Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling

<p>Abstract</p> <p>Background</p> <p>Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated.</p> <p>Results</p> <p>Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (^memGRP78⁺) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 ^memGRP78⁺HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both <it>in vitro </it>and <it>in vivo</it>. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN.</p> <p>Conclusions</p> <p>In summary, ^memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.</p

Network Biology of Tumor Stem-like Cells Identified a Regulatory Role of CBX5 in Lung Cancer

Mounting evidence links cancers possessing stem-like properties with worse prognosis. Network biology with signal processing mechanics was explored here using expression profiles of a panel of tumor stem-like cells (TSLCs). The profiles were compared to their parental tumor cells (PTCs) and the human embryonic stem cells (hESCs), for the identification of gene chromobox homolog 5, CBX5, as a potential target for lung cancer. CBX5 was found to regulate the stem-like properties of lung TSLCs and was predictive of lung cancer prognosis. The investigation was facilitated by finding target genes based on modeling epistatic signaling mechanics via a predictive and scalable network-based survival model. Topologically-weighted measurements of CBX5 were synchronized with those of BIRC5, DNMT1, E2F1, ESR1, MLH1, MSH2, RB1, SMAD1 and TAF5. We validated our findings in another Taiwanese lung cancer cohort, as well as in knockdown experiments using sh-CBX5 RNAi both in vitro and in vivo.National Science Council (China) (NSC grant 100-2325-B-010-010-MY3/98-2314-B-010-024-MY2/97-3111-B075-001-MY3/ 96-2314-075-056-MY3)National Yang-Ming University (Ministry of Education, Aim for the Top University Plan: 96ADD122, 96ADD125, 96ADT191, 97ACD113, 97ACT302, 98ACT302, 98ACD107, 98ACT192 and Brain Research Center-3T-MRI project)))Taipei Veterans General Hospital (98-C1-099/E1-003/ER3-001)Taipei Veterans General Hospital (Joint Projects of VGHUST (98-G6-6/ 98-P1-01/99-P6-39)Chi Mei Medical Center (CMYM9801)Yen-Tjing-Ling Medical Foundation (96/97/98)Taipei City Hospital (96-002-62-092)Technology Development Program for Academia (TDPA; 98-EC-17-A-19-S2-0107)Taiwan. Department of Industrial Technology, Ministry of Economic AffairsNational Science Council (China) (NSC 101-2325-B-010 -009)Taiwan. Department of Health. Cancer Research Center of Excellence (DOH101-TD-C-111-007

A Nation-Wide multicenter 10-year (1999-2008) retrospective clinical epidemiological study of female breast cancer in china

<p>Abstract</p> <p>Background</p> <p>According to the very limited cancer registry, incidence and mortality rates for female breast cancer in China are regarded to be increasing especially in the metropolitan areas. Representative data on the breast cancer profile of Chinese women and its time trend over years are relatively rare. The aims of the current study are to illustrate the breast cancer profile of Chinese women in time span and to explore the current treatment approaches to female breast cancer.</p> <p>Methods</p> <p>This was a hospital-based nation-wide and multi-center retrospective study of female primary breast cancer cases. China was divided into 7 regions according to the geographic distribution; from each region, one tertiary hospital was selected. With the exception of January and February, one month was randomly selected to represent each year from year 1999 to 2008 at every hospital. All inpatient cases within the selected month were reviewed and related information was collected based on the designed case report form (CRF). The Cancer Hospital/Institute, Chinese Academy of Medical Sciences (CICAMS) was the leading hospital in this study.</p> <p>Results</p> <p>Four-thousand two-hundred and eleven cases were randomly selected from the total pool of 45,200 patients and were included in the analysis. The mean age at diagnosis was 48.7 years (s.d. = 10.5 yrs) and breast cancer peaked in age group 40-49 yrs (38.6%). The most common subtype was infiltrating ductal carcinoma (86.5%). Clinical stage I & II accounted for 60.6% of 4,211 patients. Three-thousand five-hundred and thirty-four cases had estrogen receptor (ER) and progestin receptor (PR) tests, among them, 47.9% were positive for both. Two-thousand eight-hundred and forty-nine cases had human epidermal growth factor receptor 2(HER-2) tests, 25.8% of them were HER-2 positive. Among all treatment options, surgery (96.9% (4,078/4,211)) was predominant, followed by chemotherapy (81.4% (3,428/4,211). Much less patients underwent radiotherapy (22.6% (952/4,211)) and endocrine therapy (38.0% (1,599/4,211)).</p> <p>Conclusions</p> <p>The younger age of breast cancer onset among Chinese women and more advanced tumor stages pose a great challenge. Adjuvant therapy, especially radiotherapy and endocrine therapy are of great unmet needs.</p

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Some character variations of native kiwifruit (Actinidia spp.) in Taiwan

台灣野生獼猴桃資源豐富，種間、種內的性狀變異均大，以台灣羊桃(A. setosa)為例，果實形狀可從近圓、卵圓、橢圓至扁橢圓，果肉顏色可由黃綠、翠綠至綠肉紅心，充分軟熟之果實之口感也可從淡而無味的10.2°Brix至香甜可口的16°Brix，最可口的野生台灣羊桃是進一步複選的優良材料。 硬齒獼猴桃(A. callosa)在台灣的地理分佈上，呈現廣溫性、廣域性分佈的現象，從海拔1800m的南橫栗園沿線、海拔1200m的大漢山麓沿線至海拔400m的壽卡沿線均可見其野生族群的分佈，且3海拔之族群生育狀況均佳，每年均能正常開花結果，生育能力不受海拔影響，但3族群之物候週期卻因海拔略有不同。栗園地區之種子休眠性最深，需經3週5℃±2℃低溫層積才有少量種子發芽，隨層積週數增加，種子發芽率也增加；壽卡地區種子休眠性最淺，即使不經層積，也有20%之發芽率，這對適應較熱的氣候而言是必需具備的最基本條件；這種休眠深度與海拔成正相關的現象也反映在冬季休眠的枝條上，呈現海拔越高，休眠越深的狀況，而打破休眠所需的層積時間也越久，像這樣同種內休眠深度與海拔成正相關之差異，或許可為獼猴桃耐熱育種開創新契機。 將栗園與壽卡兩處收集的野生硬齒獼猴桃種子播種培育後，栽植於台中縣霧峰鄉中興大學園藝試驗場內進行耐熱選拔，發現壽卡地區之硬齒獼猴桃後裔平均葉片面積較大、平均枝條較長、不產生大量短而密的側枝、也不產生長而粗的徒長枝，枝條外觀性狀較為平均；而栗園地區之硬齒獼猴桃後裔則相反，有些植株易產生長而粗的徒長枝，有些植株則易產生短而密的側枝，且葉片均較狹小。 在植株同化能力方面，固定老葉光合能力隨時間推移而逐漸下降，恰成熟新葉光合能力則不因測量日期而改變，光合能力的強弱在不同族群間的差異較不明顯，族群內的實生苗光合能力差異反而較族群間差異顯著。 硬齒獼猴桃之光合能力與葉片溫度相關性低，但與氣孔導度的相關性高，由相關曲線顯示，氣孔導度小於0.2 mol•m-2•s-1即能抑制植株的光合能力，這顯示在夏秋高溫季節，植株氣孔能正常開放者，同化能力就相對較高。栗園地區硬齒獼猴桃之後裔中，不乏氣孔導度大、光合能力強之植株，但外觀性狀卻呈現不耐熱性狀之意義為：高海拔植群並非真的不耐平地夏季高熱，使葉片無法蓄積同化產物，而是植株被夏秋季被高溫所干擾，同化物傾向直接利用而不儲存，導致秋梢競相萌發，養分競爭的結果，產生大量短而小的側枝與新葉，使植株外觀呈現近似不耐熱的表徵。The characters of four wild kiwifruit species in Taiwan were investigated in this study. The wild kiwifruits in Taiwan present great diviation in genotype and phenotype. For example, the shape of Actinidia setosa fruit varies from near globose、 ovoid to flate globose；fresh color varies form yellow-green、jade-green to green with red core. The average total soluble solid contains from 10.2 °Brix to 16 °Brix. The most tasty A. setosa plant can be used to further selection. Wild A. callosa plants in Taiwan were found in mountains with different elevation from 400m、1200m and 1800m. We found out that these 3 populations could nomally grow and bear fruit in their own region, but their dormancy characteristic are quite different. In the experiment, A. callosa seeds collected from low attitude even needn’t stratification, and the germination rate can reach 20％. This machinism is very important of them to suit much hotter condition in their own region. In the other way, seeds collected from high land must be suffered 3 weeks or more cold stratification to break winter dormancy. Similar result happened in excised cane test which dormant shoots were collected wildly in November. The seeds taken from wild were breed in NCHU and later planted at Wu-Fung low land for heat resistant test. We obtained that plants originally germed from low attitude has larger leaves, longer shoot average length at the end of the research than plants from high land. In the opposite, plant from high land had smaller leaves and lots of shorter shoots. The photosynthesis ability was low correlated with different population and leave surface temperature, but much correlated with group inter-differences and leave stomatal aperture. It means that we could find plants with high photosynthesis rate in every population, and even these plants are suffering the heat stress, photosynthesis rate will still be high if the stomata can normally open. In the high altitude race, some plants show high photosynthesis rate but have shorter shoots and small leaves. This may be the result of the assimilation balance interfered by high temperature that causes the presence of numorous autumn shoots, which compete for the energy source with each other.中文摘要 ----------------------------------------------------------------- i 英文摘要 ----------------------------------------------------------------- ii 目錄 ----------------------------------------------------------------- iii 前言 ----------------------------------------------------------------- 1 前人研究 ----------------------------------------------------------------- 3 材料及方法 ----------------------------------------------------------------- 14 結果 ----------------------------------------------------------------- 20 討論 ----------------------------------------------------------------- 51 參考文獻 ----------------------------------------------------------------- 6