Outstanding young Chinese scholars making an impact in the US and China:a joint award program of the US Chinese Anti-Cancer Association and the US National Foundation for Cancer Research

Chinese researchers and physicians are being increasingly recognized for their significant contributions to advancing biomedical research, including cancer research, in China and around the world.To facilitate and strengthen collaboration among cancer researchers and physicians in the United States and China, the US Chinese Anti-Cancer Association (USCACA) and the US National Foundation for Cancer Research (NFCR) have established the USCACA-NFCR Scholar Exchange and Fellowship Program in basic, translational, and clinical studies.The goal of this joint scholar program is to recognize and reward research excellence by Chinese cancer researchers.Recipients are honored with the USCACA-NFCR Scholar Excellence Award for their achievements in cancer research performed while they were in the United States, as well as contributions to eradicating human cancers after their return to China.

The Role of Everolimus in the Treatment of Breast Cancer

The development of resistance to chemotherapy, endocrine therapy and anti HER2 agents in breast cancer is an important and common problem that impacts in the management of patients, particularly in the metastatic setting. This resistance has been explained in part by the activation of signal transduction pathways, including the PI3K/AKT/mTOR. The blockade with mTOR inhibitors such as everolimus is a new target agent for therapy that attempts to enhance treatment efficacy and restore tumor sensitivity. In this review article, we present the data about the use of everolimus for the treatment of breast cancer in all tumor phenotypes. Future studies that evaluate biomarkers for treatment response are needed to identify the specific populations that have the highest benefit of this new targeted therapy.

Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy against Human Cervical Cancer Cells in Vitro and in Mice

Background: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. Methods: CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distribution were determined. For in vitro Pc 4 photodynamic therapy, cells were irradiated at 667 nm at a fluence of 2.5 J/cm2 at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight hours after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm2. Results: The IC50s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6 μM and 0.016 μM and >10 μM and 0.026 μM;as spheroids, IC50s of Pc 4 photodynamic therapy were, 0.26 μM and 0.01 μM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. Conclusions: Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program.

Molecular subtypes of colorectal cancer:Evaluation of outcomes and treatment

Colorectal cancer(CRC) is a biologically heterogeneous disease with diverse clinical outcomes and responses to treatment. In the past two to three decades, a major effort has focused on classifying colorectal cancer subtypes based on causation, etiology, gene expression profiles, different pathways, and translational data from clinical trials. The goal is to uncover prognostic and predictive factors for outcomes in patients with colorectal cancer and to guide therapeutic approaches and management for the improvement of overall survival. Significant advances have been achieved in this area. However, tremendous work is still needed to accomplish the goal of better understanding intratumoral heterogeneity and the influence of the colonic environment, among other facets of colorectal cancer.

Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor

BACKGROUND Targeting DNA damage response(DDR)pathway is a cutting-edge strategy.It has been reported that Schlafen-11(SLFN11)contributes to increase chemosensitivity by participating in DDR.However,the detailed mechanism is unclear.AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects.METHODS To reach the purpose,eight esophageal squamous carcinoma cell lines,142 esophageal dysplasia(ED)and 1007 primary esophageal squamous cell carcinoma(ESCC)samples and various techniques were utilized,including methylationspecific polymerase chain reaction,CRISPR/Cas9 technique,Western blot,colony formation assay,and xenograft mouse model.RESULTS Methylation of SLFN11 was exhibited in 9.15%of(13/142)ED and 25.62%of primary(258/1007)ESCC cases,and its expression was regulated by promoter region methylation.SLFN11 methylation was significantly associated with tumor differentiation and tumor size(both P<0.05).However,no significant associations were observed between promoter region methylation and age,gender,smoking,alcohol consumption,TNM stage,or lymph node metastasis.Utilizing DNA damaged model induced by low dose cisplatin,SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways,while inhibiting the ATM/CHK2 signaling pathway.Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor(AZD0156),both in vitro and in vivo.CONCLUSION SLFN11 is frequently methylated in human ESCC.Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

Cancer immunotherapy in clinical practice—the past,present,and future

Considerable progress has been made in the field of cancer immunotherapy in recent years. This has been made possible in large part by the identification of new immune-based cellular targets and the development of novel approaches aimed at stimulating the immune system. The role played by the immunosuppressive microenvironment in the development of tumors has been established. The success of checkpoint-inhibiting antibodies and cancer vaccines has marked the beginning of a new era in cancer treatment. This review highlights the clinically relevant principles of cancer immunology and various immunotherapeutic approaches that have either already entered mainstream oncologic practice or are currently in the process of being evaluated in clinical trials. Furthermore, the current barriers to the development of effective immunotherapies and the potential strategies of overcoming them are also discussed.

Image-based brachytherapy for cervical cancer

Cervical cancer is the third most common cancer in women worldwide; definitive radiation therapy and concurrent chemotherapy is the accepted standard of care for patients with node positive or locally advanced tumors > 4 cm. Brachytherapy is an important part of definitive radiotherapy shown to improve overall survival. While results for two-dimensional X-ray based brachytherapy have been good in terms of local control especially for early stage disease, unexplained toxicities and treatment failures remain. Improvements in brachytherapy planning have more recently paved the way for three-dimensional image-based brachytherapy with volumetric optimization which increases tumor control, reduces toxicity, and helps predict outcomes.Advantages of image-based brachytherapy include:improved tumor coverage(especially for large volume disease), decreased dose to critical organs(especially for small cervix), confirmation of applicator placement, and accounting for sigmoid colon dose. A number of modalities for image-based brachytherapy have emerged including: magnetic resonance imaging(MRI),computed tomography(CT), CT-MRI hybrid, and ultrasound with respective benefits and outcomes data. Forpractical application of image-based brachytherapy the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology Working Group and American Brachytherapy Society working group guideline serve as invaluable tools, additionally here-in we outline our institutional clinical integration of these guidelines. While the body of literature supporting image-based brachytherapy continues to evolve a number of uncertainties and challenges remain including: applicator reconstruction, increasing resource/cost demands, mobile four-dimensional targets and organs-at-risk, and accurate contouring of "grey zones" to avoid marginal miss. Ongoing studies, including the prospective EMBRACE(an international study of MRI-guided brachytherapy in locally advanced cervical cancer) trial, along with continued improvements in imaging, contouring, quality assurance, physics, and brachytherapy delivery promise to perpetuate the advancement of image-based brachytherapy to optimize outcomes for cervical cancer patients.

Significant association between ABO blood group and pancreatic cancer

AIM:To evaluate whether the ABO blood group is related to pancreatic cancer risk in the general population of the United States.METHODS:Using the University of Pittsburgh's clinicalpancreatic cancer registry,the blood donor database from our local blood bank (Central Blood Bank),and the blood product recipient database from the regional transfusion service (Centralized Transfusion Service) in Pittsburgh,Pennsylvania,we identified 274 pancreatic cancer patients with previously determined serological ABO blood group information.The ABO blood group frequency was compared between these patients and 708842 individual,community-based blood donors who had made donations to Pittsburgh's Central Blood Bank between 1979 and 2009.RESULTS:The frequency of blood group A was statistically significantly higher amongst pancreatic cancer patients compared to its frequency amongst the regional blood donors [47.63% vs 39.10%,odds ratio (OR)=1.43,P=0.004].Conversely,the frequency of blood group O was significantly lower amongst pancreatic cancer patients relative to the community blood donors (32.12% vs 43.99%,OR=0.60,P=0.00007).There were limited blood group B (n=38) and AB (n=17) pancreatic cancer patients;the overall P trend value comparing patient to donor blood groups was 0.001.CONCLUSION:The ABO blood group is associated with pancreatic cancer risk.Future studies should examine the mechanism linking pancreatic cancer risk to ABO blood group.

Targeting proliferation and survival pathways in head and neck cancer for therapeutic benefit

Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. Recent studies have elucidated a key signaling axis, the EGFR-STAT3-Bcl-XL signaling axis, that is aberrantly activated in a majority of HNSCC and contributes to the proliferation and survival of malignant cells. Considerable effort is being placed on developing highly specific inhibitors of different components of this pathway. This review highlights the progress that is being made towards achieving potent inhibition of the EGFR-STAT3-Bcl-XL signaling axis in HNSCC and the promising therapeutic strategies that are currently under development for this disease.

Virtual drug design： Skpl-Skp2 inhibition targets cancer stem cells

The dysregulation of pathways regulat-ing cellular function is a frequent hall-mark of cancer and the development of specific pathway inhibitors that alter tumor growth and progression are the focus of multiple recent studies. E3 ubiquitin ligases are a large group of diverse protein enzymes that specifically target proteins for dear- ance, and their importance to normal cel-lular function is illustrated in the many diseases associated with their loss of func- tion or inappropriate targeting. S-phase kinase-associated protein 2 （Skp2） is an F box protein that plays critical roles in cell-cycle progression, senescence, metabolism, and acts as an Skpl-Cullin-l-F box （SCF） ubiquitin ligase substrate recognition fac-tor. Overexpression of Skp2 is associated with poor prognosis and metastasis in many cancers and is a well validated drug target. In a recent report, Chart et al. have iden-tified an Skp2 inhibitor that selectively impairs Skp2 E3 ligase activity using an integrated virtual high-throughput drug screening and experimental validation approach. This Skp2 inhibitor restricts cancer stemness and potentiates sensitivity to chemotherapeutic agents in multiple ani-mal tumor models. These findings identify a new novel small molecule that targets the Skp2 and reduces tumor growth by attenu-ating aerobic glycolysis and inducing cel-lular senescence.

Androgens and Tumor Suppressors in Prostate Cancer

Androgens are intimately associated with prostate cancer development and progression; however, the exact roles of androgens in prostate cancer cells remain unclear. Our research focuses on the identification and

Agouti和Agouti相关蛋白的一些生物学内涵

Agouti有多方面的意义。首先,它是分属几种不同物种的哺乳动物的俗称。其次,它是一些啮齿类动物的属名。第三,它代表了一种啮齿类动物特有的毛色。第四,它是一个与黑素皮质素受体信号转导途径的调控有关,存在于从人(Homo sapiens)到啮齿类动物,乃至斑马鱼(Danio rerio)的一个特定基因的名称,又是该基因产生的一种特定信号蛋白的名称。Agouti和Agouti相关蛋白是肿瘤、肥胖与糖尿病等人类疾病的研究热点之一。Agouti黄色肥胖小鼠最近成了表观遗传学研究的一个重要模型动物。本文阐述并区分了与agouti有关的一些重要概念与科学术语,并综述了相关领域的研究进展。

Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer

Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer(CRC),the third leading cause of cancer-related death in the US.In addition to their well-characterized function in driving tumor progression,KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC.Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor(EGFR)targeting antibodies,including cetuximab and panitumumab.Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells.However,the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear.Despite intensive efforts,directly targeting mutant KRAS has been largely unsuccessful.This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC,highlighting several recently developed agents and strategies for targeting mutant KRAS,such as synthetic lethal interactions.

Platelet-derived growth factor receptor alpha in glioma:a bad seed

Recent collaborative,large-scale genomic profiling of the most common and aggressive brain tumor glioblastoma multiforme(GBM) has significantly advanced our understanding of this disease.The gene encoding platelet-derived growth factor receptor alpha(PDGFR a) was identified as the third of the top 11 amplified genes in clinical GBM specimens.The important roles of PDGFR a signaling during normal brain development also implicate the possible pathologic consequences of PDGFR a over-activation in glioma.Although the initial clinical trials using PDGFR kinase inhibitors have been predominantly disappointing,diagnostic and treatment modalities involving genomic profiling and personalized medicine are expected to improve the therapy targeting PDGFR a signaling.In this review,we discuss the roles of PDGFR a signaling during development of the normal central nervous system(CNS) and in pathologic conditions such as malignant glioma.We further compare various animal models of PDGF-induced gliomagenesis and their potential as a novel platform of pre-clinical drug testing.We then summarize our recent publication and how these findings will likely impact treatments for gliomas driven by PDGFR a overexpression.A better understanding of PDGFR a signaling in glioma and their microenvironment,through the use of human or mouse models,is necessary to design a more effective therapeutic strategy against gliomas harboring the aberrant PDGFR a signaling.

HMGB1 and autophagy

The word "autophagy" is derived from the Greek roots "auto" and "phagy" which mean "self" and "to eat", respectively.As a hot topic and rapidly expanding field in biology and medicine, autophagy is a process by which cytoplasmic components, including soluble macromolecules (such as nucleic acids, proteins, carbohydrates and lipids) and organelles (such as mitochondria, peroxisomes and endoplasmic reticulum) are degraded by lysosomes.There are at least three recognized types of autophagy including chaperone-mediated autophagy, microautophagy, and macroautophagy[1].

Platelet-derived growth factor signaling in human malignancies

Platelet-derived growth factors (PDGFs) and their receptors were identified and purified decades ago. PDGFs are important during normal development and in human cancers. In particular, autocrine PDGF signaling has been implicated in various types of malignancies such as gliomas and leukemia. In contrast, paracrine signaling was found in cancers that originate from epithelial cells, where it may be involved in stromal cell recruitment, metastasis, and epithelial-mesenchymal transition. This editorial briefly discusses autocrine and paracrine PDGF signaling and their roles in human cancers, and introduces a series of review articles in this issue that address the possible roles of PDGFs in various processes involved in different types of cancers.

Healthcare Resource Utilization and Associated Costs in Patients with Advanced Melanoma Receiving First-Line Ipilimumab

Background: To describe healthcare costs, excluding ipilimumab drug costs, in patients with advanced melanoma receiving ipilimumab in the US community practice setting. Methods: This was a retrospective chart review of unresectable stage III/IV melanoma patients who received first-line ipilimumab monotherapy between 04/2011 and 09/2012. Healthcare resource utilization included inpatient, emergency, specialist and hospice visits, laboratory tests, radiation, surgeries, and nursing home stays. Publicly available US unit costs were applied to each resource type to estimate costs, which were analyzed by time periods: during ipilimumab treatment, post-ipilimumab treatment (post-regimen), and within 90 days prior to death (pre-death). Generalized linear mixed models were used to explore cost predictors during the treatment period, on a per-dose-interval basis, defined as the time between ipilimumab doses. Results: Data were abstracted from 273 patient charts at 34 sites. Excluding ipilimumab drug costs, total monthly costs during the treatment regimen, post-regimen, and pre-death periods were $690, $2151, and $5123, respectively. Total healthcare costs were 27 times higher during dose intervals with a grade 3/4 adverse event compared with intervals without a grade 3/4 adverse event. Eastern Cooperative Oncology Group performance status ≥ 2 (vs 0) was also associated with significantly higher cost per dose interval. Conclusions: In this population, monthly costs exclusive of drug were significantly lower during the treatment period than in subsequent periods. Unfavorable ECOG PS was associated with significant increases in cost per dose interval. Grade 3/4 adverse events were associated with a marked increase in healthcare costs, but occurred in a small proportion of dose intervals.

靶向攻击肿瘤的免疫疗法

用单克隆抗体治疗癌症一直是肿瘤免疫学研究的热点之一。以往的抗体治疗均以癌细胞表面蛋白为靶标,因为全抗体分子太大而不能穿过细胞膜。最近新加坡科技研究局下属的分子与细胞生物学研究所(IMCB)曾琦博士及其团队的研究发现,抗体治疗不仅能以胞外癌蛋白为靶标,也能以胞内癌蛋白为靶标,进入胞内杀死癌细胞,从而抑制癌细胞的生长;这些发现对癌症的免疫治疗具有突破性的意义。现将其主要内容摘录如下,供我国学者参考。读者有意阅读原文请看:[Ferrone S.Hidden immunotherapy targets challenge dogma,Sci Transl Med,2011,3(99):99ps38]

增强放疗作为子宫内膜癌辅助性治疗的临床结局

Objective.:To assess local control and chronic toxicity with IMRT for adjuvant treatment of endometrial carcinoma. Methods.:Forty-seven patients with endometrial cancerwere treated with adjuvant IMRT and HDR brachytherapy (HDRB). The external beam dose was between 45 and 50.4 Gy,and all patients received 10Gy in 2 fractions of HDRB to the vaginal cuff. Eight of these patients were treated with extended field to include the paraaortic region. Results.:IMRT dosimetry showed excellent coverage of the planning target volume (PTV) with mean PTV 95,PTV 110 and PTV 120 of 97.8%,8.2%and 0.9%respectively. At a median follow-up of 20 months,four patients have recurred at extra pelvic sites. No patient had pelvic recurrence. The treatment was well tolerated with late toxicities as follows:small bowel grade 1:25%,rectal grade 1:2%and bladder grade 1:13%. One patient had grade 3 small bowel toxicity. The 3-year actuarial rate of grade 2 or greater toxicity,disease-free survival and overall survival rate were 3.3%,84%and 90%,respectively. Conclusions.:The preliminary analysis of IMRT for adjuvant treatment of endometrial carcinoma shows excellent local control and low toxicity. However,longer follow-up and more patients are needed to ascertain whether the benefits of IMRT treatment seen here translate into long-term reductions in toxicities and local recurrence.

卵巢癌患者外周血中的IL-8与抗IL-8自身抗体

Objectives:In an ongoing effort to identify diagnostic ovarian cancer biomarkers,SEREX (serological analysis of recombinant cDNA expression libraries) technique was employed resulting in detection of 20 known genes,nine ESTs and one novel sequence. Interleukin-8 (IL-8) was one of ovarian cancer-associated antigens identified by SEREX screening. The objective of this study was,therefore,to evaluate the potential importance of circulating anti-IL-8 antibody as ovarian cancer biomarker. Methods:We developed and optimized a new immunofluorescent bead-based assay for detection of anti-IL-8 antibody in blood serum. Circulating IL-8 and anti-IL-8 IgG concentrations were measured in blood sera from 44 patients with early stage (I-II) ovarian cancer,50 patients with late stage (III-IV) ovarian cancer,37 patients with benign pelvic masses,and 80 healthy women using the bead-based assay. Results:Our data indicate that serum contains IL-8 cytokine,anti-IL-8 antibody,and IL-8:anti-IL-8 complexes. We found that concentrations of IL-8 and anti-IL-8 antibody were elevated in sera of patients with ovarian cancer as compared with healthy controls. Logistic regression analysis of circulating concentrations of anti-IL-8 IgG in patients with stages I-II ovarian cancer versus healthy controls allowed for prediction of early ovarian cancer with 98%specificity,65.5%sensitivity,80.3%of patients correctly classified. Combining IL-8 and anti-IL-8 IgG with CA 125 resulted in increased classification power as compared to individual markers analyzed separately. Conclusion:Thus,IL-8 and anti-IL-8 autoantibody might potentially serve as additional biomarkers for ovarian cancer.