tbuckley/cabot-search huggingface dataset:
Uterine DCs are crucial for decidua formation during embryo implantation in mice
Authors: Vicki Plaks, Tal Birnberg, Tamara Berkutzki, Shay Sela, Adi BenYashar, Vyacheslav Kalchenko, Gil Mor, Eli Keshet, Nava Dekel, Michal Neeman, Steffen Jung
Journal: Journal of Clinical Investigation (2008)

Implantation is a key stage during pregnancy, as the fate of the embryo is often decided upon its first contact with the maternal endometrium. Around this time, DCs accumulate in the uterus; however, their role in pregnancy and, more specifically, implantation, remains unknown. We investigated the function of uterine DCs (uDCs) during implantation using a transgenic mouse model that allows conditional ablation of uDCs in a spatially and temporally regulated manner. Depletion of uDCs resulted in a severe impairment of the implantation process, leading to embryo resorption. Depletion of uDCs also caused embryo resorption in syngeneic and T cell–deficient pregnancies, which argues against a failure to establish immunological tolerance during implantation. Moreover, even in the absence of embryos, experimentally induced deciduae failed to adequately form. Implantation failure was associated with impaired decidual proliferation and differentiation. Dynamic contrast-enhanced MRI revealed perturbed angiogenesis characterized by reduced vascular expansion and attenuated maturation. We suggest therefore that uDCs directly fine-tune decidual angiogenesis by providing two critical factors, sFlt1 and TGF-β1, that promote coordinated blood vessel maturation. Collectively, uDCs appear to govern uterine receptivity, independent of their predicted role in immunological tolerance, by regulating tissue remodeling and angiogenesis. Importantly, our results may aid in understanding the limited implantation success of embryos transferred following in vitro fertilization.
The importance of KRAS mutations and EGF61A&gt;G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer
Authors: K. -L. Garm Spindler, N. Pallisgaard, A.A. Rasmussen, J. Lindebjerg, R.F. Andersen, D. Crüger, A. Jakobsen
Journal: Annals of Oncology (2009)
Does reversal of oxidative stress and inflammation provide vascular protection?
Authors: K. K. Koh, P. C. Oh, M. J. Quon
Journal: Cardiovascular Research (2008)

Chronic inflammation is a pathogenic feature of atherosclerosis and cardiovascular disease mediated by substances including angiotensin II, proinflammatory cytokines, and free fatty acids. This promotes generation of reactive oxygen species in vascular endothelial cells and smooth muscle cells, which mediate injury through several mechanisms. Reciprocal relationships between endothelial dysfunction and insulin resistance as well as cross-talk between hyperlipidaemia and the renin–angiotensin–aldosterone system (RAAS) at multiple levels contribute importantly to a variety of risk factors. Therefore, combination therapy that simultaneously addresses multiple mechanisms for the pathogenesis of atherosclerosis is an attractive emerging concept for slowing progression of atherosclerosis. Combined therapy with statins, peroxisome proliferator-activated receptors, and RAAS blockade demonstrates additive beneficial effects on endothelial dysfunction and insulin resistance when compared with monotherapies in patients with cardiovascular risk factors due to both distinct and interrelated mechanisms. These additive beneficial effects of combined therapies are consistent with laboratory and recent clinical studies. Thus, combination therapy may be an important paradigm for treating and slowing progression of atherosclerosis, coronary heart disease, and co-morbid metabolic disorders characterized by endothelial dysfunction and insulin resistance.
PWE-122 How reliable is serological testing in the diagnosis of coeliac disease?
Authors: N Hansi, S Grainger
Journal: Gut (2012)

<h3>Introduction</h3> Coeliac disease is an autoimmune disorder of the small bowel with a prevalence as high as 1:100 in the UK and Ireland. The gold standard for diagnosis is to identify the characteristic histopathological changes (based on the modified Marsh criteria) from an adequate small bowel biopsy. However non-invasive serological blood tests are often the first line investigation. Serological testing is reported to have both high sensitivity and specificity with the sensitivity and specificity of IgA anti-tissue transglutaminase antibodies (tTG) being higher (99% and &gt;90%) than IgA anti-gliadin (46–100% and 86–100%) and IgA anti-endomysium (74–100% and 91–100%). However, in a study of 26 UK patients with coeliac disease Smith-Laing <i>et al</i> (Clinical Medicine 2009) raised the issue of limitations of serological testing reporting discrepancy between histology and anti-tTG in as many as 38.5%. Given our reliance on serological testing the results were of concern. The objective of this retrospective study was to analyse the results of serological tests for coeliac disease in consecutive patients with duodenal biopsies confirming the diagnosis. <h3>Methods</h3> Results of duodenal biopsies which fulfilled the histological criteria for coeliac disease between 2005 and 2010 at two UK district general hospitals (King George hospital, Ilford and Queen9s hospital, Romford) were correlated with coeliac serological tests. IgA tTG antibodies, IgA anti-endomysium antibodies, and serum IgA levels were recorded. Serological testing done before or within a month of biopsy was noted. Reference range for tTG was &gt;15 U positive. <h3>Results</h3> There were 182 positive duodenal biopsies. Serological tests were not performed in 35 patients. Of the remaining 147, sixteen were excluded (IgA not measured—6, IgA deficient—3, serological testing done more than a month after biopsy date—6, other—1). Complete data were therefore available in 131. Nine patients with confirmed coeliac disease had anti-tTG levels below the diagnostic range. Of these, three had positive anti- endomysium antibody. Thus anti-tTG levels suggestive of coeliac disease were found in 122 of 131, demonstrating sensitivity of 0.93 with combined sensitivity of tTG and anti-endomysium of 0.954. <h3>Conclusion</h3> This retrospective study reassuringly demonstrates that there is not a significant number of serologically negative but positive biopsy cases. A proportion of patients will not have serological tests going straight to endoscopy as first line investigation for their anaemia. Serological testing remains useful in primary care and for physicians to diagnose coeliac disease; however it is important to be aware of the small number of cases (approximately 5%) that will be missed when relying on serology alone. <h3>Competing interests</h3> None declared.
American Society of Clinical Oncology Guideline on Weight-Based Dosing and Its Impact on Trial Design
Authors: Pinkie Chambers, Susanna Daniels, Lindsay C. Thompson, Richard Stephens
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: We fully support the new guidelines from the American Society of Clinical Oncology (ASCO) concerning chemotherapy dosing in obese patients. We have been concerned that underdosing occurs with dose capping for the obese (and for patients with a large surface area), which is widely practiced, and mandated in most clinical trial protocols. This results in a lack of toxicity data for fully dosed obese patients and potentially poorer patient outcomes. The lack of information about outcomes in trials for fully dosed patients with a large surface area has further persuaded clinicians to follow this practice routinely. Griggs et al note the lack of retrospective analyses of trial data to clarify the role of dose capping in the obese patients, although they do not cite our recent publication. In three recent United Kingdom Medical Research Center colorectal trials, dose capping was left to the discretion of individual clinicians. We conducted a retrospective study collating data from these trials to compare the outcomes of those patients with dose capping and those fully dosed. Of the 4,856 patients, 2,202 (45%) were classified as normal weight (body mass index [BMI] 25), 1,774 (37%) as overweight (BMI 25-29), and 880 (18%) as obese (BMI 30). There was a significant association between increasing weight subgroup and the proportion with a reduced dose (normal weight, 6%; overweight, 17%; obese, 55%; P .001). There was no evidence that obese patients experienced more toxicity in those fully dosed (normal weight, 21%; overweight, 20%; obese, 17%) or that reducing the doses of obese patients resulted in less toxicity (full dose, 17%; reduced dose, 16%). An important additional piece of information from our analysis was a suggestion that those obese patients who were given reduced doses had a slightly worse survival than those who were fully dosed (hazard ratio, 1.16; 95% CI, 1.00 to 1.35; P .055). Although not randomized, this adds considerable weight to the argument against dose capping. Thus our results complement and add to the evidence for the new ASCO guidelines. We would encourage clinical practice and future trial designs to adopt the new guidelines to ensure that obese and overweight patients are dosed appropriately.
Inhibition of Epidermal Growth Factor Receptor Signaling Elevates 15-Hydroxyprostaglandin Dehydrogenase in Non–Small-Cell Lung Cancer
Authors: Li Yang, Joseph M. Amann, Takefumi Kikuchi, Rut Porta, Marta Guix, Adriana Gonzalez, Kyung-Ho Park, Dean Billheimer, Carlos L. Arteaga, Hsin-Hsiung Tai, Raymond DuBois, David P. Carbone, David H. Johnson
Journal: Cancer Research (2007)

Abstract Evidence indicates that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of non–small-cell lung cancer (NSCLC). In addition to overproduction by COX-2, PGE2 concentrations also depend upon the levels of the PGE2 catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We find a dramatic down-regulation of PGDH protein in NSCLC cell lines and in resected human tumors when compared with matched normal lung. Affymetrix array analysis of 10 normal lung tissue samples and 49 resected lung tumors revealed a much lower expression of PGDH transcripts in all NSCLC histologic groups. In addition, treatment with the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) erlotinib increased the expression of 15-PGDH in a subset of NSCLC cell lines. This effect may be due in part to an inhibition of the extracellular signal-regulated kinase (ERK) pathway as treatment with mitogen-activated protein kinase kinase (MEK) inhibitor U0126 mimics the erlotinib results. We show by quantitative reverse transcription-PCR that the transcript levels of ZEB1 and Slug transcriptional repressors are dramatically reduced in a responsive cell line upon EGFR and MEK/ERK inhibition. In addition, the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. As these repressors function by recruiting histone deacetylases to promoters, it is likely that PGDH is repressed by an epigenetic mechanism involving histone deacetylation, resulting in increased PGE2 activity in tumors. This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI. [Cancer Res 2007;67(12):5587–93]
The failure of a major histocompatibility antigen to stimulate a thyroid allograft reaction after culture in oxygen.
Authors: F G La Rosa, D W Talmage
Journal: The Journal of Experimental Medicine (1983)

The lymphocytic infiltration found in multiple cultured BALB/c thyroids placed in the same C57BL/6 recipient was found to be highly correlated and the high variability between animals was not influenced by the number of lobes. It was concluded that the variable infiltration was largely due to host factors. Because a similar correlation was found between BALB/c and C3H grafts, the response to a minor antigen common to these two strains was suggested as a cause of the infiltration. When the response of C57BL/6 mice to cultured B6.C (H-2d) and BALB.B (H-2b) grafts was compared, a synergism between major and minor antigens was suggested. However, when the time of culture was increased from 48 to 60 h and the response of BALB/c and C57BL/6 mice were compared with identically cultured B6.C (H-2d) grafts, a striking difference between major and minor antigens was observed. None of 10 such grafts in C57BL/6 recipients (major antigens only) showed any infiltration, whereas 8 out of the 9 grafts in BALB/c recipients (minor antigens only) were infiltrated.
ACCF/AHA/CDC Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats
Authors: George A. Mensah, Augustus O. Grant, Carl J. Pepine, Larry M. Baddour, Leslie T. Cooper, Sandra B. Dunbar, Erika S. Froelicher, Kurt J. Greenlund, Edward L. Kaplan, Robert A. Kloner, Darwin R. Labarthe, Russell V. Luepker, Mohammad Madjid, James E. Muller, Siobhán O’Connor, Joseph P. Ornato, Rose Marie Robertson, Michael J. Roy, Prediman K. Shah, Kathryn A. Taubert, Walter R. Wilson, Zhi-Jie Zheng, Robert A. Harrington, Jonathan Abrams, Jeffrey L. Anderson, Eric R. Bates, Mark J. Eisenberg, Cindy L. Grines, Mark A. Hlatky, Robert C. Lichtenberg, Jonathan R. Lindner, Gerald M. Pohost, Richard S. Schofield, Samuel J. Shubrooks, James H. Stein, Cynthia M. Tracy, Robert A. Vogel, Deborah J. Wesley
Journal: Circulation (2007)
The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn's Disease
Authors: M.F. Neurath, B. Weigmann, S. Finotto, J. Glickman, E. Nieuwenhuis, H. Iijima, A. Mizoguchi, E. Mizoguchi, J. Mudter, P.R. Galle, A. Bhan, F. Autschbach, B.M. Sullivan, S.J. Szabo, L.H. Glimcher, R.S. Blumberg
Journal: The Journal of Experimental Medicine (2002)

The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-γ/interleukin (IL)-4 and transforming growth factor (TGF)-β activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L+ CD4+ T cells exacerbated colitis in reconstituted SCID mice, T-bet–deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet–deficient CD62L− CD4+ T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-β signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-γ/IL-4 and TGF-β responses and the development of chronic intestinal inflammation in T cell–mediated colitis. Furthermore, TGF-β was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-β and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell–mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.
Adding network structure onto the map of collective behavior
Authors: Santo Fortunato, Jari Saramäki, Jukka-Pekka Onnela
Journal: Behavioral and Brain Sciences (2014)

Abstract We propose an extension to the map of Bentley et al. by incorporating an aspect of underlying network structure that is likely relevant for many modes of collective behavior. This dimension, which captures a feature of network community structure, is known both from theory and from experiments to be relevant for decision-making processes.
Radiation Dose-Response Relationships for Thyroid Nodules and Autoimmune Thyroid Diseases in Hiroshima and Nagasaki Atomic Bomb Survivors 55-58 Years After Radiation Exposure
Authors: Misa Imaizumi, Toshiro Usa, Tan Tominaga, Kazuo Neriishi, Masazumi Akahoshi, Eiji Nakashima, Kiyoto Ashizawa, Ayumi Hida, Midori Soda, Saeko Fujiwara, Michiko Yamada, Eri Ejima, Naokata Yokoyama, Masamichi Okubo, Keizo Sugino, Gen Suzuki, Renju Maeda, Shigenobu Nagataki, Katsumi Eguchi
Journal: JAMA (2006)

Effects of irradiation on thyroid diseases such as thyroid nodules and autoimmune thyroid diseases have not been evaluated among people exposed to radiation more than 50 years in the past.To evaluate the prevalence of thyroid diseases and their radiation-dose responses in atomic bomb survivors.Survey study comprising 4091 cohort members (mean age, 70 [SD, 9] years; 1352 men and 2739 women) who participated in the thyroid study at the Radiation Effects Research Foundation. Thyroid examinations were conducted between March 2000 and February 2003.Prevalence of thyroid diseases, including thyroid nodules (malignant and benign) and autoimmune thyroid diseases, and the dose-response relationship of atomic bomb radiation in each thyroid disease.Thyroid diseases were identified in 1833 (44.8%) of the total participants (436 men [32.2% of men] and 1397 women [51.0% of women]) (P<.001). In 3185 participants, excluding persons exposed in utero, not in the city at the time of the atomic bombings, or with unknown radiation dose, the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts was 14.6%, 2.2%, 4.9%, and 7.7%, respectively. The prevalence of positive thyroid antibodies, antithyroid antibody-positive hypothyroidism, and Graves disease was 28.2%, 3.2%, and 1.2%, respectively. A significant linear dose-response relationship was observed for the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts (P<.001). We estimate that about 28% of all solid nodules, 37% of malignant tumors, 31% of benign nodules, and 25% of cysts are associated with radiation exposure at a mean and median thyroid radiation dose of 0.449 Sv and 0.087 Sv, respectively. No significant dose-response relationship was observed for positive antithyroid antibodies (P = .20), antithyroid antibody-positive hypothyroidism (P = .92), or Graves disease (P = .10).A significant linear radiation dose response for thyroid nodules, including malignant tumors and benign nodules, exists in atomic bomb survivors. However, there is no significant dose response for autoimmune thyroid diseases.
Evolution of the Caenorhabditis elegans Genome
Authors: A. D. Cutter, A. Dey, R. L. Murray
Journal: Molecular Biology and Evolution (2009)

A fundamental problem in genome biology is to elucidate the evolutionary forces responsible for generating nonrandom patterns of genome organization. As the first metazoan to benefit from full-genome sequencing, Caenorhabditis elegans has been at the forefront of research in this area. Studies of genomic patterns, and their evolutionary underpinnings, continue to be augmented by the recent push to obtain additional full-genome sequences of related Caenorhabditis taxa. In the near future, we expect to see major advances with the onset of whole-genome resequencing of multiple wild individuals of the same species. In this review, we synthesize many of the important insights to date in our understanding of genome organization and function that derive from the evolutionary principles made explicit by theoretical population genetics and molecular evolution and highlight fertile areas for future research on unanswered questions in C. elegans genome evolution. We call attention to the need for C. elegans researchers to generate and critically assess nonadaptive hypotheses for genomic and developmental patterns, in addition to adaptive scenarios. We also emphasize the potential importance of evolution in the gonochoristic (female and male) ancestors of the androdioecious (hermaphrodite and male) C. elegans as the source for many of its genomic and developmental patterns.
Medical Marijuana, American Federalism, and the Supreme Court
Authors: Lawrence O Gostin
Journal: JAMA (2005)

IN GONZALEZ V RAICH, THE US SUPREME COURT HELD THAT federal law enforcement authorities could criminally prosecute patients for possessing marijuana prescribed by a physician in accordance with state law. The Court did not overturn state medical marijuana laws but did open the door to criminal prosecution under federal drug statutes. The Court also did not foreclose future challenges to federal enforcement on other constitutional grounds (eg, an unwarranted invasion of patient-physician privacy). Explaining the significance of Raich requires examination of 2 issues. The first concerns American federalism and raises an important constitutional principle about the appropriate scope of federal public health powers. The second issue concerns the use of marijuana as a medical treatment and raises intriguing questions about the practice of medicine and the patient-physician relationship. In Raich, the Supreme Court pointedly questioned the wisdom of prosecuting patients: “The case is made difficult by respondents’ strong arguments that they will suffer irreparable harm because . . . marijuana does have valid therapeutic purposes. The question before us, however, is not whether [the policy] is wise, [but] whether Congress has the power to regulate . . . medicinal substances . . . produced and consumed locally.”
P-Selectin Glycoprotein Ligand-1 Is Highly Expressed on Ly-6C <sup>hi</sup> Monocytes and a Major Determinant for Ly-6C <sup>hi</sup> Monocyte Recruitment to Sites of Atherosclerosis in Mice
Authors: Guangyu An, Huan Wang, Rong Tang, Tadayuki Yago, J. Michael McDaniel, Samuel McGee, Yuqing Huo, Lijun Xia
Journal: Circulation (2008)

Background— Ly-6C hi monocytes are key contributors to atherosclerosis in mice. However, the manner in which Ly-6C hi monocytes selectively accumulate in atherosclerotic lesions is largely unknown. Monocyte homing to sites of atherosclerosis is primarily initiated by rolling on P- and E-selectin expressed on endothelium. We hypothesize that P-selectin glycoprotein ligand-1 (PSGL-1), the common ligand of P- and E-selectin on leukocytes, contributes to the preferential homing of Ly-6C hi monocytes to atherosclerotic lesions. Methods and Results— To test this hypothesis, we examined the expression and function of PSGL-1 on Ly-6C hi and Ly-6C lo monocytes from wild-type mice, ApoE −/− mice, and mice lacking both ApoE and PSGL-1 genes ( ApoE −/− /PSGL-1 −/− ). We found that Ly-6C hi monocytes expressed a higher level of PSGL-1 and had enhanced binding to fluid-phase P- and E-selectin compared with Ly-6C lo monocytes. Under in vitro flow conditions, more Ly-6C hi monocytes rolled on P-, E-, and L-selectin at slower velocities than Ly-6C lo cells. In an ex vivo perfused carotid artery model, Ly-6C hi monocytes interacted preferentially with atherosclerotic endothelium compared with Ly-6C lo monocytes in a PSGL-1–dependent manner. In vivo, ApoE −/− mice lacking PSGL-1 had impaired Ly-6C hi monocyte recruitment to atherosclerotic lesions. Moreover, ApoE −/− /PSGL-1 −/− mice exhibited significantly reduced monocyte infiltration in wire injury–induced neointima and in atherosclerotic lesions. ApoE −/− /PSGL-1 −/− mice also developed smaller neointima and atherosclerotic plaques. Conclusions— These data indicate that PSGL-1 is a new marker for Ly-6C hi monocytes and a major determinant for Ly-6C hi cell recruitment to sites of atherosclerosis in mice.