FGFR3 Nuclear Translocation Contributes to Proliferative Potential and Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Fibroblast growth factor receptor 3 (FGFR3) was revealed to have divergent, even opposite roles in different neoplasms. In pancreatic ductal adenocarcinoma (PDAC), its impact on biological behavior and prognosis was not well elucidated. METHODS: Fibroblast growth factor receptor 3 was downregulated by RNA interference to explore its impact on cell proliferative proclivity in PDAC cells. Furthermore, tissue microarray-based immunohistochemistry for FGFR3 was performed in 326 patients with PDAC who underwent radical resection, and its clinicopathologic and prognostic implications were then evaluated. RESULTS: First, successful FGFR3 knockdown remarkably decreased its expression, cell proliferation, and S-phase ratio in the cell cycle in 2 PDAC cell lines, BxPC-3 and AsPC-1. Meanwhile, alterations in p-Akt, cyclin D1, cyclin B1, and p21 were also observed. Subsequently, high nuclear FGFR3 expression, but not cytoplasmic, was significantly common in tumor tissues and positively associated with N stage and dismal overall survival in the entire cohort. In addition, nuclear FGFR3 expression was also prognostic in 10 of 14 subsets. Univariate and multivariate Cox regression analyses identified nuclear expression of FGFR3 as an independent prognosticator in the entire cohort. CONCLUSIONS: Our data showed that FGFR3 nuclear translocation contributes to cell proliferative potential and predicts poor long-term prognosis in PDAC after surgical resection.

Expression and Prognostic Value of Small Mothers Against Decapentaplegic 7, Matrix Metalloproteinase 2, and Matrix Metalloproteinase 9 in Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: Thus far, expression, clinicopathologic, and prognostic implication of small mothers against decapentaplegic 7 (Smad7), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) in pancreatic ductal adenocarcinoma (PDAC) were rarely investigated or controversial. METHODS: Expression of Smad7, MMP2, and MMP9 was detected using immunohistochemistry in tissue microarrays based on 322 patients with curatively resected PDAC. Their expression pattern, clinicopathologic, and prognostic relevance were further evaluated. RESULTS: Smad7 expression was found to be lower in tumor than in adjacent nontumor tissues, whereas tumoral MMP2 and MMP9 staining scores were much higher than in adjacent nontumor ones. Furthermore, Smad7 was negatively associated with serum carbohydrate antigen 19-9 level. Univariate survival analyses showed that patients with high Smad7 tumors had significantly better disease-specific survival (P = 0.0007), whereas MMP2 and MMP9 predicted poor disease-specific survival (P = 0.0211 and 0.0404). In multivariate Cox regression test, Smad7 was an independent prognostic indicator (P = 0.021). In addition, these 3 proteins were also prognostic in many subgroups. CONCLUSIONS: Smad7 and MMP2/9 significantly predict good or poor prognosis in resectable PDAC, respectively. Therefore, the genes might serve as a tool or targets for molecular therapy in PDAC.

Clinicopathological and prognostic significance of ubiquitin-specific peptidase 15 and its relationship with transforming growth factor-ß receptors in patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND AIM: Ubiquitin-specific peptidase 15 (USP15) has been correlated to aggressive oncogenic behavior in several types of carcinomas, but its function in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the clinicopathological and prognostic value of USP15 and its relationship with transforming growth factor-ß (TGF-ß) receptors (TßRs) in PDAC. METHODS: By immunohistochemical staining of tissue microarrays, the expression patterns of USP15 and TßRs were retrospectively analyzed in 287 PDAC patients who underwent radical surgical resection without neoadjuvant therapy. Cancer-specific survival was compared based on USP15 expression, and the correlations between USP15 and TßRs were analyzed. RESULTS: Ubiquitin-specific peptidase 15 expression in tumor tissues was significantly higher than that in para-tumor tissues (P < 0.0001), and high USP15 expression was associated with the pathological N (pN) stage (P = 0.033). In addition, high USP15 expression was significantly associated with shorter cancer-specific survival (P = 0.019). Univariate analyses showed that high USP15 expression (P = 0.024), a poor histopathological grade (P = 0.003), and the pN1 stage (P = 0.009) were significantly correlated with shorter survival. Although the independent prognostic value of USP15 alone was not established, the combination of USP15 and the histological grade was identified as an independent prognostic factor in multivariate analyses (P = 0.015). USP15 expression was correlated with TßR-I, TßR-II, or TßR-III expression in PDAC. CONCLUSIONS: High USP15 expression is a potential prognostic indicator in patients with PDAC, and it might affect the TGF-ß signaling pathway in PDAC.

Elevated TIAM2 expression promotes tumor progression and is associated with unfavorable prognosis in pancreatic cancer.

BACKGROUND AND AIM: As a Rac1 guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 2 (TIAM2) has been reported to be correlated with malignant phenotypes in several cancers, but its prognostic significance and function in pancreatic ductal adenocarcinoma (PDAC) was not investigated. METHODS: The expression patterns of TIAM2 and patient survival were analyzed in a large cohort of 303 patients with radical surgical resection of PDAC, using immunohistochemical staining in tissue microarrays. Data mining was applied to evaluate TIAM2 expression and patient survival at the mRNA level. The function of TIAM2 in proliferation, motility and invasion of pancreactic cancer (PC) cells was also investigated. RESULTS: TIAM2 expression was significantly increased in PDAC compared with para-tumor tissues (p < .0001). The expression of TIAM2 was associated with histopathological grade (p = .008), tumor location (p = .013), and pathological T stage (p = .029). For survival, patients with high TIAM2 expression had significantly poor prognosis in some subgroups. In addition, multivariate analyses showed that the combination of TIAM2 and the pathological N stage largely enhanced the prognostic efficiency, and was found to be as an independent prognostic indicator in patients with PDAC. Data mining elucidated that TIAM2 mRNA expression level was increased in tumor tissues and correlated with patient survival. Furthermore, high TIAM2 expression was common in PC cells. Downregulation of TIAM2 suppressed cell proliferation, migration and invasion in PC. CONCLUSIONS: High expression of TIAM2 might be a meaningful prognostic factor for PDAC patients, and TIAM2 participates in tumor progression in PDAC.

Stroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides?

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with one of the worst prognoses worldwide and has an overall 5-year survival rate of only 9%. Although chemotherapy is the recommended treatment for patients with advanced PDAC, its efficacy is not satisfactory. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC. Therefore, stroma-targeting therapy is considered a potential treatment strategy to improve the efficacy of chemotherapy and patient survival. While several preclinical studies have shown encouraging results, the anti-tumor potential of the PDAC stroma has also been revealed, and the extreme depletion might promote tumor progression and undermine patient survival. Therefore, achieving a balance between stromal abundance and depletion might be the further of stroma-targeting therapy. This review summarized the current progress of stroma-targeting therapy in PDAC and discussed the double-edged sword of its therapeutic effects.

Prognostic Biomarkers for Pancreatic Ductal Adenocarcinoma: An Umbrella Review.

Background: Pancreatic ductal adenocarcinoma (PDAC) leads to the majority of cancer-related deaths due to its morbidity with similar mortality. Lack of effective prognostic biomarkers are the main reason for belated post-operative intervention of recurrence which causes high mortality. Numerous systematic reviews and meta-analyses have explored the prognostic value of biomarkers in PDAC so far. In this article, we performed an umbrella review analyzing these studies to provide an overview of associations between prognostic biomarkers and PDAC survival outcome and synthesized these results to guide better clinical practice. Methods: Systematic reviews and meta-analyses investigating the associations between PDAC survival outcomes and prognostic biomarkers were acquired via the PubMed and Embase databases from inception till February 1, 2020. Associations supported by nominally statistically significant results were classified into strong, highly suggestive, suggestive, and weak based on several critical factors such as the statistical significance of summary estimates, the number of events, the estimate of the largest study included, interstudy heterogeneity, small-study effects, 95% predictive interval (PI), excess significance bias, and the results of credibility ceiling sensitivity analyses. Results: We included 41 meta-analyses containing 63 associations between PDAC survival outcomes and prognostic biomarkers. Although, none was supported by strong evidence among these associations, an association between C-reactive protein to albumin ratio (CAR) and PDAC overall survival (OS) and an association between neutrophil-lymphocyte ratio (NLR) and PDAC OS were supported by highly suggestive evidence. Otherwise, the association between lactate dehydrogenase (LDH) and PDAC OS was supported by suggestive evidence. The remaining 60 associations were supported by weak or not suggestive evidence. Conclusion: Associations between CAR or NLR and PDAC OS were supported by highly suggestive evidence. And the association between LDH and PDAC OS was supported by suggestive evidence. Although the methodological quality of the included systematic reviews and meta-analyses which were evaluated by AMSTAR2.0 is generally poor, the identification of the relatively robust prognostic biomarkers of PDAC may guide better post-operative intervention and follow-up to prolong patients' survival.

Ubiquitin-specific protease 4 predicts an unfavorable prognosis and promotes malignant behaviors in vitro in pancreatic cancer.

Ubiquitin-specific protease 4 (USP4), has been reported to participate in the progression of various cancers due to its role in post-translational modulation. However, the prognostic significance and mechanism of USP4 in pancreatic cancer (PC) have not been well elucidated before. In the present study, we found that USP4 expression was higher in PC tissues than that in adjacent normal tissues and PC patients with high level of USP4 expression have a poor prognosis via immunohistochemistry and bioinformatics analyses. In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion. Mechanistically, USP4 can activate nuclear factor kappa-B signaling pathway via stabilizing TNF receptor associated factor 6 at its protein level to promote the ability of proliferation, migration and invasion of PC cells. The results of this study revealed that USP4 plays a tumor-promoting role in PC and can be used as a prognostic indicator and therapeutic target for patients with resected PC.

Research progress on long non-coding RNAs and their roles as potential biomarkers for diagnosis and prognosis in pancreatic cancer.

Pancreatic cancer is one of the main causes of tumor-related deaths worldwide because of its low morbidity but extremely high mortality, and is therefore colloquially known as the "king of cancer." Sudden onset and lack of early diagnostic biomarkers directly contribute to the extremely high mortality rate of pancreatic cancer patients, and also make it indistinguishable from benign pancreatic diseases and precancerous pancreatic lesions. Additionally, the lack of effective prognostic biomarkers makes it difficult for clinicians to formulate precise follow-up strategies based on the postoperative characteristics of the patients, which results in missed early diagnosis of recurrent pancreatic cancer. Long non-coding RNAs (lncRNAs) can influence cell proliferation, invasion/migration, apoptosis, and even chemoresistance via regulation of various signaling pathways, leading to pro- or anti-cancer outcomes. Given the versatile effects of lncRNAs on tumor progression, using a single lncRNA or combination of several lncRNAs may be an effective method for tumor diagnosis and prognostic predictions. This review will give a comprehensive overview of the most recent research related to lncRNAs in pancreatic cancer progression, as targeted therapies, and as biomarkers for the diagnosis and prognosis of pancreatic cancer.

Predictors of lymph node metastasis and residual tumor in early gastric cancer patients after noncurative endoscopic resection: a systematic review and meta-analysis.

BACKGROUND: It is challenging to identify the prevalence of lymph node metastasis (LNM) and residual tumor in patients with early gastric cancer (EGC) who underwent noncurative endoscopic resection (ER). This present meta-analysis was aimed to establish imperative potential predictive factors in order to select the optimal treatment method. METHODS: A systematic literature search of PubMed, Embase, and Cochrane Library databases was performed through 1 February 2019 to identify relevant studies, which investigated risk factors for LNM and residual tumor in patients with EGC who underwent noncurative ER. Eligible data were systematically reviewed through a meta-analysis. RESULTS: Overall, 12 studies investigating the risk factor of LNM were included, totaling 3015 patients, 7 of which also involved cancer residues. After the present meta-analysis, six predictors, including tumor size >30 mm, tumor invasion depth (⩾500 µm from the muscularis mucosae), macroscopic appearance, undifferentiated histopathological type, positive vertical margin, and presence of lymphovascular invasion (including lymphatic invasion and vascular invasion) were significantly associated with LNM, whereas tumor size >30 mm, positive horizontal margin, and positive vertical margin were identified as significant predictors for the risk of residual tumor. No evidence of publication bias was observed. CONCLUSIONS: Six and three variables were established as significant risk factors for LNM and residual tumor in patients with EGC who underwent noncurative ER, respectively. Patients with EGC who present these risk factors after noncurative ER are strongly suggested to receive additional surgery, while others might be suitable for strict follow-up. This might shed some new light on the selection of follow-up treatment for noncurative ER.

USP4 function and multifaceted roles in cancer: a possible and potential therapeutic target.

Cancer remains one of the major culprits causing disease-related deaths and leads to a high morbidity and similar mortality. Insidious onset, difficult early detection and a lack of broad-spectrum and effective multi-cancer therapeutic targets have limited the prolongation of cancer patients' survival for decades. Therefore, a versatile therapeutic target which is involved in various cancer-related signaling pathways and different cancers may be more effective for cancer targeted therapy. USP4, one of the DUBs members which participates in deubiquitination, an inverse process of ubiquitination, can regulate various classical cancer-related signaling pathways, and thereby plays a vital role in some pathological and physiological processes including tumor initiation and progression. Recently, USP4 has been found to exert versatile influences on cells proliferation, migration and invasion, also apoptosis of various tumors. Moreover, USP4 can also act as a prognostic biomarker in several cancers. This review will give a comprehensive introduction of USP4 about its regulatory mechanisms, related signaling pathways, pathophysiological functions and the roles in various cancers which may help us better understand its biological functions and improve future studies to construct suitable USP4-targeted cancer therapy system.

Photodynamic therapy of pancreatic cancer: Where have we come from and where are we going?

Photodynamic therapy (PDT) is a potential adjuvant therapy in pancreatic cancer with several advantages. Mechanistically, pancreatic cancer PDT can induce apoptosis and necrosis of pancreatic cancer cells and lead to vascular damage and enhance anti-tumor immune response in tumor tissues. However, limitations of current photosensitizers such as limited penetration depth, poor targeted therapy and inadequate reactive oxygen species (ROS) generation still exist. Recently, several novel photosensitizers have been reported to break through limits in pancreatic cancer PDT. Methods combined with biomedical engineering, materialogy and chemical engineering have been employed to overcome the difficulties and to realize targeted therapy. Preclinical and clinical trials also preliminarily confirmed the technical feasibility and safety of pancreatic cancer PDT. Therefore, PDT may be potential to be used as an effective adjuvant therapy in pancreatic cancer multimodality therapy. This review will give an overview about pancreatic cancer PDT from basic experimental studies, preclinical and clinical application to future direction of pancreatic cancer PDT.

Transducin-Like Enhancer of Split-1 Inhibits Malignant Behaviors in vitro and Predicts a Better Prognosis in Pancreatic Ductal Adenocarcinoma.

Background: Transducin-like enhancer of split-1 (TLE1), a member of the Groucho/TLE family of transcriptional corepressors, has been reported to be involved in the tumorigenesis of various cancers and function as a clinical prognostic indicator. However, the mechanisms and prognostic significance of TLE1 in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated. Methods: In this study, western blot analyses and real-time polymerase chain reaction (RT-PCR) were employed to evaluate the expression of TLE1 and related proteins in PDAC cell lines. Wound healing, transwell migration and invasion, and Cell Counting Kit-8 (CCK-8) assays were used to determine cell line-specific differences in metastasis and proliferation. Flow cytometry was performed for cell cycle detection. RNA sequencing and bioinformatics were undertaken to explore the molecular mechanisms and potential targeted molecules of TLE1. TLE1 expression in tumor and para-tumor tissues was evaluated by tissue microarray-based immunohistochemistry using a semiquantitative method (H-score) in 262 patients with radical PDAC resection. Correlation, Kaplan-Meier survival, univariate, and multivariate analyses were also performed. Results: Our findings showed that TLE1 expression was common in PDAC cell lines. Upregulation of TLE1 inhibited PDAC cell migration, invasion, and proliferation in vitro by delaying the G0/G1 transition. Immunohistochemistry revealed that TLE1 was specifically expressed in the nucleus and at higher levels in tumor tissues compared with para-tumor tissues. Generally, high TLE1 expression was associated with no vascular invasion. In univariate analyses, high TLE1 expression was associated with longer disease-specific survival (DSS) in all patients and in 16 patient subgroups. In multivariate analyses, TLE1 expression was independently associated with DSS in all patients and four patient subgroups. Conclusion: In conclusion, these results suggest that TLE1 has an inhibitory role in PDAC progression and is a favorable prognostic indicator for patients with resectable PDAC.

The roles of curcumin in regulating the tumor immunosuppressive microenvironment.

Cancer is a harmful threat to human health. In addition to surgery, a variety of anticancer drugs are increasingly used in cancer therapy; however, despite the developments in multimodality treatment, the morbidity and mortality of patients with cancer patients are on the increase. The tumor-specific immunosuppressive microenvironment serves an important function in tumor tolerance and escape from immune surveillance leading to tumor progression. Therefore, identifying new drugs or foods that can enhance the tumor immune response is critical to develop improved cancer prevention methods and treatment. Curcumin, a polyphenolic compound extracted from ginger, has been shown to effectively inhibit tumor growth, proliferation, invasion, metastasis and angiogenesis in a variety of tumors. Recent studies have also indicated that curcumin can modulate the tumor immune response and remodel the tumor immunosuppressive microenvironment, indicating its potential in the immunotherapy of cancer. In this review, a brief introduction to the effects of curcumin on the tumor immune response and tumor immune microenvironment is provided and recent clinical trials investigating the potential of curcumin in cancer therapy are discussed.

Intraductal oncocytic papillary neoplasm of the pancreas: A systematic review.

BACKGROUND: Intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) is a rare subtype of intraductal papillary mucinous neoplasm (IPMN). This study was performed to summarize the clinicopathological features and management of IOPN-P. METHODS: English-language articles were searched from MEDLINE and EMBASE from the first report of IOPN-P in 1996 until 1 May 2019 following the methodology in the PRISMA guidelines. RESULTS: In total, 66 patients from 24 full articles were included in the final data analysis. The patients' average age was 61 years, and the male/female ratio was 1. Most lesions were large (average size, 5.50 cm), located in the pancreatic head, and found either incidentally or by uncharacteristic abdominal symptoms. IOPN-P was usually a cystic and solid lesion with or without mural nodules on radiological examination. A definitive diagnosis was often acquired from fine needle aspiration biopsy or postoperative pathology. All tumors were diagnosed as carcinoma in situ or minimally invasive carcinoma, necessitating surgical resection. The prognosis of IOPN-P was better than that of other IPMN subtypes, even when metastasis occurred. Recurrence after surgical resection of IOPN-P was rare. CONCLUSIONS: IOPN-P is rare among IPMN subtypes with unique pathological characteristics. Because of the nontypical symptoms and radiological findings, a definitive preoperative diagnosis usually depends on multimodal examinations. Management and surveillance of IOPN-P after surgical resection should be differentiated from those of other pancreatic benign cystic lesions because of its relative malignancy, but IOPN-P should also be differentiated from other IPMN subtypes and malignant cystic tumors because of its favorable prognosis.

Dual Core-Shell Structured Si@SiOx@C Nanocomposite Synthesized via a One-Step Pyrolysis Method as a Highly Stable Anode Material for Lithium-Ion Batteries.

Silicon (Si) has been regarded as a promising high-capacity anode material for developing advanced lithium-ion batteries (LIBs), but the practical application of Si anodes is still unsuccessful mainly due to the insufficient cyclability. To deal with this issue, we propose a new route to construct a dual core-shell structured Si@SiOx@C nanocomposite by direct pyrolysis of poly(methyl methacrylate) (PMMA) polymer on the surface of Si nanoparticles. Since the PMMA polymers can be chemically bonded on the nano-Si surface through the interaction between ester group and Si surface group, and thermally decomposed in the subsequent pyrolysis process with their alkyl chains converted to carbon and the residue oxygen recombining with Si to form SiOx, the dual core-shell structure can be conveniently formed in a one-step procedure. Benefiting from the strong buffering effect of the SiOx interlayer and the efficient blocking action of dense outer carbon layer in preventing electrolyte permeation, the obtained nanocomposite demonstrates a high capacity of 1972 mA h g-1, a stable cycling performance with a capacity retention of >1030 mA h g-1 over 500 cycles, and particularly a superiorly high Coulombic efficiency of >99.5% upon extended cycling, exhibiting a great promise for practical uses. More importantly, the synthetic method proposed in this work is facile and low cost, making it more suitable for large-scale production of high capacity anode for advanced LIBs.