Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity

Lung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base

Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions

Strongly exchange-coupled triplet pairs in an organic semiconductor

From biological complexes to devices based on organic semiconductors, spin interactions play a key role in the function of molecular systems. For instance, triplet-pair reactions impact operation of organic light-emitting diodes as well as photovoltaic devices. Conventional models for triplet pairs assume they interact only weakly. Here, using electron spin resonance, we observe long-lived, strongly-interacting triplet pairs in an organic semiconductor, generated via singlet fission. Using coherent spin-manipulation of these two-triplet states, we identify exchange-coupled (spin-2) quintet complexes co-existing with weakly coupled (spin-1) triplets. We measure strongly coupled pairs with a lifetime approaching 3 µs and a spin coherence time approaching 1 µs, at 10 K. Our results pave the way for the utilization of high-spin systems in organic semiconductors.Gates-Cambridge Trust, Winton Programme for the Physics of Sustainability, Freie Universität Berlin within the Excellence Initiative of the German Research Foundation, Engineering and Physical Sciences Research Council (Grant ID: EP/G060738/1)This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nphys3908

A REPORT ON THE STATUS OF GAS LUBRICATION FOR TURBOMACHINERY

A discussion is presented concerning the reasons why gas bearings are being used in specialized turbomachinery. An outline of the factors that must be considered in bearing selection and design is included. Gas bearing limitations and problem areas are examined. (J.R.D.

HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can behave as a tumor suppressor, by pushing the cells towards epithelial differentiation.Landspitali University Hospital Science Fund, University of Iceland Research Fund, Science and Technology Policy Council Research Fund and Grant of Excellence, ‘Göngum saman’, a supporting group for breast cancer research in Iceland

Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion

Background Stromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion. Methods Primary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided. Results Tumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04). Conclusion This study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively

The Midwest Quarterly; Vol. 9 No. 4

in this issue. . . DURING TIMES of incessant change any practice or custom that maintains itself for as long as six years may fairly claim to be a hallowed tradition. Just such a tradition THE MIDWEST QUARTERLY is building for itself with this sixth Summer Literary Number. Not that we ever wholly close our pages to a good study of literature at other seasons of the year, and not that our literary number involves any really basic difference from the other three quarterly issues. The emphasis, the approach, may vary somewhat, but all four issues are alike concerned with the quality of life in our own times. Superficially the contents of the present number, ranging in subject from Henry James and Andre Gide through Aldous Huxley and William Carlos Williams and William Golding down to the leading American novelists of the present decade, may seem to vary widely and to have little in common other than their contemporaneity. Closer inspection reveals that one and all are probing the quality of this contemporary life. THE COMMON THEME is explicitly stated in the opening sentences of our opening article, William Carlos Williams: The Leech-Gatherer of Paterson. Author THOMAS W. LOMBARDI says that Williams, like Wordsworth\u27s ancient leech-gatherer, fixedly did look upon the muddy water of his own Passaic River in search of a cure for the ills of our present life and that he found this cure once more in the willingness of one man to endure, to remain in place, to deal with evils rather than to flee them. Assistant Professor Lombardi teaches English at the University of Massachusetts, Amherst, and would seem to have an abiding interest \u27in the work of that unlikely leech-gatherer, George Gordon Lord Byron. A recent article, Byron\u27s Letters,” appeared in the January 1967 Bulletin of the New York Public Library; an article entitled Byron\u27s Hebrew Melodies is forthcoming in the Keats-Shelley Journal; and his critical edition of Byron\u27s lyrics will be published in London this year. An article on Samuel Beckett in the Spring 1968 Chelsea Review and the present study of Williams\u27 Paterson suggest promising new interests. ALTHOUGH his work is pervaded by anxiety for the destiny of man, Aldous Huxley retained, or perhaps achieved, a desperate hope that man might still prevail over his technology and restore a sense of meaning and significance to his life. The cynical pessimism of Brave New World, the despairing nihilism of Ape and Essence, yield to the more hopeful vision of his final utopia, Island. This change of attitude may be partially accounted for by a greater interest in and respect for the spirituality and mysticism of Indian thought. Appropriately this study of the parallels between Huxley\u27s ideas and Indian philosophy comes to us from India. Both of our authors are associated with the University of Rajasthan at Jaipur. G. S. P. MISRA received his M.A. in ancient history and archaeology at the University of Gorakhpur in 1962 and his Ph. D. at the University of Rajasthan in 1966. His publications, largely concerned with Buddhist philosophy and religion, have appeared in such Indian journals as Quest, Indian Antiquary, Journal of the Gujarat Research Society, and others. A paper entitled Logical and Scientific Method in Early Buddhism will shortly appear in the Journal of the Royal Asiatic Society of Great Britain and Ireland. At present he is teaching in the Department of History and Indian Culture at the University of Rajasthan. NORA SATIN received her M.A. in English at the University of Rajasthan in 1965 and is now working toward a doctorate, with a study of India in modern English fiction, particularly in the writing of Kipling, Forster, and Huxley. IF TIIE BASIC PROBLEM of the American novel in the sixties is one of diversity, of finding a link among such diverse writers as Nabokov, Cheever, Bellow, Mailer, Michener, and others, it might be supposed that no common theme existed. Yet a reader of our study of the current American novel soon finds himself on uncomfortably familiar ground with references to a growing spirit of despair and resignation,” to a time of anxiety, alienation, sexual frustration, to the human psyche, abused and bewildered, to a solipsistic and anarchical reaction against the world. It is the dismaying world that we have already explored with Aldous Huxley and William Carlos Williams. Our young author, MICHAEL R. FRENCH, took his B. A. in creative writing at Stanford University as recently as 1966. He now has the M. S. in journalism from Northwestern University, has won several prizes for his fiction, including first prize in the 1966 national Alpha Delta Phi contest, has published in the Stanford Workshop and Daily, and is currently writing his own novel for the sixties. SOCIOLOGISTS might question the propriety of selecting little boys to enact the fall of man on the ground that preadolescent boys could not fall from a grace to which they had never risen, but the astonishing appeal of Golding\u27s Lord of the Flies to high school and college youth would suggest some special meaning for late adolescence at least, and critics in general have found in the novel either a Wordsworthian or a Freudian loss of childhood innocence. Taking a different tack, SANFORD STERNLICHT juxtaposes Lord of the Flies with Golding\u27s later work The Inheritors and comes to a different interpretation. Professor Sternlicht made his first contribution to the QUARTERLY as a poet, most recently in the October 1965 issue. Since that time he has been Leverhulme Visiting Fellow in the University of York, England (1965-66), has brought out a new book of poetry, Love in Pompeii, and has had several articles published or scheduled for publication in such journals as College English, Minnesota Review, Studies in Language and Literature, and others. He teaches English at State University College, Oswego, New York. LOSS OF INNOCENCE, as its title suggests, is the theme of What Maisie Knew, Henry James\u27 study of a small girl tossed back and forth between brutal or psychopathic parents, then between the latter\u27s somewhat kinder new spouses, until abandoned at last to the inadequate care of an ignorant though well-meaning \u27\u27governess. In no other work, according to ABIGAIL ANN HAMBLEN, does James show more forcefully the amoral power and destructiveness of unqualified raw sex. Mrs. Hamblen is another former contributor, her study of Faulkner appearing in our July 1965 issue and a study of Pamela Moore in the July 1966 issue. Most recently her work has appeared in Trace, the Mark Twain Journal, The University Review, and Forum. She has also published a study of Mary E. Wilkins Freeman. EXAMINING the treatment of sickness, death, and responsibility by Andre Gide and Henry James, ROBERT ABEL comes to the surprising though persuasive conclusion that Gide is the romantic and James the modem man. His argument is too closely and carefully reasoned for summary treatment here; it invites thoughtful reading. Mr. Abel took his M. A. degree at Kansas State College and was until recently an instructor in our English Department. He now lives in Cincinnati, where he is engaged in writing and research. THE TEN AUTHORS of our usual dozen poems divide rather neatly into five old contributors and five new. In number of poems the newcomers have a slight advantage, but in warmth of welcome the QUARTERLY makes no difference. As to seniority, MENKE KATZ is by some years our oldest contributor, with poems as early as October 1962 and as late as last October. Resident of Brooklyn, genial editor of Bitterroot, author of many volumes of verse in Yiddish and English, he has been honored with translation into Japanese and Greek and will shortly appear in an African tongue and in a Hindu dialect, not to forget earlier translation into Italian, Czech, Hebrew, and French. A happy diaspora, we assure him, and are his debtors for a copy of his Twelve Poems translated into Japanese (fourth edition). May our poets continue to travel to the ends of the earth. . . . Second in order of seniority, MARGARET BARBRICK PURCELL also strikes the Oriental note with a poem about the famous woman painter Ch\u27ên Shu. In a letter just received she writes of girlhood memories of Bermuda--Shakespeare\u27s “still-vex\u27d Bermoothes --which she was planning to revisit, when unhappily the newspapers reported that they were vex\u27 d once more. Several of her poems appeared in earlier issues of the journal, beginning with October 1964. . . . It is a second appearance for NANCY PRICE (Mrs. H. J. Thompson), who writes that she is still teaching English at the University of Northern Iowa, still working on her doctorate at the State University of Iowa, and still publishing poetry -- most recently in Atlantic Monthly, Nation, McCalls, The Ladies Home Journal, and others. WESLEY WALTON appears for the second time, and he also sends us a sheaf of translations of his poems into the Japanese literary magazine Hyo Heki. He is working on a doctorate at Johns Hopkins University, where he has just been granted an Arts and Science Fellowship for the coming year. . . . Rounding out our first group is that very recent old contributor, SONYA DORMAN, whose work appeared in our April issue. COMING to our new poets, COLETTE INEZ has contributed poems to Prairie Schooner, Nation, Antioch Review, and a number of the littles. Born in Belgium shortly before World War II, she escaped from bomb shelters to rural Long Island at the outbreak of war. Recently she has been teaching English in the Poverty Program to a lovely class of Cuban, Chinese and Puerto Rican ladies. . . . IRENE DAYTON (Mrs. Benjamin B.) of Rochester, New York, began publishing poetry at thirteen and has continued publishing it in poetry journals and literary magazines over the United States, Europe, Australia, and Japan. She has received numerous awards and distinctions, has traveled widely, and speaks with pride of a physicist-husband and two sons. . . . Our third newcomer, IVAN DOIG, has only recently begun to write poetry after several years of editorial work and free-lance journalism. He has a B. S. and an M. S. in journalism from Northwestern University and is now working on a doctorate in American history at the University of Washington. . . . ALASTAIR MACDONALD, British by birth, holds the M.A. from Aberdeen, the B. Litt. from Oxford (Christ Church), and the Ph.D. from the University of Manchester. He is an associate professor in the English Department of Memorial University, St. John\u27s, Newfoundland, Canada. He began writing poetry as recently as 1966 and has had poems published in The University Review, Twentieth Century, Canadian Forum, and a number of other journals. He has also published various scholarly articles and reviews and is now preparing an edition of Thomas Gray\u27s prose for the Oxford Clarendon Press and the volume on Gray for Routledge\u27s Critical Heritage series. . . . The (alphabetical) last of our new poets is O. HOWARD WINN, an alumnus of Stanford with an advanced degree from its Creative Writing Center. He is now teaching English at Dutchess Community College of the State University of New York at Poughkeepsie. His poems have appeared in Laurel Review and Quartet

Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis

Part of how the mammary gland fulfills its function of producing and delivering adequate amounts of milk is by forming an extensive tree-like network of branched ducts from a rudimentary epithelial bud. This process, termed branching morphogenesis, begins in fetal development, pauses after birth, resumes in response to estrogens at puberty, and is refined in response to cyclic ovarian stimulation once the margins of the mammary fat pad are met. Thus it is driven by systemic hormonal stimuli that elicit local paracrine interactions between the developing epithelial ducts and their adjacent embryonic mesenchyme or postnatal stroma. This local cellular cross-talk, in turn, orchestrates the tissue remodeling that ultimately produces a mature ductal tree. Although the precise mechanisms are still unclear, our understanding of branching in the mammary gland and elsewhere is rapidly improving. Moreover, many of these mechanisms are hijacked, bypassed, or corrupted during the development and progression of cancer. Thus a clearer understanding of the underlying endocrine and paracrine pathways that regulate mammary branching may shed light on how they contribute to cancer and how their ill effects might be overcome or entirely avoided

An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema

BACKGROUND: Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear. METHODS AND FINDINGS: We studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4(+) and CD8(+) T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma—often associated with T helper 1 cells—and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema. CONCLUSIONS: These data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon