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.

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

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.

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.

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.

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.

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.

迈向精准医学:液体活检中5-羟甲基胞嘧啶类癌症生物标志物发现的研究进展

将性能稳定且便于临床应用的生物标志物应用于癌症诊断、早期检测和预测预后可提高患者生存率,也是精准医学的关键所在。第二代测序技术可以更加灵敏而全面地分析肿瘤来源的材料的遗传和表观遗传信息。现在,研究人员能够在新的维度上监测肿瘤发生的动态变化,例如使用循环无细胞DNA(circulating cell-free DNA,cf DNA)和循环肿瘤DNA(circulating tumor DNA,ctDNA)。基于突变分析的液体活检通常无法在不同研究中得到一致的结果,部分原因在于肿瘤内和肿瘤间的异质性以及技术的限制。相比之下,患者来源的cf DNA的表观遗传分析是一个很有前景的替代方案,特别是对于早期检测和疾病监测,因为表观遗传修饰是组织特异性的,并且反映了癌症进展的动态过程。因此,基于cf DNA的表观遗传分析正成为癌症诊断和预后预测的高灵敏度且微创的手段,在未来癌症患者的精准护理中具有巨大潜力。然而,应用cf DNA的表观遗传分析的主要障碍是缺乏具有高灵敏度和稳定性的技术。我们在本文中总结了cf DNA中5-羟甲基-胞嘧啶(5-hydroxymethylcytosine,5hmC)的表观基因组分析的研究进展,重点关注其对不同癌症类型的检测方法和作为生物标志物的潜在应用。

胰腺癌辅助治疗：点滴进步

胰腺癌患者预后极差，死亡率很高，多数新发病例会在1年内死亡。手术是胰腺癌患者唯一可以取得治愈效果的治疗手段。大约20％的患者可以接受手术治疗，其中仅一半的患者可以接受根治性切除术。在就诊量大且经验丰富的医院，胰腺癌手术的并发症率和死亡率较低。目前尚不清楚术前新辅助治疗能否提高手术切除率。美国和欧洲的多项临床试验结果显示，胰腺癌患者是否需要进行术后辅助放疗、化疗或放化疗仍无定论。

选择性雌激素受体调节剂以及浸润性乳腺癌的预防

本年度美国有20万以上的妇女被诊断患有浸润性乳腺癌。过去20年的研究已将对基础生物学的了解转化为治疗实践，导致乳腺癌患者生存率和生活质量的很大改善。对预防乳腺癌的其他策略也进行了研究。这些策略包括改变生活方式（如饮食、酒精摄入、理想体重、外源性雌激素治疗）、手术切除（预防性乳房切除术、卵巢切除术或二者同时进行）以及最近采用的选择性雌激素受体调节剂（selective estrogen receptor modulators，SERMs）如他莫西芬进行化学预防。

IDO1 in cancer: a Gemini of immune checkpoints

Indoleamine 2,3-dioxygenase 1(IDO1)is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan(Trp)into downstream catabolites known as kynurenines.Coincidently,numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer.Preclinical studies have further introduced an interesting paradox:while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden,approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival.Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy,these data suggest that there is a more complex mechanism of action than previously appreciated.Similar to the dual faces of the astrological Gemini,we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism,as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects.The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration,but the lack of a universal prognostic significance among all cancer subtypes.Finally,ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients。

EZH2, an epigenetic driver of prostate cancer

The histone methyltransferase EZH2 has been in the limelight of the fi eld of cancer epigenetics for a decade now since it was fi rst discovered to exhibit an elevated expression in metastatic prostate cancer.It persists to attract much scientifi c attention due to its important role in the process of cancer development and its potential of being an effective therapeutic target.Thus here we review the dysregulation of EZH2 in prostate cancer,its function,upstream regulators,downstream effectors,and current status of EZH2-targeting approaches.This review there-fore provides a comprehensive overview of EZH2 in the context of prostate cancer.

Transcriptional repression by androgen receptor: roles in castration-resistant prostate cancer

Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.