postsurgical Relapse of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.

Exosomes-Loaded Electroconductive Hydrogel Synergistically Promotes Tissue Repair after Spinal Cord Injury via Immunoregulation and Enhancement of Myelinated Axon Growth.

Electroconductive hydrogels are very attractive candidates for accelerated spinal cord injury (SCI) repair because they match the electrical and mechanical properties of neural tissue. However, electroconductive hydrogel implantation can potentially aggravate inflammation, and hinder its repair efficacy. Bone marrow stem cell-derived exosomes (BMSC-exosomes) have shown immunomodulatory and tissue regeneration effects, therefore, neural tissue-like electroconductive hydrogels loaded with BMSC-exosomes are developed for the synergistic treatment of SCI. These exosomes-loaded electroconductive hydrogels modulate microglial M2 polarization via the NF-κB pathway, and synergistically enhance neuronal and oligodendrocyte differentiation of neural stem cells (NSCs) while inhibiting astrocyte differentiation, and also increase axon outgrowth via the PTEN/PI3K/AKT/mTOR pathway. Furthermore, exosomes combined electroconductive hydrogels significantly decrease the number of CD68-positive microglia, enhance local NSCs recruitment, and promote neuronal and axonal regeneration, resulting in significant functional recovery at the early stage in an SCI mouse model. Hence, the findings of this study demonstrate that the combination of electroconductive hydrogels and BMSC-exosomes is a promising therapeutic strategy for SCI repair.

Injectable adhesive hemostatic gel with tumor acidity neutralizer and neutrophil extracellular traps lyase for enhancing adoptive NK cell therapy prevents post-resection recurrence of hepatocellular carcinoma.

Post-resection recurrence remains an intractable problem in hepatocellular carcinoma (HCC) management. Natural killer (NK) cell infusion is considered as a promising cancer therapy, but acidic tumor microenvironment (TME) and neutrophil extracellular traps (NETs) greatly counteract its efficacy. Recently, polymer hydrogels have aroused much interest in tumor combination therapy, since they load and controllably release therapeutic agents with high bioavailability and low systemic toxicity. Therefore, a biocompatible hydrogel with tumor acidity neutralizer and NETs lyase may show promise for enhancing NK infusion to prevent post-resection HCC recurrence. Herein, a dual pH-responsive hydrogel with tumor acidity neutralizer (mesoporous bioactive glass nanoparticles) and NETs lyase (Deoxyribonuclease I, DNase I) is developed and used in combination with NK cell infusion for preventing post-resection HCC recurrence. The hydrogel can be injected to surgical margin and form an adhesive gel with a rapid hemostasis. Besides, it neutralizes tumor acidity to reduce tumor infiltration of immunosuppressive cells, and releases DNase I in a pH-responsive manner to degrade NETs. Moreover, this combination therapy significantly enhances NK cell infusion to combat post-surgical HCC recurrence without systemic toxicity. This study provides proof of concept that combination of NK cell adoptive therapy and hydrogel-based delivery system can successfully prevent post-resection HCC recurrence.

A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis.

BACKGROUND: The clinical risk score (CRS) for prediction and treatment decision in colorectal liver metastasis (CRLM) is important, but imprecise. Exosomal miRNAs play critical roles in CRLM-related biological behavior. However, an exosomal miRNA score system for predicting posthepatectomy survival and the adjuvant chemotherapy benefit of CRLM remains elusive. METHODS: miRNA sequencing was used to identify differentially expressed miRNAs, and the LASSO model was used to select miRNAs to construct the intent model. The predictive performance of the model was evaluated by the area under the ROC curve (AUC) in the training, internal validation, and external validation cohorts. RESULTS: Sixteen differentially expressed exosomal miRNAs were identified, and four miRNAs were selected for model construction. Our model performed well in predicting prognosis with five-year AUCs of 0.70 (95% CI: 0.59-0.81), 0.70 (0.61-0.81), and 0.72 (057-0.86) in the training, internal, and external validation cohorts, respectively. miRNA classifier high-risk patients had better survival benefit from adjuvant chemotherapy regardless of CRS. All four miRNAs target signaling molecules play crucial roles in colorectal cancer metastasis, vesicle-related processing, and T cell activation. It also negatively correlated with the liver metastasis Immunoscore. CONCLUSION: We developed a circulating exosomal miRNA signature that can predict the prognosis and guide adjuvant chemotherapy decisions after hepatectomy in CRLM.

Immune Cell Infiltration of the Primary Tumor Microenvironment Predicted the Treatment Outcome of Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients.

BACKGROUND: With the interest in cancer immunotherapy, it may be possible to combine immunotherapy with bevacizumab and chemotherapy. We evaluated whether tumor-infiltrating immune cells are associated with the efficacy of chemotherapy with or without bevacizumab for the treatment of metastatic colorectal cancer (mCRC). METHODS: This study enrolled mCRC patients on standard treatment with available detailed data and tumor tissue at Sun Yat-sen University Cancer Center between July 1, 2005, and October 1, 2017. CD3+ and CD8+ T cell densities examined by immunohistochemistry in both the tumor core (CT) and invasive margin (IM) were summed as the Immunoscore, and the CD8+/CD3+ T cell ratio was calculated. The predictive and prognostic efficacies of tumor-infiltrating immune cells for progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier and Cox analyses. RESULTS: The CD8+/CD3+ T cell ratio in the microenvironment was an independent prognostic factor for OS (28.12 mo vs. 16.56 mo, P = 0.017) among the 108 studied patients. In the chemotherapy only group, patients with a high Immunoscore had a high overall response rate (ORR, 40.0% vs. 60.0%, P = 0.022), those with a low CD8+/CD3+ T cell ratio in the microenvironment had a significantly longer PFS (8.64 mo vs. 6.01 mo, P = 0.017), and those with a high CD3+ T cell density in the CT had a longer OS (16.56 mo vs. 25.66 mo, P = 0.029). In the chemotherapy combined with bevacizumab group, patients with a higher CD8+ T cell density in the IM had a longer PFS (7.62 mo vs. 11.66 mo, P = 0.034) and OS (14.55 mo vs. 23.72 mo, P = 0.033). CONCLUSION: Immune cells in primary tumors play an important role in predicting mCRC treatment efficacy. CD8 predicts the effect of bevacizumab plus chemotherapy, while CD3 and CD8/CD3 predict chemotherapy efficacy.

Real World First-Line Treatments and Outcomes of Nab-Paclitaxel Plus Gemcitabine, mFOLFIRINOX and GEMOX in Unresectable Pancreatic Cancer from a Chinese Single Institution.

BACKGROUND: There have not been any head-to-head prospective studies to compare the effects of different chemotherapy regimens as first-line treatments for unresectable pancreatic cancer (UPC). We aimed to compare the effectiveness of nab-paclitaxel plus gemcitabine, mFOLFIRINOX and gemcitabine plus oxaliplatin (GEMOX) as first-line treatments by using real-world data from Chinese patients. METHODS: We retrospectively included patients with UPC treated with nab-paclitaxel plus gemcitabine, mFOLFIRINOX or GEMOX as a first-line treatment at Sun Yat-sen University Cancer Center. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were assessed. RESULTS: A total of 117 patients were administered nab-paclitaxel plus gemcitabine (n = 62), mFOLFIRINOX (n = 30) or GEMOX (n = 25) as first-line chemotherapy. The median OS was 11.1, 10.1 and 10.2 months (p = 0.75) in the nab-paclitaxel plus gemcitabine, mFOLFIRINOX and GEMOX, respectively. The ORR was similar among the three groups (24%, 23% and 32%, p = 0.76) and the DCR was higher in the nab-paclitaxel-gemcitabine group (82%) than the other two groups (60% and 64%, p = 0.04). The most common adverse events of grade 3 or 4 were neutropenia (32%, 28% and 5%), peripheral neuropathy (13%, 16% and 0) and fatigue (9%, 16% and 5%). Febrile neutropenia occurred in 2%, 4% and 5% of the patients in the three groups. CONCLUSION: In the first line treatment of UPC, our results suggest that nab-paclitaxel plus gemcitabine was associated with a higher DCR than mFOLFIRINOX or GEMOX, while all groups demonstrated similar OS, PFS and ORR.

A Novel Ferroptosis-related Gene Signature for Overall Survival Prediction in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. Ferroptosis, an iron-dependent form of regulated cell death, can be induced by sorafenib. However, the prognostic value of ferroptosis-related genes in HCC remains to be further elucidated. In this study, the mRNA expression profiles and corresponding clinical data of HCC patients were downloaded from public databases. The least absolute shrinkage and selection operator (LASSO) Cox regression model was utilized to construct a multigene signature in the TCGA cohort. HCC patients from the ICGC cohort were used for validation. Our results showed that most of the ferroptosis-related genes (81.7%) were differentially expressed between HCC and adjacent normal tissues in the TCGA cohort. Twenty-six differentially expressed genes (DEGs) were correlated with overall survival (OS) in the univariate Cox regression analysis (all adjusted P< 0.05). A 10-gene signature was constructed to stratify patients into two risk groups. Patients in the high-risk group showed significantly reduced OS compared with patients in the low-risk group (P < 0.001 in the TCGA cohort and P = 0.001 in the ICGC cohort). The risk score was an independent predictor for OS in multivariate Cox regression analyses (HR> 1, P< 0.01). Receiver operating characteristic (ROC) curve analysis confirmed the signature's predictive capacity. Functional analysis revealed that immune-related pathways were enriched, and immune status were different between two risk groups. In conclusion, a novel ferroptosis-related gene signature can be used for prognostic prediction in HCC. Targeting ferroptosis may be a therapeutic alternative for HCC.

Surgery vs conservative treatment for type II and III odontoid fractures in a geriatric population: A meta-analysis.

BACKGROUND: It is unclear whether surgery or conservative treatment is more suitable for elderly patients with type II and type III odontoid fractures. We performed this meta-analysis to compare the efficacy of surgical and conservative treatments for type II and type III odontoid fractures. METHODS: A literature search was performed in PubMed, Embase, Web of Science, and Cochrane Library in January 2017. Only articles comparing surgery with conservative treatment in elderly patients with type II and type III odontoid fractures were selected. After 2 authors independently assessed the retrieved studies, 18 articles were included in this meta-analysis, and the primary endpoints were the nonunion rate and mortality rate. The secondary outcomes were patient satisfaction, complications, and the length of the hospital stay. The quality of the included studies was evaluated using the modified Newcastle-Ottawa scale. Sensitivity analyses were performed for high-quality studies, and the publication bias was evaluated using a funnel plot. RESULTS: Lower nonunion (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.18-0.40, P < .05) and mortality rates (OR: 0.52, 95% CI: 0.34-0.79, P < .05) confirmed the superiority of surgery in treating type II and type III fractures. The secondary outcomes differed. Patients in the surgery group felt more satisfied with the outcome (OR: 3.44, 95% CI: 1.19-9.95, P < .05), and the complications were similar in the 2 groups (OR: 1.14, 95% CI: 0.78-1.68, P = .5), whereas patients in conservative groups spent less time in the hospital (OR: 5.10, 95% CI: 2.73-7.47, P < .05). The results of the subgroup analyses and sensitivity analysis were similar to the original outcomes, and no obvious publication bias was observed in the funnel plot. CONCLUSION: Most elderly (younger than 70 years) patients with type II or type III odontoid fractures should be considered candidates for surgical treatment, due to the higher union rate and lower mortality rate, while statistically significant differences were not observed in the population with an advanced age (older than 70 years). Therefore, the selection of the therapeutic approach for elderly patients with odontoid fractures requires further exploration. Simultaneously, based on our meta-analysis, a posterior arthrodesis treatment was significantly superior to the anterior odontoid screw treatment.

Inflammation-based markers can predict the prognosis of geriatric patients with metastatic colorectal cancer receiving first-line chemotherapy.

BACKGROUND: Relationship between inflammatory factors and survival or efficacy of first-line treatment in elderly patients with metastatic colorectal cancer (MCRC) who received first-line chemotherapy has not been clarified. METHODS: A total of 186 MCRC patients aged ≥65 years, receiving chemotherapy between January 1, 2004 and October 1, 2015 were identified. Pretreatment levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), lactate dehydrogenase (LDH), C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR) were measured. Effect of these inflammatory factors on overall survival (OS) and first-line progression-free survival were analyzed. RESULTS: Median age was 72 years. Median PFS and OS were 6.70 months and 25.62 months. CEA ≥85 ng/mL (P=0.010), CA 19-9 ≥32.97 U/mL (P=0.010), LDH ≥325 U/L (P=0.015), CRP ≥11 mg/L (P=0.004) and NLR ≥2.12 (P=0.045) were associated with poor OS. Furthermore, LDH (P=0.025) was demonstrated as an independent prognostic factor of OS for all patients, so did the combination of CEA with CA 19-9 (P=0.009). When predicting the one, three and five-year survival, combination of CEA with CA 19-9 had higher sensitivity compared with CEA alone or CA 19-9 alone respectively. For right-sided colon cancer, CEA (P<0.001) and CA 19-9 (P=0.003) were related with OS and CEA (P=0.002) was the independent prognostic factor. For left-sided colorectal cancer, inflammatory factors related with OS were LDH (P=0.039), CRP (P=0.004) and NLR (P=0.020) and CRP (P=0.040) was the independent prognostic factor. Only high level CA19-9 (≥32.97 U/mL P=0.024) was related with decreased PFS in univariate analysis. However, no inflammatory factors were contained in multivariate COX regression. CONCLUSIONS: CEA, CA 19-9, LDH, CRP and NLR were related with OS in geriatric patients with MCRC. Right-sided and left-sided groups had different independent prognostic markers, CEA and CRP respectively.

Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data.

BACKGROUND: Colorectal cancer (CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC (ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic. AIM: To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS. METHODS: ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005, to October 1, 2015, were studied. Expression of autophagy-related proteins [Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed. RESULTS: In CACO-2 cells exposed to cetuximab, LC3 and 4E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients, immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3 (0.657, P < 0.001) and 4E-BP1 (0.211, P = 0.042) in ACRC tissues. LC3 was significantly overexpressed in tumor tissues compared to normal tissues (P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1 (P = 0.010) and 4E-BP1 (P = 0.005), pathological grade (P = 0.002), and T stage (P = 0.004) were independent prognostic factors for overall survival (OS). CONCLUSION: The effect of cetuximab on colon cancer cells might be improved by autophagy. LC3 is overexpressed in tumor tissues, and Beclin1 and 4E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.

Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma.

Rationale: Advanced nasopharyngeal carcinoma (NPC) is an aggressive disease with no targeted therapies and poor outcomes. New innovative targets are urgently needed. KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene. Here, we found that KLF4 played as a tumor-promoting gene in NPC, and could be mediated by PLK1. Methods: Tissue immunohistochemistry (IHC) assay was performed to identify the role of KLF4 in NPC. Global gene expression experiments were performed to explore the molecular mechanisms underlying KLF4-dependent tumorigenesis. Small-molecule kinase inhibitor screening was performed to identify potential upstream kinases of KLF4. The pharmacologic activity of polo-like kinase inhibitor volasertib (BI6727) in vitro and in vivo was determined. Result: Our investigation showed that high expression of KLF4 was correlated with poor prognosis in NPC. Moreover, genome-wide profiling revealed that KLF4 directly activated oncogenic programmes, including gene sets associated with KRAS, VEGF, and MYC signalling. We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. Moreover, KLF4 could enhance TRAF6 expression at the transcriptional level, thus initiating a KLF4-TRAF6 feed-forward loop. Treatment with the PLK1 inhibitor volasertib (BI6727) significantly inhibited tumor growth in nude mice. Conclusion: Our study unveiled a new PLK1-TRAF6-KLF4 feed-forward loop. The resulting increase in KLF4 ubiquitination leads to stabilization and upregulation of KLF4, which leads to tumorigenesis in NPC. These results expand our understanding of the role of KLF4 in NPC and validate PLK1 inhibitors as potential therapeutic agents for NPC, especially cancer patients with KLF4 overexpression.

Establishment of inflammation biomarkers-based nomograms to predict prognosis of advanced colorectal cancer patients based on real world data.

PURPOSE: To establish three novel prognostic nomograms with inflammatory factors for advanced colorectal cancer (ACRC), right-sided colon cancer (RSCC) and left-sided colorectal cancer (LSCRC) according to real world data. MATERIALS AND METHODS: ACRC patients receiving medicine therapy from January 1st, 2005 to September 31th, 2015 in Sun Yat-sen University Cancer Center were enrolled. Inflammatory indicators such as the neutrophil-to-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were analyzed for establishing nomograms predicting overall survival (OS). Concordance index (C-index) determined predictive accuracy and discriminative ability. RESULTS: Our study selected 807 ACRC patients, 29.6% RSCC and 70.4% LSCRC. Median OS was 23.36 months. Patients at lower level of NLR, PLR, CEA, CA 19-9, LDH and CRP showed longer OS (P < 0.001). For all patients, pathological grade (P = 0.018), treatments (P = 0.042), sidedness (P = 0.003), NLR (P < 0.001), CA 19-9 (P < 0.001), LDH (P < 0.001) and CRP (P = 0.0012) contributed to OS independently. For RSCC, pathological grade (P = 0.022), CA 19-9 (P < 0.001), LDH (P < 0.001) and CRP (P = 0.001) were significantly related with OS. For LSCRC patients, treatments (cetuximab vs chemotherapy: P = 0.008; bevacizumab vs chemotherapy: P = 0.166), NLR (P < 0.001), CA 19-9 (P = 0.030) and LDH (P < 0.001) were independent factors for OS. Final models showed acceptable internal validity with C-indexes of 0.687, 0.697 and 0.667 in all, RSCC and LSCRC patients. CONCLUSIONS: Inflammatory factors enrolled in the proposed nomograms showed accurately individualized prognostic prediction, and prognostic factors for RSCC and LSCRC were different.

Effect of HK2, PKM2 and LDHA on Cetuximab efficacy in metastatic colorectal cancer.

Although hexokinase (HK) 2, pyruvate kinase muscle (PKM) isozyme 2 and lactate dehydrogenase (LDH) A predict the efficacy of medicines in various solid tumors, their ability to predict the efficacy of cetuximab in metastatic colorectal cancer (mCRC) remains unclear. mCRC patients with pathological specimens who received cetuximab and chemotherapy from 2005 to 2015 in the present institution were enrolled. Immunohistochemistry was used to detect HK2, PKM2 and LDHA expression. SPSS20 was used for statistical analysis. A total of 68 patients were included; 33 received cetuximab plus chemotherapy as first-line therapy, and the rest, as second- or later-line therapy. HK2 expression levels were increased in cancer compared with normal tissue (75.4% vs. 40%; P<0.001), however PKM2 (P=0.243) and LDHA (P=0.067) expression levels were not. For progression-free survival (PFS) with first-line cetuximab plus chemotherapy, patients with high HK2 expression exhibited longer PFS compared with those with low HK2 expression (23.9 months vs. 6.9 months; P=0.021). However, this positive association was absent in 35 cases administered first-line chemotherapy alone (13.4 months vs. 13.5 months; P=0.539). LDHA expression was associated with the PFS of patients receiving first-line chemotherapy (18.3 and 10.1 months for high and low expression, respectively; P=0.005), whereas this association was absent in cetuximab plus chemotherapy cases (19.9 months vs. 12 months; P=0.522). Furthermore, high LDHA expression correlated with high overall response rate (ORR) (72.2% vs. 15.4%, P=0.006) for chemotherapy, however not disease control rate (DCR) (P=0.074). Neither DCR nor ORR were associated with HK2 expression. PKM2 expression did not affect PFS, DCR or ORR. LDHA expression (P=0.005), pathological differentiation (P=0.019) and synchronous/metachronous metastasis (P=0.014) were independent predictive factors of PFS for all first-line patients, and tumor differentiation (P=0.002) was associated with overall survival (OS) in multivariate analysis. HK2, PKM2 and LDHA did not impact OS. It was concluded that HK2 expression was increased in colorectal cancer tissue and may predict cetuximab efficacy and LDHA for chemotherapy treatment of mCRC.

Soft Conducting Polymer Hydrogels Cross-Linked and Doped by Tannic Acid for Spinal Cord Injury Repair.

Mimicking soft tissue mechanical properties and the high conductivity required for electrical transmission in the native spinal cord is critical in nerve tissue regeneration scaffold designs. However, fabricating scaffolds of high conductivity, tissue-like mechanical properties, and excellent biocompatibility simultaneously remains a great challenge. Here, a soft, highly conductive, biocompatible conducting polymer hydrogel (CPH) based on a plant-derived polyphenol, tannic acid (TA), cross-linking and doping conducting polypyrrole (PPy) chains is developed to explore its therapeutic efficacy after a spinal cord injury (SCI). The developed hydrogels exhibit an excellent electronic conductivity (0.05-0.18 S/cm) and appropriate mechanical properties (0.3-2.2 kPa), which can be achieved by controlling TA concentration. In vitro, a CPH with a higher conductivity accelerated the differentiation of neural stem cells (NSCs) into neurons while suppressing the development of astrocytes. In vivo, with relatively high conductivity, the CPH can activate endogenous NSC neurogenesis in the lesion area, resulting in significant recovery of locomotor function. Overall, our findings evidence that the CPHs without being combined with any other therapeutic agents have stimulated tissue repair following an SCI and thus have important implications for future biomaterial designs for SCI therapy.

Directing Induced Pluripotent Stem Cell Derived Neural Stem Cell Fate with a Three-Dimensional Biomimetic Hydrogel for Spinal Cord Injury Repair.

Current treatment approaches for spinal cord injuries (SCIs) are mainly based on cellular transplantation. Induced pluripotent stem cells (iPSCs) without supply constraints and ethical concerns have emerged as a viable treatment option for repairing neurological disorders. However, the primarily limitations in the neuroregeneration field are uncontrolled cell differentiation, and low cell viability caused by the ischemic environment. The mechanical property of three-dimensional (3D) hydrogel can be easily controlled and shared similar characteristics with nerve tissue, thus promoting cell survival and controlled cell differentiation. We propose the combination of a 3D gelatin methacrylate (GelMA) hydrogel with iPSC-derived NSCs (iNSCs) to promote regeneration after SCI. In vitro, the iNSCs photoencapsulated in the 3D GelMA hydrogel survived and differentiated well, especially in lower-moduli hydrogels. More robust neurite outgrowth and more neuronal differentiation were detected in the soft hydrogel group. To further evaluate the in vivo neuronal regeneration effect of the GelMA hydrogels, a mouse spinal cord transection model was generated. We found that GelMA/iNSC implants significantly promoted functional recovery. Further histological analysis showed that the cavity areas were significantly reduced, and less collagen was deposited in the GelMA/iNSC group. Furthermore, the GelMA and iNSC combined transplantation decreased inflammation by reducing activated macrophages/microglia (CD68-positive cells). Additionally, GelMA/iNSC implantation showed striking therapeutic effects of inhibiting GFAP-positive cells and glial scar formation while simultaneously promoting axonal regeneration. Undoubtedly, use of this 3D hydrogel stem cell-loaded system is a promising therapeutic strategy for SCI repair.

Efficacy and safety of bevacizumab in elderly patients with advanced colorectal cancer: A meta-analysis.

AIMS: Bevacizumab plus chemotherapy (CT) has been the standard treatment for advanced colorectal cancer (ACRC) in the last decade. However, whether geriatric patients treated with this combination achieved more benefits or suffered severer toxicities than CT alone remained controversial. This meta-analysis was aimed to provide more convincing evidence. SUBJECTS AND METHODS: Randomized control trials (RCTs) and retrospective comparative studies on the comparison between bevacizumab plus CT and CT for geriatric ACRC patients were retrieved in PubMed, Web of Science, EMBASE, and Ovid until June 2016. One RCT, five subgroup analyses of RCTs, and two retrospective studies with efficacy and safety data were identified, involving a total of 2813 cases. The included primary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). RESULTS: For geriatric ACRC, both OS (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.74-0.94, P = 0.003) and PFS (HR 0.55, 95% CI 0.48-0.63, P < 0.001) have been improved after the addition of bevacizumab to CT. The odds ratios (ORs) for total grade and grade 3-5 AEs were 1.85 (95% CI 1.12-3.04, P = 0.02) and 2.09 (95% CI 1.69-2.58, P < 0.001), respectively. For overall grade toxicities, proteinuria (OR 10.89, 95% CI 1.37-86.28, P = 0.02), hypertension (OR 4.44, 95% CI 1.85-10.62, P < 0.05), and fistulae/abscess (OR 12.07, 95% CI 1.54-94.88, P < 0.05) were significantly higher in the bevacizumab arm. For grades 3-5, increased risk of hypertension (OR 3.91, 95% CI 2.48-6.16, P < 0.001), arterial thromboembolism (OR 3.25, 95% CI 1.70-6.19, P < 0.001), and venous thromboembolism (OR 2.17, 95% CI 1.11-4.25, P = 0.02) was observed in the bevacizumab group. CONCLUSIONS: After the addition of bevacizumab to CT in geriatric ACRC, both PFS and OS could be significantly improved, while it would also lead to some high-grade AEs, hypertension, and arterial and venous thromboembolism.