Involvement of eicosanoids in the pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and 5-lipoxygenase

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.

Noncoding RNAs in cancer and cancer stem cells

In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.

Four outstanding young Chinese scientists received the 2013 Scholar Award from the US Chinese Anti-Cancer Association and the National Foundation for Cancer Research

To facilitate and strengthen collaborations among cancer researchers and physicians in the United States and China,the US Chinese AntiCancer Association(USCACA)and the National Foundation for Cancer Research(NFCR)have established the Scholar Excellence Award for the USCACA-NFCR Scholar Exchange and Fellowship Program in Basic,Translational,and Clinical Studies.Since 2010,10 young Chinese researchers and physicians have received the award for their outstanding achievements in cancer research accomplished while in the

Five outstanding young Chinese scholars received the Third Scholar Award from the Asian Fund for Cancer Research (AFCR) and the US Chinese Anti-Cancer Association (USCACA)

Chinese researchers and physicians are being increasingly recognized for making significant contributions that advance biomedical research,including cancer research,in both China and the world.

Novel therapeutic agents in the treatment of metastatic colorectal cancer

Over the past couple of decades considerable progress has been made in the management of metastatic colorectal cancers(mCRC) leading to a significant improvement in five-year survival. Although part of this success has been rightly attributed to aggressive surgical management and advances in other adjunct treatments, our understanding of the pathogenesis of cancer and emergence of newer molecular targets for colon cancer has created a powerful impact. In this review article we will discuss various targeted therapies in the management of mCRC. Newer agents on the horizon soon to be incorporated in clinical practice will be briefly reviewed as well.

The US Chinese Anti-Cancer Association and the National Foundation for Cancer Research recognize five young Chinese investigators with the 2014 USCACA-NFCR Scholar Awards

To facilitate and strengthen collaborations among cancer researchers and physicians in the United States and China,the US Chinese AntiCancer Association(USCACA)and the National Foundation for Cancer Research(NFCR)have established the Scholar Excellence Award for the USCACA-NFCR Scholar Exchange and Fellowship Program in Basic,Translational,and Clinical Studies.From 2010 to 2013,14 young

Epidemiological transition of colorectal cancer in developing countries: Environmental factors, molecular pathways, and opportunities for prevention

Colorectal cancer(CRC)is one of the leading causes of cancer and cancer-related mortality worldwide.The disease has been traditionally a major health problem in industrial countries,however the CRC rates are increasing in the developing countries that are undergoing economic growth.Several environmental risk factors,mainly changes in diet and life style,have been suggested to underlie the rise of CRC in these populations.Diet and lifestyle impinge on nuclear receptors,on the intestinal microbiota and on crucial molecular pathways that are implicated in intestinal carcinogenesis.In this respect,the epidemiological transition in several regions of the world offers a unique opportunity to better understand CRC carcinogenesis by studying the disease phenotypes and their environmental and molecular associations in different populations.The data from these studies may have important implications for the global prevention and treatment of CRC.

Cancer cell migration： when red light switched to green

The doctrine of＇the golden mean＇ of the Confucian certainly applies at the molecular level to cell growth and migration. It is critically important for tissue architecture and homeostasis that cells stop prolifera- tion when reaching appropriate density and halt migration in a direction to avoid collision with others. This ＇red light＇ to hinder cell movement is essential for maintaining contact inhibition of locomotion （CIL）--a phe- nomenon that a cell ceases to continue moving in the same direction when it comes into contact with another cell. The concept of CIL emerged initially from the early work of Abercrombie and Heaysman in the 1950s.

The path toward prognostication and prediction in stage Ⅱ colon cancer

Currently,there are several newer biomarkers that may be clinically useful in colon cancer. This paper focuses on a few of these biomarkers,namely microsatellite instability,loss of heterozygosity at chromosome 18q(LOH18q) and multi-gene assays,and discusses the clinical evidence behind their predictive or prognostic abilities. The results show that although there have been several newer prognostic factors identified,such as LOH18 q and multi-gene assays,none of these factors can predict benefit from treatment. Therefore,ongoing prospective clinical trials are still needed to further assess the role and optimal use of these tests.

Automated Detection and Quantification of Prostate Cancer in Needle Biopsies by Digital Image Analysis

Introduction: Triple immunohistochemical (IHC) stains including antibodies specific for alpha-methylacyl-CoA-racemase and basal cell markers have been a valuable aid in accurate identification of prostate carcinoma. However, accurate quantification of minuscule areas of prostate carcinoma in biopsy specimens can often be a challenge. Here we assessed the diagnostic value and quantitative use of automated digital image analysis on triple IHC stained prostate needle biopsies. Methods: Twelve cases of prostate needle biopsy material including 75 needle cores were stained with triple-antibody cocktail (P504S + 34βE12 + p63). Slides were digitally scanned with the APERIO digital image analyzer and evaluated with the GENIE pattern and color recognition digital image analysis that we developed. A slide with known areas of adenocarcinoma, high grade prostatic intraepithelial neoplasia (PIN), benign glands and stroma was used as a training set for the automated digital image analysis platform. Results: Among 75 needle biopsy cores, 19 (25.33%) contained adenocarcinoma by histology. Digital image analysis recognized adenocarcinoma in 95% of these needle biopsies. The average area of the needle biopsy was 7.63 mm2 and overall the average area of tumor was 0.196 mm2. The smallest area of tumor recognized by the program was 0.0022 mm2 (0.0363% of the core) and the largest was 0.62 mm2 (8.17% of the core) among needle core biopsies. False positives resulted from areas of high grade PIN with patchy basal cells. The false negative was caused by uneven AMACR staining in one area of adenocarcinoma. Digital recognition of areas of interest was improved by three successive image analysis training which increased the sensitivity and specificity from 83% and 89% to 90% and 93%, respectively. Conclusions: Digital image analysis in concert with IHC triple staining may be useful for accurate detection and quantitative analysis of small foci of prostatic adenocarcinoma. Defining methods to increase the sensitivity and specificity of quantitative automated digital image analysis will likely evolve as an area of investigation. Future automated digital scanning and innovative pattern and color recognition technologies may open avenues for classifying a variety of prostate lesions.

与神经退行性疾病相关的RNA结合蛋白在线粒体损伤中的作用

线粒体是细胞内制造能量的细胞器,它还负责各种细胞信号的整合,参与协调多种复杂的细胞功能.线粒体是动态变化的,连续不断地进行分裂与融合,这是其功能维持和增殖遗传的关键.在过去20年中,参与线粒体分裂与融合的核心因子陆续被发现,它们在进化上高度保守,但是在形成分裂与融合复合物中的详细分子机制还有待于深入研究.线粒体分裂与融合的动态变化,是线粒体质量控制的重要组成部分,其动态平衡在细胞发育和稳态维持中起重要作用.线粒体动态变化失衡和功能失调,则会导致多种神经退行性疾病的发生.这些研究的发现为探索线粒体生物学及与疾病的关系开拓了令人振奋的新方向.

转录后基因调控异常与老年性痴呆

转录后基因调控异常与阿尔茨海默病(Alzheimer's disease,AD)发生发展的关系研究越来越受到重视.本文重点论述了tau基因(MAPT)发生可变剪接异常与AD发生的关系,以及参与转录后调控的RNA结合蛋白和非编码RNA在AD发生发展中的作用.

肝细胞癌基因组DNA拷贝数变异的性别差异性

目的比较男性与女性肝细胞癌(HCC)在基因组DNA拷贝数变异(CNA)方面的差异性。方法采用高分辨率微阵列比较基因组杂交技术(array-CGH)检测17例女性与46例男性HCC患者的CNA差异。结果女性HCC染色体片段1q21.3-q22扩增频率(76.5%vs 37.0%,P=0.009)、11q11扩增频率(35.3%vs 0.0%,P=0.000 2)、19q13.31-q13.32扩增频率(23.5%vs 0.0%,P=0.004)和16p11.2丢失频率(35.3%vs 6.5%,P=0.009)显著高于男性,而男性则有更高频率的11q11丢失(63.0%vs 17.6%,P=0.002)。进一步统计分析结果显示,11q11扩增与19q13.31-q13.32扩增(P=0.042)及16p11.2丢失(P=0.033)显著相关,而1q21.3-q22扩增与19q13.31-q13.32扩增(P=0.046)显著相关。结论 CNA在性别特异性HCC演进过程中可能发挥重要作用。

肝细胞癌远处转移相关DNA拷贝数变异的全基因组分析

目的探讨与肝细胞癌(HCC)远处转移相关的DNA拷贝数变异(copy number alteration,CNA)分子标志。方法采用高分辨率Agilent 244K微阵列比较基因组杂交(aCGH)方法检测63例HCC样本基因组DNA的CNA特征。以Log-rank检验、Kaplan-Meier生存分析以及Cox风险比例模型,分析各DNA片段CNA与HCC远处转移的相关性。结果染色体片段12p12.2-13.31丢失是HCC患者远处转移的显著危险因素(P<0.01,Log-rank检验)。与非丢失者相比,12p12.2-13.31丢失HCC患者的远处转移风险比(hazard ratio,HR)为22.98(95%CI=4.29～123.22,P<0.01)。多变量Cox回归分析显示,12p12.2-13.31丢失是HCC远处转移的独立预测因素(HR=7.94,95%CI=1.14～55.61,P<0.05)。结论染色体片段12p12.2-13.31丢失增加HCC远处转移风险,可作为预测HCC远处转移的一个分子标志。

Radioembolization for the treatment of unresectable hepatocellular carcinoma:A clinical review

Hepatocellular carcinoma(HCC)is the sixth most common cancer in the world.The majority of patients with HCC present with unresectable disease.These patients have historically had limited treatment options secondary to HCC demonstrating chemoresistance to the currently available systemic therapies.Additionally, normal liver parenchyma has shown intolerance to tumoricidal radiation doses,limiting the use of external beam radiation.Because of these limitations,novel percutaneous liver-directed therapies have emerged. The targeted infusion of radioactive microspheres (radioembolization)represents one such therapy. Radioembolization is a minimally invasive transcatheter therapy through which radioactive microspheres are infused into the hepatic arteries that supply tumor. Once infused,these microspheres traverse the hepatic vascular plexus and selectively implant within the tumor arterioles.Embedded within the arterioles, the 90Y impregnated microspheres emit high energy and low penetrating radiation doses selectively to the tumor.Radioembolization has recently shown promise for the treatment of patients with unresectable HCC. The objective of this review article is to highlight twocurrently available radioembolic devices(90Y,188Rh)and provide the reader with a recent review of the literature.

Mnk kinase pathway: Cellular functions and biological outcomes

The mitogen-activated protein kinase(MAPK) interacting protein kinases 1 and 2(Mnk1 and Mnk2) play important roles in controlling signals involved in mRNA translation. In addition to the MAPKs(p38 or Erk), multiple studies suggest that the Mnk kinases can be regulated by other known kinases such as Pak2 and/or other unidentified kinases by phosphorylation of residues distinct from the sites phosphorylated by the MAPKs. Several studies have established multiple Mnk protein targets, including PSF, heterogenous nuclear ribonucleoprotein A1, Sprouty 2 and have lead to the identification of distinct biological functions and substrate specificity for the Mnk kinases. In this review we discuss the pathways regulating the Mnk kinases, their known substrates as well as the functional consequences of engagement of pathways controlled by Mnk kinases. These kinases play an important role in mRNA translation via their regulation of eukaryotic initiation factor 4E(eIF4E) and their functions have important implications in tumor biology as well as the regulation of drug resistance to anti-oncogenic therapies. Other studies have identified a role for the Mnk kinases in cap-independent mRNA translation, suggesting that the Mnk kinases can exert important functional effects independently of the phosphorylation of eIF4 E. The role of Mnk kinases in inflammation and inflammationinduced malignancies is also discussed.

Diffusion-weighted magnetic resonance imaging to predict response of hepatocellular carcinoma to chemoembolization

AIM: To investigate whether intra-procedural diffusion- weighted magnetic resonance imaging can predict response of hepatocellular carcinoma (HCC) during trans- catheter arterial chemoembolization (TACE). METHODS: Sixteen patients (15 male), aged 59 ±11 years (range: 42-81 years) underwent a total of 21 separate treatments for unresectable HCC in a hybrid magnetic resonance/interventional radiology suite. Ana- tomical imaging and diffusion-weighted imaging (b = 0, 500 s/mm2) were performed on a 1.5-T unit. Tumor enhancement and apparent diffusion coefficient (ADC, mm2/s) values were assessed immediately before and at 1 and 3 mo after TACE. We calculated the percent change (PC) in ADC values at all time points. We compared follow-up ADC values to baseline values using a paired t test (α = 0.05). RESULTS: The intra-procedural sensitivity, specificity, and positive and negative predictive values (%) for detecting a complete or partial 1-mo tumor response using ADC PC thresholds of ±5%, ±10%, and ±15% were 77, 67, 91, and 40; 54, 67, 88, and 25; and 46, 100, 100, and 30, respectively. There was no clear predictive value for the 3-mo follow-up. Compared to baseline, the immediate post-procedure and 1-mo mean ADC values both increased; the latter obtaining statistical significance (1.48 ± 0.29 mm2/s vs 1.65 ± 0.35 × 10-3 mm2/s, P < 0.014). CONCLUSION: Intra-procedural ADC changes of > 15% predicted 1-mo anatomical HCC response with the greatest accuracy, and can provide valuable feedback at the time of TACE.

Recurrent gastrointestinal bleeding and hepatic infarction after liver biopsy

Hepatic artery pseudoaneurysms(HAP)are rare events,particularly after liver biopsy,but can be associated with serious complications.Therefore a high suspicion is necessary for timely diagnosis and appropriate treatment.We report on a case of HAP that potentially formed after a liver biopsy in a patient with sarcoidosis.The HAP in our case was virtually undetectable initially by angiography but resulted in several complications including recurrent gastrointestinal bleeding,hemorrhagic cholecystitis and finally hepatic infarction with abscess formation until it became detectable at a size of 5-mm.The patient remains asymptomatic over a year after endovascular embolization of the HAP.In this report,we demonstrate that a small HAP can avoid detection by angiography at an early stage while being symptomatic for a prolonged course.A high clinical suspicion with a close clinical/radiological follow-up is needed in symptomatic patients with history of liver biopsy despite initial negative work up.Once diagnosed,HAP can be safely and effectively treated by endovascular embolization.

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

Tumor microenvironment signaling and therapeutics in cancer progression

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Stromal cells can adopt new phenotypes to promote tumor cell invasion.Adeep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions.In this review,we describe the tumor microenvironment(TME)components and associated therapeutics.We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these pathways.These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling pathways.We also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the TME.In addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies.We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response.Overall,this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME,highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology.We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors,such as the inhabitant human microbiome,which have the potential to modulate TME biology and drug responses.