tbuckley/cabot-search huggingface dataset:
Abstract B05: Invadopodium formation is enriched in perivascular niches and leads to cancer cell intravasation
Authors: Aviv Bergman, John Condeelis, Bojana Gligorijevic
Journal: Cancer Research (2016)

Abstract Invadopodia are actin-rich protrusions used for cancer cell movement across obstacles. In the past, they were mostly studied in cell cultures, where they form in contact with extracellular matrix. Our past work has suggested that elimination of key molecular components of invadopodia in cancer cells can lead to elimination of metastasis. In the current study, we use high resolution multiphoton microscopy to understand how the tumor microenvironment controls formation of invadopodia, followed by cancer cell locomotion, intravasation and metastasis. We demonstrate that the motile cancer cells in breast carcinoma in vivo can exhibit either invadopodium-related, slow locomotion or invadopodium-independent rapid locomotion along collagen fibers. These two phenotypes occur in spatially separate tumor regions, the location of which can be predicted from measurements of microenvironmental features. For example, cancer cells form invadopodia predominantly in perivascular niches, regions surrounding major blood vessels and characterized by cross-linked collagen fibers and dense macrophages. Invadopodia in vivo extend towards blood vessels and their density decreases with blood vessel distance. We observe that only cells with invadopodia are capable of intravasation, while fast locomotion results in cell dispersal throughout tumor. Further, either invadopodium-specific TkS5 knock-down or short-term inhibition of metalloproteases eliminate invadopodia and stop dissemination to lung. Interestingly, external modulation of collagen cross-linking also inhibits invadopodia, switching the cancer cell phenotype to fast locomotion. Our results suggest that the perivascular niche is the site of invadopodium formation and cancer cell intravasation. Moreover, invadopodia and hence metastasis, can be inhibited by external modulation of the microenvironment. In summary, the presence of invadopodia is a great candidate for a novel early-metastasis marker, while their elimination via microenvironment modulation has therapeutic potential. Citation Format: Aviv Bergman, John Condeelis, Bojana Gligorijevic. Invadopodium formation is enriched in perivascular niches and leads to cancer cell intravasation. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B05.
The American Health-Care Scene
Authors: David E. Rogers
Journal: New England Journal of Medicine (1973)

YOU do me great honor in permitting me to give the 83d Shattuck Lecture. The Massachusetts Medical Society and this lectureship have a long and distinguished record in American medicine, and I thank you.A review of the history of this lectureship since the legacy of your distinguished early president, Dr. George Cheyne Shattuck the elder, was announced to the Society in 1854 gives clear evidence of the change of pace and focus in medical affairs over the years. First, and not unique to the mid-19th century, there was considerable delay in establishing the lectureship. Indeed, a series of events . . .
PTPS-08HEMATOGENOUS DISSEMINATION OF MEDULLOBLASTOMA METASTASES TO THE LEPTOMENINGES
Authors: Livia Garzia, Noriyuki Kijima, A. Morrissy, Laura Donovan, Xiaochong Wu, Betty Luu, Vijay Ramaswamy, John Peacock, Borja Lopez-Holgado, Xin Wang, Florence Cavalli, Adi Rolider, David Shih, Patryk Skowron, John Lee, Antony Michealraj, David Malkin, Daniel Fults, Marco Marra, Michael Taylor
Journal: Neuro-Oncology (2015)

Metastatic medulloblastoma is a high-risk disease, because the majority of children dying of medulloblastoma expire from metastases rather than recurrence of the primary tumor. Current dogma dictates that medulloblastoma cells are shed from the primary tumor into the CSF, float through the spinal fluid and establish metastatic colonies on the leptomeningeal surface and spinal cord. Empirical evidence for this mechanism is lacking in the literature. Whole genome sequencing on matched trios of human primary tumor, metastases, and peripheral blood showed somatic mutations from the medulloblastoma at low clonal frequency in the blood samples — consistent with circulating tumor cells. In addition, we identified circulating tumor cells (CTC) in the blood of transgenic mice bearing metastatic medulloblastoma, and in mice intra-cranially implanted with patient derived MB. Surprisingly, when we implanted human or mouse medulloblastoma cells in the flank of immunocompromised mice, the MB cells colonized the leptomeningeal space causing death. As these MB xenografts are not in continuity with the CSF, they must have arisen through hematogenous dissemination. Importantly, flow cytometry shows that MB CTCs express CD34, the cell-surface marker used clinically in children to collect peripheral blood stem cells; suggesting that autologous bone marrow transplants from children with medulloblastoma are likely contaminated with CTCs. Finally we established a parabiosis model where two immunocompromised, sibling mice are surgically joined, and a common blood circulation is established. After parabiosis, one mouse is intra-cranially implanted with MB, and the mice are subsequently separated when the xenografted twin becomes symptomatic. The surviving twin goes on to die from leptomeningeal metastases. Our data challenge the existing paradigm of CSF mediated dissemination of medulloblastoma by demonstrating the capacity of medulloblastoma to spread through the blood system. Identification of a systemic route for MB metastases offers new avenues for the diagnosis and therapy of metastatic medulloblastoma.
Cancer Prevention and Interception: A New Era for Chemopreventive Approaches
Authors: Adriana Albini, Andrea DeCensi, Franco Cavalli, Alberto Costa
Journal: Clinical Cancer Research (2016)

At several recent, internationally attended scientific meetings, including the American Association for Cancer Research (AACR)'s "Shaping the Future of Cancer Prevention: A Roadmap for Integrative Cancer Science and Public Health" summit in Leesburg (VA) and the AACR Annual Meeting in New Orleans, the focus on cancer prevention to reduce cancer-related deaths was extensively discussed with renewed attention and emphasis. Cancer prevention should be actively proposed even to healthy individuals, and not just to individuals with high cancer risk. We discuss evaluation of a high cancer risk versus the relatively low risk for side effects of chemopreventive agents. The concept of cancer interception, which is halting transformed cells from becoming malignant cancers, should be adopted for cancer prevention. Potential prevention/interception actions include adopting healthy life style and avoiding carcinogens, repressing inflammation and pathologic angiogenesis, controlling metabolism, correcting insulin resistance and other metabolic alterations. Current drugs with limited toxicity can be repurposed to reduce cancer incidence. Aspirin is now being recommended for the prevention of colorectal cancer and it prevents other neoplasms as well. Metformin and β-blockers could be valuable for reducing pancreatic and breast cancer onset. On the basis of the evaluation of cancer risk, we here call for personalized approaches for cancer prevention and preventive interception and we envisage a list of measures and potential guidelines for preventive and interceptive strategies to reduce cancer burden. Investment into translational research to bring these approaches into public health policies and in the clinic is urgently needed. Clin Cancer Res; 22(17); 4322-7. ©2016 AACR.
Psychiatrists' life and work patterns: a statewide comparison of women and men
Authors: M Z Goldstein, E J Bromet, B H Hanusa, R L Lasell
Journal: American Journal of Psychiatry (1981)

The author systematically assessed the backgrounds, training and career experiences, and perceptions of career-marriage interactions of women and men psychiatrists in a large mid-Atlantic state. Although there were many similarities, the women differed on several sociodemographic characteristics (e.g., marital status, religious affiliation, number of children, and professional status of parents). Women also reported lower incomes than men, even when Board certification and number of hours worked were considered. In addition, compared with men, women perceived less support from their professional colleagues, and a larger proportions of married women felt that career and marriage were mutually enhancing.
Abstract IA10: Regulating transcription elongation at stimulus responsive genes
Authors: Karen Adelman, Benjamin S. Scruggs, Telmo Henriques, Adam Burkholder, David C. Fargo
Journal: Cancer Research (2016)

Abstract The majority of mammalian protein-coding genes display transcription in both sense and anti-sense directions. At such bidirectional promoters, Pol II has been shown to initiate transcription and undergo promoter-proximal pausing near both the sense-strand mRNA transcription start site (TSS) and from within the upstream region in the anti-sense direction. This enigmatic, dual promoter structure raises fundamental questions about the specificity, purpose and regulation of upstream anti-sense transcription. Interestingly, transcription in the anti-sense direction is generally non-processive and creates short, unstable non-coding RNAs (ncRNAs). Intriguingly, many distal enhancer regions display bidirectional transcription and generate short unstable ncRNAs, raising parallels between enhancers and anti-sense promoters near protein-coding genes. Importantly, enhancers and upstream anti-sense promoters show exquisite cell type specificity in their location and activity, suggesting key roles in establishing cell state and behavior. Further, perturbation of either transcription or chromatin structure at such non-coding loci has been implicated in the development of cancer and disease, with a profound impact on maintenance of cell state and responsiveness to stimuli. These recent findings raise a number of intriguing questions about the communication between promoters and non-coding loci. Our work has recently defined a mechanism through which upstream anti-sense transcription impacts stimulus-responsive gene expression. Specifically, we found that the distance between sense and anti-sense TSSs at bidirectional promoters strongly influences activation of pro-inflammatory genes in macrophages. We discovered that anti-sense TSSs organize chromatin structure, creating a region of open chromatin between bidirectional TSSs that is optimal for recruitment of the transcription machinery and signal-dependent transcription factors like NF-kB. Further, we discovered that key inflammatory genes possess enhancer-like histone modifications around the anti-sense TSS, and that this characteristic selectively marks genes that are highly activated upon immune stimulation. Citation Format: Karen Adelman, Benjamin S. Scruggs, Telmo Henriques, Adam Burkholder, David C. Fargo. Regulating transcription elongation at stimulus responsive genes. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA10.
Abstract A27: An in vivo gain-of-function screening identified the Williams-Beuren syndrome gene GTF2IRD1 as a mammary tumor promoter
Authors: Yongliang Huo, Yinghao Su, Qiuyin Cai, Ian Macara
Journal: Cancer Research (2016)

Abstract Precision medicine has shown great efficacy in oncology, but its broad application requires a full understanding of the cancer genome. We have performed the first gain-of-function screening in mice to functionally identify candidates from a “druggable” gene set for their roles in breast cancer. We transduced mammary gland stem/progenitor cells isolated from MMTV-ErbB2 transgenic mice with a lentiviral cDNA library and implanted them into the cleared fat pads of syngeneic recipients. The transplanted mammary gland cells formed a normal mammary ductal tree within 6 weeks. After another 8 months latency, small lesions were detected along the mammary ducts in mice harboring cells that had been transduced with the lentiviral library. We isolated genomic DNA from these lesions to amplify any lentiviral cDNA sequences within the lesions and identified individual genes by sequencing. Gain-of-function of five genes, including RET, GTF2IRD1, ADORA1, LARS2, and DPP8, was found to promote mammary tumor growth consistently. We further studied one novel tumor promoting gene, transcription factor GTF2IRD1. GTF2IRD1 regulates the expression of multiple genes in the mammary gland system, including OPN, TβR2, and BMPR1b. In tissue culture, high levels of GTF2IRD1 inhibited cell proliferation but increased the colony formation ability of the un-transformed mammary gland cell line MCF10A. In mice, the mis-regulation of GTF2IRD1, OPN, TβR2, and BMPR1b, also individually promoted mammary cancer development. Silencing of TβR2 delayed the incidence of tumor formation by GTF2IRD1. We also found that GTF2IRD1 is highly expressed in human breast tumors, correlating with high tumor grades and poor prognosis. In conclusion, we performed the first gain-of-function screening in vivo for breast cancer promoting genes. All candidate genes from this study are potential drug targets to treat cancer. We showed that GTF2IRD1 promotes breast cancer development in mice through regulation of its downstream targets, and correlates clinically with high tumor grades and poor prognosis. We believe our in vivo screening method is readily expandable to whole genome annotation of cancer genes. Citation Format: Yongliang Huo, Yinghao Su, Qiuyin Cai, Ian Macara. An in vivo gain-of-function screening identified the Williams-Beuren syndrome gene GTF2IRD1 as a mammary tumor promoter. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A27.
Race and Sex Differences in the Incidence and Prognostic Significance of Silent Myocardial Infarction in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Zhu-Ming Zhang, Pentti M. Rautaharju, Ronald J. Prineas, Carlos J. Rodriguez, Laura Loehr, Wayne D. Rosamond, Dalane Kitzman, David Couper, Elsayed Z. Soliman
Journal: Circulation (2016)

Background— Race and sex differences in silent myocardial infarction (SMI) are not well established. Methods and Results— The analysis included 9498 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of cardiovascular disease at baseline (visit 1, 1987–1989). Incident SMI was defined as ECG evidence of MI without clinically documented MI (CMI) after the baseline until ARIC visit 4 (1996–1998). Coronary heart disease and all-cause deaths were ascertained starting from ARIC visit 4 until 2010. During a median follow-up of 8.9 years, 317 participants (3.3%) developed SMI and 386 (4.1%) developed CMI. The incidence rates of both SMI and CMI were higher in men (5.08 and 7.96 per 1000-person years, respectively) than in women (2.93 and 2.25 per 1000-person years, respectively; P &lt;0.0001 for both). Blacks had a nonsignificantly higher rate of SMI than whites (4.45 versus 3.69 per 1000-person years; P =0.217), but whites had higher rate of CMI than blacks (5.04 versus 3.24 per 1000-person years; P =0.002). SMI and CMI (compared with no MI) were associated with increased risk of coronary heart disease death (hazard ratio, 3.06 [95% confidence interval, 1.88–4.99] and 4.74 [95% confidence interval, 3.26–6.90], respectively) and all-cause mortality (hazard ratio, 1.34 [95% confidence interval, 1.09–1.65] and 1.55 [95% confidence interval, 1.30–1.85], respectively). However, SMI and CMI were associated with increased mortality among both men and women, with potentially greater increased risk among women (interaction P =0.089 and 0.051, respectively). No significant interactions by race were detected. Conclusions— SMI represents &gt;45% of incident MIs and is associated with poor prognosis. Race and sex differences in the incidence and prognostic significance of SMI exist that may warrant considering SMI in personalized assessments of coronary heart disease risk.
Bisphenol A and Adiposity in an Inner-City Birth Cohort
Authors: Lori A. Hoepner, Robin M. Whyatt, Elizabeth M. Widen, Abeer Hassoun, Sharon E. Oberfield, Noel T. Mueller, Diurka Diaz, Antonia M. Calafat, Frederica P. Perera, Andrew G. Rundle
Journal: Environmental Health Perspectives (2016)

Background:Early-life exposure to the endocrine disruptor bisphenol A (BPA) may contribute to the development of obesity. Prospective evidence in humans on this topic is limited.Objectives:We examined prenatal and early-childhood BPA exposures in relation to childhood measures of adiposity in the Columbia Center for Children’s Environmental Health (CCCEH) New York City birth cohort.Methods:BPA concentrations were measured in prenatal (n = 375) and child ages 3 (n = 408) and 5 years (n = 518) spot urine samples. Childhood anthropometric and bioelectrical impedance outcomes included body mass index z-scores (BMIZ) at 5 and 7 years, and fat mass index (FMI), percent body fat (%BF), and waist circumference (WC) at 7 years. Associations were evaluated using multiple linear regression with continuous and tertile BPA concentrations.Results:Prenatal urinary BPA concentrations were positively associated with child age 7 FMI (β = 0.31 kg/m2; 95% CI: 0.01, 0.60, p = 0.04), %BF (β = 0.79; 95% CI: 0.03, 1.55, p = 0.04), and WC (β = 1.29 cm; 95% CI: 0.29, 2.30, p = 0.01), but not BMIZ, or change in BMIZ between ages 5 and 7 years (all p-values &gt; 0.1). FMI results were sex-specific. Child urinary BPA concentrations were not associated with child anthropometric outcomes (all p-values &gt; 0.05).Conclusions:Analyses of the CCCEH longitudinal birth cohort found associations between prenatal urinary BPA concentrations and FMI, %BF, and WC. Our results suggest that prenatal BPA exposure may contribute to developmental origins of adiposity. These findings are consistent with several prior studies, raising concern about the pervasiveness of BPA.Citation:Hoepner LA, Whyatt RM, Widen EM, Hassoun A, Oberfield SE, Mueller NT, Diaz D, Calafat AM, Perera FP, Rundle AG. 2016. Bisphenol A and adiposity in an inner-city birth cohort. Environ Health Perspect 124:1644–1650; http://dx.doi.org/10.1289/EHP205
Athletic amenorrhea, major affective disorders, and eating disorders
Authors: W J Gadpaille, C F Sanborn, W W Wagner
Journal: American Journal of Psychiatry (1987)

While studying amenorrheic runners, the authors became aware of psychiatric differences between them. Psychiatric interviews of 13 amenorrheic and 19 regularly menstruating runners revealed that of the amenorrheic runners, 11 reported major affective disorders in themselves or in first- and second-degree relatives and eight reported eating disorders in themselves. Among the regularly menstruating runners, however, there were no eating disorders or major affective disorders, and only one had first-degree relatives with major affective disorders. These data suggest a link between athletic amenorrhea in runners, major affective disorders, and eating disorders.
Abstract ES7-1: Neoadjuvant endocrine therapy
Authors: CX Ma
Journal: Cancer Research (2016)

Abstract Neoadjuvant endocrine therapy has become a standard approach in clinical practice to improve the chance of breast conservation in postmenopausal women with locally advanced estrogen receptor positive breast cancer based on results from several neoadjuvant endocrine trials. Although data is limited, neoadjuvant endocrine therapy appears to as effective as chemotherapy in converting mastectomy to lumpectomy. In addition, neoadjuvant endocrine therapy allows an early assessement of tumor responsiveness to endocrine therapy so that adjuvant treatments could be tailored accordingly. Persistent cell proliferation on neoadjuvant endocrine therapy predicts a high risk of early relapse, for whom novel treatment strategies are in great need. In contrast, the Preoperative Endocrine Prognostic Index score of 0 (pathologic T2/3 N0 Ki67 &amp;lt;2.7% ER+) in response to neoadjuvant endocrine therapy is being prospectively evaluated in the ongoing Alliance A011106 (ALTERNATE) as a marker of endocrine sensitive disease, for whom chemotherapy could be avoided. Furthermore, neoadjuvant endocrine trials provide a unique research platform for biomarker studies and the testing of novel therapeutic hypothesis. Citation Format: Ma CX. Neoadjuvant endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES7-1.
Abstract 22: Inferring regulatory element landscapes and transcription factor networks from cancer methylomes
Authors: Lijing Yao, Hui Shen, Peter Laird, Peggy Farnham, Berman Benjamin
Journal: Clinical Cancer Research (2016)

Abstract Genome-wide DNA methylation studies have established that transcriptional enhancers can be detected from changes in methylation patterns. However, no systematic approach has been developed to infer the function of these elements within larger transcription factor networks. We developed ELMER (Enhancer Linking by Methylation/Expression Relationships), a computational tool that combines DNA methylation and gene expression data from tissue samples, along with annotations from epigenomic repositories, to infer multi-level cis-regulatory networks. ELMER uses DNA methylation to identify enhancers that differ between normal and disease tissues, and correlates these with gene expression to identify a target gene or genes (typically not the nearest gene). Transcription factor (TF) binding site analysis is then used in conjunction with TF expression patterns to infer the upstream regulators that drive enhancer changes. We applied ELMER to Infinium HM450k methylation and RNA-seq data for 2,000+ tumor samples and ten cancer types from The Cancer Genome Atlas (TCGA). Our multi-level analysis identified enhancer networks regulated by known cancer driver transcription factors, such as GATA3 and FOXA1 in breast cancer, FOXA2 and SOX17 in endometrial cancer, and NFE2L2, SOX2, and TP63 in squamous cell lung cancer. We also identified several novel networks with prognostic associations, including RUNX1 in kidney cancer, and putative target genes of these transcription factors in primary tumor. Citation Format: Lijing Yao, Hui Shen, Peter Laird, Peggy Farnham, Berman Benjamin. Inferring regulatory element landscapes and transcription factor networks from cancer methylomes. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 22.
PRIMER ON THE RHEUMATIC DISEASES
Authors: C McEWEN, J J BUNIM
Journal: JAMA (1953)

<h3>RHEUMATOID ARTHRITIS</h3><h3>ETIOLOGY</h3> Rheumatoid arthritis is a disease of unknown cause. It has a slight tendency to be familial; the sex ratio in peripheral rheumatoid arthritis is 3 women to 1 man, and 80% of the cases occur between the ages of 25 to 50, with the peak at 35 to 40. No indexes of abnormal function of the pituitary or adrenal glands can be detected by current methods. Rheumatoid arthritis is variously claimed to be (1) an infectious disease, (2) a metabolic disease, (3) a disease with an endocrinologic basis, (4) a disease of the peripheral circulatory apparatus, (5) a disease of the nervous system, (6) a psychogenic disease, and (7) a disease of hypersensitivity. Such a list indicates how little actually is known about the cause of this disease. <h3>PATHOLOGY</h3> Rheumatoid arthritis is invariably described as a systemic disorder. Scudamore, as early as 1827, pointed out that the