Analytical Trends and Pathogenesis of Microplastics in Human Cancer Tissues: A Toxicology Mini-review

Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pHi) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na+,HCO3– cotransport and Na+/H+ exchange dominate cellular net acid extrusion in human breast carcinomas. Na+/H+ exchange elevates pHi preferentially in estrogen receptor-negative breast carcinomas, whereas Na+,HCO3– cotransport raises pHi more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na+/H+ exchanger NHE1/SLC9A1 and Na+,HCO3– cotransporter NBCn1/SLC4A7. Increased dependency on Na+,HCO3– cotransport associates with severe breast cancer: enlarged CO2/HCO3–-dependent rises in pHi predict accelerated cell proliferation, whereas enhanced CO2/HCO3–-dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high SLC4A7 and/or low SLC9A1 mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na+,HCO3– cotransport for pHi regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.

Objective : Disabled-2 (Dab2) is an important endocytic adaptor which plays an inhibition role in cancer cell growth. The objective of this study was to systematically review expressions of Dab2 in human cancers. Methods : Eligible studies about Dab2 in human cancers were retrieved from databases of PubMed, Embase, Web of Science. Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated using Review Manager 5.0 software and statistical analyses were performed by the SPSS 13.0 software. Results : Fourteen case-control studies with a total of 689 human tumor tissues, 332 control tissues and 32 cancer cell lines were included in the meta-analysis study. The results indicated loss expressions of Dab2 were observed in 74.9% and 46.9% in human malignant cancer tissues and cancer cell lines, respectively. The ratio of Dab2 promotor hypermethylation is 34.54% in cancer tissues which Dab2 expression are lost, but none in the control tissues or cells by Methylation-specific PCR (MSP). Conclusions : The expressions of Dab2 are frequently lost in human malignant cancer tissues, and promotor hypermethylation of Dab2 are common in human malignant cancer tissues, which is an important factor for the loss expression of Dab2 in human cancers tissues.

VEGFR3 plays a key role in the regulation of lymphangiogenesis in adults, and is also important for tumor angiogenesis and metastasis. In order to characterize human cancer tissues for imunohistochemical (IHC) localization and prevalence of VEGFR3 protein, we developed a robust IHC assay in our lab using a mouse monoclonal primary antibody (Millipore). To optimize the various assay parameters, we utilized high-quality VEGFR3 positive (and internal negative) control tissues (Kaposi's sarcoma, angiosarcoma, lymph node). Reagent negative controls were satisfactory. Specificity of the primary anti-VEGFR3-antibody was supported by a discrete band at the expected molecular weight on western blots using a VEGFR3 transfected cell lysate and negative control cell lines. We also demonstrated lack of specific vascular VEGFR3 staining in pre-absorption experiments with VEGFR3 (but not VEGFR1 or 2) recombinant protein, supporting selectivity of the primary antibody for VEGFR3. Using the fully optimized assay, we stained a human multi-tumor screening tissue microarray (TMA) to demonstrate full range of specific vascular VEGFR3 staining in glioblastoma and carcinomas of the colon, breast, ovary, pancreas, lung, larynx, kidney, cervix, bladder, extrahepatic cholangiocarcinoma and malignant melanoma. Specific, unequivocal VEGFR3 immunoreactivity was interpreted qualitatively (VEGFR3 positive/negative) in tumor blood and lymphatic vessels. No tumor cell staining was seen. Some colon cancer tissues in multi-tumor TMA were VEGFR3+, while others were VEGFR3-. The observed variation in VEGFR3 expression and vascular distribution on screening TMA were further evaluated in two independent cohorts of well-characterized human colorectal cancer tissues (organ-specific TMAs) by a Board-certified, subspecialty GI pathologist (AN), with overall VEGFR3 prevalence rates of 62% (36 of 58 cases) and 56% (55 of 98 cases). Using CD34 and D2-40 IHC assays from a CLIA-certified lab, we confirmed IHC localization of VEGFR3 protein both in the stromal blood vessels and lymphatics within the invasive colorectal cancer stroma. In conclusion, following well-established IHC assay development and standardization protocols and efficient workflow paradigm, we have used a technically robust IHC assay to characterize routinely processed archival human cancer tissues and have demonstrated specific VEGFR3 expression patterns, tissue localization and prevalence in human colorectal cancer tissues. Based on its performance in our hands, this assay can be used to further evaluate patterns of VEGFR3 expression in areas of tumor angiogenesis in other human cancer tissues. Data-driven hypotheses generated from such investigations will be relevant to corroborate VEGF receptor biology and emerging clinical experience with anti-VEGF/anti-VEGFR therapies. Citation Format: Timothy R. Holzer, Drew M. Nedderman, Aejaz Nasir. Robust immunohistochemical assay to characterize human cancer tissues for prevalence of vascular endothelial growth factor receptor 3 (VEGFR3). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4175. doi:10.1158/1538-7445.AM2015-4175

Nucleotide synthesis is essential to proliferating cells, but the preferred precursors for de novo biosynthesis are not defined in human cancer tissues. We have employed multiplexed stable isotope-resolved metabolomics to track the metabolism of [13C6]glucose, D2-glycine, [13C2]glycine, and D3-serine into purine nucleotides in freshly resected cancerous and matched noncancerous lung tissues from nonsmall cell lung cancer (NSCLC) patients, and we compared the metabolism with established NSCLC PC9 and A549 cell lines in vitro Surprisingly, [13C6]glucose was the best carbon source for purine synthesis in human NSCLC tissues, in contrast to the noncancerous lung tissues from the same patient, which showed lower mitotic indices and MYC expression. We also observed that D3-Ser was preferentially incorporated into purine rings over D2-glycine in both tissues and cell lines. MYC suppression attenuated [13C6]glucose, D3-serine, and [13C2]glycine incorporation into purines and reduced proliferation in PC9 but not in A549 cells. Using detailed kinetic modeling, we showed that the preferred use of glucose as a carbon source for purine ring synthesis in NSCLC tissues involves cytoplasmic activation/compartmentation of the glucose-to-serine pathway and enhanced reversed one-carbon fluxes that attenuate exogenous serine incorporation into purines. Our findings also indicate that the substrate for de novo nucleotide synthesis differs profoundly between cancer cell lines and fresh human lung cancer tissues; the latter preferred glucose to exogenous serine or glycine but not the former. This distinction in substrate utilization in purine synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy.

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase with elevated expression in most human cancers, most notably in invasive metastasis. FAK is involved in cell adhesion, motility, and apoptosis, and it is a target for oncology therapeutics. FAK activation occurs by phosphorylation at Tyr397 in response to integrin clustering caused by cell adhesion. The development of a sensitive and specific immunohistochemical assay for phosphorylated FAK (pFAK) is important for pharmacodynamic biomarker studies. The purpose of this study was to investigate 4 commercially available anti-pFAK antibodies in human tissues and cell lines. Antibodies included 3 rabbit monoclonals (EP2160Y, 141-9, and 31H5L17) and 1 rabbit polyclonal. Antibody specificity was evaluated in a variety of cell lines (BxPC3, HCT-116, LOVO, MDA-MB-231, and MiaPaca2) treated with 2 FAK inhibitors: TAE226 (NVP-TAE226) and PF-562271. Decreased immunohistochemical staining for pFAK was observed in post-treatment samples of cell lines with baseline pFAK expression. TAE226 was more potent at inhibiting pFAK staining. Membrane staining was observed with the rabbit polyclonal and rabbit clone EP2160Y only. Each of the 4 antibodies was tested in human breast cancer tissues using tissue microarrays created by Mosaic Laboratories. The percentage of breast cancer samples that were pFAK positive was 96% with clone EP2160Y, 83% with clone 141-9, 92% with clone 31H5L17 and 96% with the polyclonal. The percentage of cells that were positive within each breast cancer sample ranged from 63% to 83%, depending on the antibody used (standard deviations between 30% and 44%). Immunohistochemistry with the polyclonal and clone EP2160Y antibodies demonstrated membrane and cytoplasmic staining, while clones 141-9 and 31H5L17 demonstrated primarily cytoplasmic staining. Based on reduction of pFAK staining in treated cells and acceptable performance in human cancer tissues, pFAK immunohistochemistry is “fit for purpose” for evaluation of FAK inhibitor activity in pre- and post-treatment clinical trial tissue biopsies. Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Patricia A. Cash, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Rana Richeh, Christopher A. Kerfoot. Optimization of an assay for the detection of phosphorylated FAK by immunohistochemistry in formalin-fixed, paraffin-embedded human tissue and cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3745. doi:10.1158/1538-7445.AM2014-3745

BACKGROUND Archival formalin fixed paraffin embedded (FFPE) tissues are an excellent and abundant source of human cancer and normal tissues, useful for cancer research and diagnosis. Moreover, FFPE tissue microarrays enable analysis of hundreds of samples from many different patients on the same slide. Super resolution microscopes have been used for cancer tissue imaging; however, these methods are expensive and require long recording times, limiting their usefulness for the cancer research community. Recently, a new approach (Expansion Microscopy) was developed to enable physical magnification and high resolution imaging of cell lines and fresh-frozen (and fixed) mouse brain with conventional microscopes (Chen F, Tillberg PW, Boyden ES, 2015, Science 347:543-548). In the current study, we developed expansion microscopy for expanding and imaging formalin fixed paraffin embedded normal and cancer human tissues, both in tissue microarrays and whole tissue slides. METHODS Expansion microscopy (ExM) physically magnifies tissue samples by embedding them in a dense swellable polymer, anchoring key biomolecules to the polymer mesh, and adding water to swell the polymer. ExM physically magnifies the brain tissue with nanoscale isotropy and a post-expansion measurement error of 2-4%. Proteins can also be visualized by a modified immunofluorescence assay (Chen F et al., Science, 2015). In the present study, we optimized the ExM chemistry, labeling, and imaging methodologies to enable ExM to be used in cancer research and diagnosis, for morphological and protein imaging and analysis of both tissue microarrays and whole tissue slides on a wide variety of human tissues. Nuclei were detected by DAPI, and protein markers, including those of stroma (vimentin) and epithelium (keratins), were detected using immunofluorescence. RESULTS and CONCLUSIONS We developed ExM protocols to enable expansion of human normal and cancer tissues ∼4.5x in linear dimension, with a post-expansion measurement error of 5% or less. We successfully expanded normal and cancer human FFPE tissue microarrays containing over eight different tissue origins, including breast, prostate, lung, colon, pancreas and ovary. We expanded fresh frozen tissue samples of normal and cancer tissues. Our method makes possible the use of ExM on routinely collected FFPE pathology samples, enabling super resolution optical investigation of morphology and protein expression/localization in tissue microarrays with conventional fluorescent microscopy. Future applications include both large-scale retrospective and prospective studies of carcinogenesis in clinical tissue samples. * Yongxin Zhao and Octavian Bucur contributed equally; # Edward Boyden (esb@media.mit.edu) and Andrew H. Beck are corresponding authors (abeck2@bidmc.harvard.edu); Citation Format: Octavian Bucur, Yongxin Zhao, Edward Boyden, Andrew H. Beck. Physical expansion of tissue microarrays for high-resolution imaging of normal and cancer samples with conventional microscopy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4229.

Fluorescence spectrum is known to be a sensitive tool for detecting microscopic changes in the environment of fluorophores. Steady state fluorescence spectroscopy has been utilized to probe the environment of these molecules in normal and diseased skin human tissue. For fluorescence polarization spectroscopy of human skin tissues, the sample were excited with a plane polarized 50mW argon ion laser operated at 488 nm and the luminescence spectra were recorded after passing through an analyzer. The spectra were recorded with SPEX 1877E triplemate attached with a cooled PMT and DM3000R data acquisition system. The polarized fluorescence spectra of cancerous human skin tissue is different from normal human tissue. The maxima of the spectra of normal and cancerous human tissue are located around 540 nm and 530 nm respectively. The main feature of the computed anisotropy at different wavelengths is the higher value of degree of anisotropy of cancerous tissue compared to the normal counterpart. Higher degree of anisotropy of cancerous tissue may imply that the fluorophores are more tightly bound to proteins or are in a more viscous environment.

Identification of a new organic anion transporting polypeptide 1B3 mRNA isoform primarily expressed in human cancerous tissues and cells

A truncated naturally occurring variant of the human receptor P2X7 was identified in cancer cervical cells. The novel protein (P2X7-j), a polypeptide of 258 amino acids, lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the full-length P2X7 receptor. The P2X7-j was expressed in the plasma membrane; it showed diminished ligand-binding and channel function capacities and failed to form pores and mediate apoptosis in response to treatment with the P2X7 receptor agonist benzoyl-ATP. The P2X7-j interacted with the full-length P2X7 in a manner suggesting heterooligomerization and blocked the P2X7-mediated actions. Interestingly, P2X7-j immunoreactivity and mRNA expression were similar in lysates of human cancer and normal cervical tissues, but full-length P2X7 immunoreactivity and mRNA expression were higher in normal than in cancer tissues, and cancer tissues lacked 205-kDa P2X7 immunoreactivity suggesting lack of P2X7 homo(tri)-oligomerization. These results identify a novel P2X7 variant with apoptosis-inhibitory actions, and demonstrate a distinct regulatory property for a truncated variant to antagonize its full-length counterpart through hetero-oligomerization. This may represent a general paradigm for regulation of a protein function by its variant.

1132 Background: Routine intra-operative distinction between normal breast tissue and tumor is currently not possible in breast conserving surgery (BCS). This limitation affects the success of surgery, resulting in up to 40% requiring more than one operative procedure. Desorption electrospray ionization mass spectrometry (DESI MS) has been successfully used to discriminate between normal and cancerous human tissues from anatomical sites such as the liver and brain. The aim of this proof of concept study was to determine the feasibility of using DESI MS imaging for tissue identification and differentiation of breast cancer versus normal tissue. Methods: DESI MS imaging was carried out on 14 human invasive breast cancer samples. Breast cancer and adjacent normal paired human tissue sections (margin of tumor, 2cm and 5 cm from tumor) from 14 patients undergoing mastectomy were flash frozen in liquid nitrogen, sectioned, and thaw mounted to glass slides. All samples were imaged using DESI MS at 200 μm imaging resolution. DESI MS images were overlaid and compared with hematoxylin and eosin (H&E) images of the same sections. Results: Discrimination between cancer and adjacent normal tissue was achieved on the basis of the spatial distribution and varying intensities of particular fatty acids and lipid species. Several fatty acids such as oleic acid (m/z 281) and arachidonic acid (m/z 303) displayed much greater signal intensities in the cancer specimen compared to low or undetectable intensities in normal tissue. The cancer margins delineated by the DESI MS images of these molecules were consistent with H and E images of the tumor edge. Cancerous tissue was distinguished from normal tissue based on the qualitative assessment of molecular signatures and the distinction was in agreement with expert histopathology evaluation in 85% of samples. Conclusions: Our findings offer proof of concept that examination and classification of breast normal and cancer tissue by mass spectrometry imaging is highly accurate. The results are encouraging for development of a MS-based method that could be utilized intra-operatively for rapid detection of residual cancer tissue in the lumpectomy bed in BCS.

With the recent advancements in internet facilities, selection of effective keywords has now become an easy task.[1] These keywords help in indexing published literature in a journal. The success of any published literature depends on the number of citations of an article. A wise selection of keywords by the authors help in the wider dissemination of an article. Medical Subject Headings (MeSH) are standardised keywords present in the MeSH database to index articles in MEDLINE/PubMed.[2] The MeSH database is a vocabulary thesaurus developed by the National Library of Medicine (NLM) for indexing articles in PubMed.[3] MeSH terms provide information on the content of an article. Changes in medical terminology in published literature is reflected by MeSH headings which are regularly updated by the NLM. Four terms are included in the MeSH vocabulary. These are MeSH headings, subheadings, supplementary concept records (SCR) and publication type. The concept mentioned in biomedical literature is called 'MeSH headings' (descriptors). Attached to the MeSH headings are 'subheadings' (qualifiers) that clearly describe a definite aspect of a concept. Chemicals, drugs, and rare diseases are labelled as 'SCR'. 'Publication type' describes the type of research that is indexed. The next question that arises in the mind of the researcher is to how to search for MeSH keywords on the PubMed database. Currently, authors use mainly three methods to search for said keywords: first, using the MeSH browser; second, using MeSH keywords from the selected PubMed articles; and third, using the MeSH on Demand tool. In the MeSH browser method, you can open the PubMed home page and then look for 'Explore' or 'More Resources' and click on the MeSH database link. The window showing the word 'MeSH' on the left-hand side of the ribbon will be seen. From here, look for the horizontal panel where you can type words for direct search of MeSH terms. You can type any word related to your research; for example, you can type in 'nerve block' and then click on 'Search'. The next page will show the definition of the word that was typed (if it is a PubMed MeSH keyword), or else it will suggest an existing MeSH keyword to you.[4] The second method for finding MeSH keywords in PubMed is to open an abstract of the relevant article and look below the abstract for MeSH terms. It will show all of the MeSH terms related to that article. The third method involves the MeSH on Demand tool in which you can copy and paste up to 10,000 characters. Following this, MeSH terms are highlighted using natural language processing and the NLM Medical Text Indexer. This method assists authors in looking up MeSH keywords even without having done the MeSH indexing or even in looking up any downloads of MeSH for the article. You can start by pasting the link (https://meshb.nlm.nih.gov /MeSHonDemand) on the browser to open MeSH on Demand. After copying and pasting the concerned text or abstract, press the button that reads 'Find MeSH term'. All MeSH terms will be highlighted in the paragraph and a list of ranked MeSH words or an alphabetical list of MeSH terms will be displayed on the right side of the screen.[5] The impact of using MeSH terms for keywords in publications are that it increases the scientific visibility of the article and its chances of it being retrieved by authors who are performing a literature search for relevant topics.[6] The MeSH database has a hierarchy or tree structure because of which both broader and more specific searches yield better results.[7,8] The terms are annually updated in the English language to reflect changes in terminology and account for variations in language, synonyms, and alternate spellings. MeSH terms provide a universal article labelling system. The official words or phrases that are labelled as MeSH terms represent a particular biomedical concept in MEDLINE. The official MeSH list provides terms for indexers to label an article. This particularly helps in locating an article specific to a topic. Efficient search is facilitated by MeSH terms. If MeSH terms are not used as keywords by authors and the journal does not insist on its use, this leads to poor visibility of the article, thereby reducing the chances of the article being cited. The impact of this is dual: for the author, there are less chances of their paper being cited and them being recognised and acknowledged for their research; and for the journal, there is a lower impact factor. The impact factor is calculated by the number of articles that are cited from the journal in the last two years.[9] The MeSH browser has certain limitations.[10] One may not be able to retrieve an article that was recently published and that is yet to be indexed on MEDLINE due to the short lag time between the citations that are entered into the PubMed database and their description with MeSH terms. As MeSH terms are not available for most genes, it is difficult to find research topics with gene names. MeSH terms may not be added to the latest emerging research. The articles are also difficult to retrieve if they are not indexed for MEDLINE. For any further questions or queries regarding PubMed MeSH keywords, the authors can send them to at [email protected]

Resources currently available to the scientific community that may be of interest for endocrinology research are described briefly here. More information is available through The Endocrine Society Home Page (http://www.endo-society.org) or the information provided below. HUMAN TISSUE AND BIOLOGIC SPECIMEN RESOURCES NCI - Cooperative Human Tissue Network (CHTN) The NCI Cooperative Human Tissue Network (CHTN) provides normal, benign, precancerous, and cancerous human tissue to the scientific community for biomedical research. Specimens are collected according to the investigator’s individual protocol. Information provided with the specimens includes routine histopathologic and demographic data. The CHTN can also provide a variety of tissue microarrays. Contact the CHTN Web site at http://www-chtn.ims.nci.nih.gov, or 1-866-GO2-CHTN (1-866-462-2486). NCI - Cooperative Breast Cancer Tissue Resource (CBCTR) The NCI Cooperative Breast Cancer Tissue Resource (CBCTR) can provide researchers with access to formalin-fixed, paraffin-embedded primary breast cancer specimens, with associated pathologic, clinical, and outcome data. All specimens are evaluated for pathologic diagnosis by CBCTR pathologists using standard diagnostic criteria. The collection is particularly well suited for validation studies of diagnostic and prognostic markers. The CBCTR also makes available breast cancer tissue microarrays designed by NCI statisticians to provide high statistical power for studies of stage-specific markers of breast cancer. Contact CBCTR’s Web site at http://cbctr.nci.nih.gov, or contact Steve Marroulis at Information Management Services, Inc.: telephone: (301) 680-9770; e-mail: marrouliss@imsweb.com NCI - Cooperative Prostate Cancer Tissue Resource (CPCTR) The NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) can provide access to over 4,000 cases of formalin-fixed, paraffin-embedded primary prostate cancer specimens, with associated pathology and clinical data. Fresh-frozen tissue is also available with limited clinical follow-up information. In addition, slides from prostate cancer tissue microarrays with associated pathology and clinical data are now available. Contact the CPCTR Web site at http://www.prostatetissues.org, or contact Steve Marroulis at Information Management Services, Inc.: telephone: (301) 680-9770; e-mail: marrouliss@imsweb.com NCI - AIDS and Cancer Specimen Resource (ACSR) The AIDS and Cancer Specimen Resource (ACSR) provides qualified researchers with tissue, cell, blood, and fluid specimens, as well as clinical data from patients with AIDS and cancer. The specimens and clinical data are available for research studies, particularly those that translate basic research findings to clinical application. Contact the ACSR Web site (http://acsr.ucsf.edu/) or Dr. Kishor Bhatia, (301) 496-7147; e-mail: bhatiak@mail.nih.gov NCI - Breast and Ovarian Cancer Family Registries (CFRs) The Breast and Ovarian CFRs facilitate and support interdisciplinary and population-based research on the identification and characterization of breast and ovarian cancer susceptibility genes, with particular emphasis on gene-gene and gene-environment interaction research. Available from the registries are: a) family history, epidemiologic and clinical data, b) updates on cancer recurrence, morbidity and mortality in participating families, and c) biospecimens, including plasma, lymphocytes, serum, DNA, Guthrie cards or buccal smears, and paraffin blocks of tumor tissue. For further information on these registries, contact the CFR Web site (http://epi.grants.cancer.gov/BCFR) or (301) 496-9600. NCI - Specimen Resource Locator The NCI Specimen Resource Locator (http://cancer.gov/specimens) is a database that helps researchers locate specimens for research. The database includes resources such as tissue banks and tissue procurement systems with access to normal, benign, precancerous, and/or cancerous human tissue covering a wide variety of organ sites. Researchers specify the types of specimens, number of cases, preservation methods, and associated data they require. The Locator will search the database and return a list of tissue resources most likely to meet their requirements. When no match is obtained, the researcher is referred to the NCI Tissue Expediter [(301) 496-7147; e-mail: tissexp@mail.nih.gov]. The Tissue Expediter is a scientist who can help match researchers with appropriate resources or identify appropriate collaborators when those are necessary. NIDDK - Biologic Samples from Diabetic Study Foundation A portion (1/3) of all stored nonrenewable samples (plasma, serum, urine) from subjects enrolled in the Diabetes Control and Complications Trial (DCCT) is available for use by the scientific community to address questions for which these samples may be invaluable. Announcements for using this resource appear in the NIH Guide for Grants and Contracts periodically. Inquiries may be addressed to: Catherine C. Cowie, Ph.D., Director, Diabetes Epidemiology Program, NIDDK, 6707 Democracy Blvd., Room 691, MSC 5460, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892-5460. Phone: (301) 594-8804; fax: (301) 480-3503; e-mail: cowiec@extra.niddk.nih.gov NIDDK - NIDDK Central Repositories (Diabetes Prevention Study) The NIDDK Central Repositories have selected biosamples from the DPT-1 (The Diabetes Prevention Type 1) study that are available to qualified investigators through an application process. These samples are supplied for research purposes only, not for therapeutic, diagnostic, or commercial uses. Information about how to apply for these materials can be obtained from the NIDDK Central Repositories by contacting Ms. Helen Ray of RTI, 1-919-316-3418, or hmp@rti.org. Direct scientific-technical inquiry to the Project Officer of the NIDDK Central Repositories, Dr. Rebekah Rasooly, at phone: (301) 594-6007; e-mail: rr185i@nih.gov Visit the Repositories Web site at http://www.niddkrepository.org. NICHD - Brain and Tissue Bank for Developmental Disorders The purpose of the Bank is to collect, preserve, and distribute human tissues to investigators interested in autism and developmental disorders; normal tissues may be available for other research purposes. Further information can be obtained at www.btbank.org. The contact persons are H. Ron Zielke or Sally Wisniewsky, University of Maryland (1-800-847-1539), and Carol Petito or Stephanie Lojko, University of Miami (1-800-592-7246). NICHD - Reproductive Tissue Sample Repository (RTSaR) The Reproductive Tissue Sample Repository (RTSaR) is a virtual repository with online tissue sample acquisition capabilities. The RTSaR provides investigators with real-time access to human and nonhuman primate tissue and fluid inventories from four tissue bank facilities that are supported through the Specialized Cooperative Centers Program in Reproduction Research. The tissue banks are located at the University of California, San Diego (human ovary bank), Stanford University (human endometrium and DNA bank), Johns Hopkins University (male reproductive tissues and fluids), and the Oregon National Primate Research Center (nonhuman primate tissues). The web site for the RTSaR is https://rtsar.nichd.nih.gov/rtsar/login. If you wish to access the RTSaR, you can request an id and password to access the system by contacting the network administrator at RTSaR@mail.nih.gov Once you access the system, contact information for each bank is provided. Access is open to all investigators living in North America who are supported by research and research training grants from the NIH. One id and password will be provided to each principal investigator that can be utilized by any person working in the P.I.’s laboratory, or, in the case of institutional training grants (T32) and institutional career development award programs (K12), any person supported by the aforementioned awards. NCRR - Human Tissues and Organs Resource (HTOR) The Human Tissues and Organs Resource (HTOR) cooperative agreement supports a procurement network developed by the National Disease Research Interchange (NDRI), a not-for-profit organization. By collaborating with various medical centers, hospitals, pathology services, eye banks, tissue banks, and organ procurement organizations, HTOR provides a wide variety of human

Development of synchrotron, synchrocyclotron and LASER radiations increased significantly in human cancer cells, tissues and tumors that led to their effective of attention to the creation of human cancer cells, tissues and tumors treatment trend. The best methods and techniques for decreasing human cancer cells, tissues and tumors is investigation of energy production by synchrotron, synchrocyclotron and LASER radiations in human cancer cells, tissues and tumors and evaluation of their effective on human cancer cells, tissues and tumors treatment trend. To achieve this goal, according to the studies by factors in the process such as pH, temperature and retention time, among the systems were used for this purpose, single–stage systems under synchrotron, synchrocyclotron and LASER radiations possesses higher efficiency. In the conversion process of the system, human benign cancer cells, tissues and tumors were produced with efficiency 99% in total.

Endocrine-Related Resources from the National Institutes of Health

Resources currently available to the scientific community that may be of interest for endocrinology research are described briefly here. More information is available through The Endocrine Society Home Page (http://www.endo-society.org) or the information provided below. Human Tissue and Biologic Specimen Resources NCI - Cooperative Human Tissue Network (CHTN) The NCI Cooperative Human Tissue Network (CHTN) provides normal, benign, precancerous, and cancerous human tissue to the scientific community for biomedical research. Specimens are collected according to the investigator’s individual protocol. Information provided with the specimens includes routine histopathologic and demographic data. The CHTN can also provide a variety of tissue microarrays. Contact the CHTN Web site at http://www-chtn.ims.nci.nih.gov, or 1-866-GO2-CHTN (1-866-462-2486). NCI - Cooperative Breast Cancer Tissue Resource (CBCTR) The NCI Cooperative Breast Cancer Tissue Resource (CBCTR) can provide researchers with access to formalin-fixed, paraffin-embedded primary breast cancer specimens, with associated pathologic, clinical, and outcome data. All specimens are evaluated for pathologic diagnosis by CBCTR pathologists using standard diagnostic criteria. The collection is particularly well suited for validation studies of diagnostic and prognostic markers. The CBCTR also makes available breast cancer tissue microarrays designed by NCI statisticians to provide high statistical power for studies of stage-specific markers of breast cancer. Contact CBCTR’s Web site at http://cbctr.nci.nih.gov, or contact Steve Marroulis at Information Management Services, Inc.: telephone: (301) 680-9770;marrouliss@imsweb.com. NCI - Cooperative Prostate Cancer Tissue Resource (CPCTR) The NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) can provide access to over 4,000 cases of formalin-fixed, paraffin-embedded primary prostate cancer specimens, with associated pathology and clinical data. Fresh-frozen tissue is also available with limited clinical follow-up information. In addition, slides from prostate cancer tissue microarrays with associated pathology and clinical data are now available. Contact the CPCTR Web site at http://www.prostatetissues.org, or contact Steve Marroulis at Information Management Services, Inc.: telephone: (301) 680-9770;marrouliss@imsweb.com. NCI - AIDS and Cancer Specimen Resource (ACSR) The AIDS and Cancer Specimen Resource (ACSR) provides qualified researchers with tissue, cell, blood, and fluid specimens, as well as clinical data from patients with AIDS and cancer. The specimens and clinical data are available for research studies, particularly those that translate basic research findings to clinical application. Contact the ACSR Web site (http://acsr.ucsf.edu/) or Dr. Kishor Bhatia, (301) 496-7147;bhatiak@mail.nih.gov. NCI - Breast and Ovarian Cancer Family Registries (CFRs) The Breast and Ovarian CFRs facilitate and support interdisciplinary and population-based research on the identification and characterization of breast and ovarian cancer susceptibility genes, with particular emphasis on gene-gene and gene-environment interaction research. Available from the registries are: a) family history, epidemiologic and clinical data, b) updates on cancer recurrence, morbidity and mortality in participating families, and c) biospecimens, including plasma, lymphocytes, serum, DNA, Guthrie cards or buccal smears, and paraffin blocks of tumor tissue. For further information on these registries, contact the CFR Web site (http://epi.grants.cancer.gov/BCFR) or (301) 496-9600. NCI - Specimen Resource Locator The NCI Specimen Resource Locator (http://cancer.gov/specimens) is a database that helps researchers locate specimens for research. The database includes resources such as tissue banks and tissue procurement systems with access to normal, benign, precancerous, and/or cancerous human tissue covering a wide variety of organ sites. Researchers specify the types of specimens, number of cases, preservation methods, and associated data they require. The Locator will search the database and return a list of tissue resources most likely to meet their requirements. When no match is obtained, the researcher is referred to the NCI Tissue Expediter [(301) 496-7147;tissexp@mail.nih.gov]. The Tissue Expediter is a scientist who can help match researchers with appropriate resources or identify appropriate collaborators when those are necessary. NIDDK - Biologic Samples from Diabetic Study Foundation A portion (1/3) of all stored nonrenewable samples (plasma, serum, urine) from subjects enrolled in the Diabetes Control and Complications Trial (DCCT) is available for use by the scientific community to address questions for which these samples may be invaluable. Announcements for using this resource appear in the NIH Guide for Grants and Contracts periodically. Inquiries may be addressed to: Catherine C. Cowie, Ph.D., Director, Diabetes Epidemiology Program, NIDDK, 6707 Democracy Blvd., Room 691, MSC 5460, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892-5460. Phone: (301) 594-8804; fax: (301) 480-3503;cowiec@extra.niddk.nih.gov. NIDDK - NIDDK Central Repositories (Diabetes Prevention Study) The NIDDK Central Repositories have selected biosamples from the DPT-1 (The Diabetes Prevention Type 1) study that are available to qualified investigators through an application process. These samples are supplied for research purposes only, not for therapeutic, diagnostic, or commercial uses. Information about how to apply for these materials can be obtained from the NIDDK Central Repositories by contacting Ms. Helen Ray of RTI, 1-919-316-3418, or hmp@rti.org. Direct scientific-technical inquiry to the Project Officer of the NIDDK Central Repositories, Dr. Rebekah Rasooly, at phone: (301) 594-6007;rr185i@nih.gov. Visit the Repositories Web site at http://www.niddkrepository.org. NICHD - Brain and Tissue Bank for Developmental Disorders The purpose of the Bank is to collect, preserve, and distribute human tissues to investigators interested in autism and developmental disorders; normal tissues may be available for other research purposes. Further information can be obtained at www.btbank.org. The contact persons are H. Ron Zielke or Sally Wisniewsky, University of Maryland (1-800-847-1539), and Carol Petito or Stephanie Lojko, University of Miami (1-800-592-7246). NICHD - Reproductive Tissue Sample Repository (RTSaR) The Reproductive Tissue Sample Repository (RTSaR) is a virtual repository with online tissue sample acquisition capabilities. The RTSaR provides investigators with real-time access to human and nonhuman primate tissue and fluid inventories from four tissue bank facilities that are supported through the Specialized Cooperative Centers Program in Reproduction Research. The tissue banks are located at the University of California, San Diego (human ovary bank), Stanford University (human endometrium and DNA bank), Johns Hopkins University (male reproductive tissues and fluids), and the Oregon National Primate Research Center (nonhuman primate tissues). The web site for the RTSaR is https://rtsar.nichd.nih.gov/rtsar/login. If you wish to access the RTSaR, you can request an id and password to access the system by contacting the network administrator at RTSaR@mail.nih.gov. Once you access the system, contact information for each bank is provided. Access is open to all investigators living in North America who are supported by research and research training grants from the NIH. One id and password will be provided to each principal investigator that can be utilized by any person working in the P.I.’s laboratory, or, in the case of institutional training grants (T32) and institutional career development award programs (K12), any person supported by the aforementioned awards. NCRR - Human Tissues and Organs Resource (HTOR) The Human Tissues and Organs Resource (HTOR) cooperative agreement supports a procurement network developed by the National Disease Research Interchange (NDRI), a not-for-profit organization. By collaborating with various medical centers, hospitals, pathology services, eye banks, tissue banks, and organ procurement organizations, HTOR provides a wide variety of human tissues and organs—both diseased and normal—to r