tbuckley/cabot-search huggingface dataset:
Inhibition of hedgehog signaling attenuates carcinogenesis<i>in vitro</i>and increases necrosis of cholangiocellular carcinoma
Authors: Mona El Khatib, Anna Kalnytska, Vindhya Palagani, Uta Kossatz, Michael P. Manns, Nisar P. Malek, Ludwig Wilkens, Ruben R. Plentz
Journal: Hepatology (2012)

The Hedgehog signaling pathway plays a pivotal role during embryonic development, stem cell maintenance, and wound healing. Hedgehog signaling also is deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of cholangiocarcinoma (CCC) is still unknown. In this study, we investigated the effects of Hedgehog inhibition by cyclopamine and 5E1 in cultured human CCC cell lines and in vivo using a xenograft mouse model. We also investigated the involvement of Hedgehog in epithelial to mesenchymal transition (EMT), migration, and CCC tumor growth. Sonic hedgehog (Shh) ligand was highly expressed in 89% of human CCC tissues and in CCC cell lines. Cyclopamine and 5E1 treatments effectively inhibited cell proliferation, migration, and invasion by down-regulating the Hedgehog target genes glioblastoma 1 and glioblastoma 2. In vitro and in vivo, we detected an increase in epithelial marker, E-cadherin, after Hedgehog inhibition. In addition, we saw an increase in necrotic areas and a decrease in mitotic figures in cyclopamine and 5E1-treated CCC xenograft tumors.This study supports the presence of autocrine Hedgehog signaling in human CCC, where CCC cells produce and respond to Shh ligand. Blocking the Hedgehog pathway inhibited EMT and decreased the viability of CCC cells. In addition, cyclopamine and 5E1 inhibited the growth of CCC xenograft tumors.
Fetal parathyroids are not required to maintain placental calcium transport
Authors: Christopher S. Kovacs, Nancy R. Manley, Jane M. Moseley, T. John Martin, Henry M. Kronenberg
Journal: Journal of Clinical Investigation (2001)

We used Hoxa3 knockout mice and other mouse models to study the role of the fetal parathyroids in fetal calcium homeostasis. Hoxa3-null fetuses lack parathyroid glands, and absence of parathyroid hormone (PTH) was confirmed with a rodent PTH immunoradiometric assay. The ionized calcium level of Hoxa3-null fetuses was significantly lower than that of wild-type or heterozygous littermates or of the mother. Both the rate of placental calcium transfer and the plasma PTHrP level were normal in Hoxa3 mutants and their heterozygous siblings. Because we had previously observed an increase in placental calcium transfer in PTH/PTHrP receptor 1–null (Pthr1-null) fetuses, we assayed plasma PTHrP in those mice. Pthr1-null fetuses had plasma PTHrP levels 11-fold higher than those of their littermates. Northern analysis, immunohistochemical, and in situ hybridization studies of Pthr1-null fetuses indicated that liver and placenta had increased expression of PTHrP. In summary, loss of fetal parathyroids in Hoxa3-null fetuses caused marked hypocalcemia but did not alter placental calcium transfer or the circulating PTHrP level. The findings in the Pthr1-null fetuses indicate that several tissues may contribute to the circulating PTHrP level in fetal mice.
The American Diabetes Association, the American Cancer Society, and the American Heart Association
Authors: Eugene J. Barrett, Carolé Mensing
Journal: Diabetes Care (2004)

In this issue of Diabetes Care , the American Diabetes Association (ADA) together with the American Heart Association (AHA) and American Cancer Society (ACS) jointly review the scientific evidence supporting the efficacy of preventive measures in decreasing the incidence of, and morbidity associated with, cardiovascular disease, cancer, and diabetes (1). One rationale behind this joint initiative by the three organizations is to highlight the importance of common preventive efforts with demonstrated efficacy. More than that, this joint publication is a clarion call that signals a new era of joined efforts by volunteers and staff in these organizations to place an appropriate emphasis on the enormous health benefits gained by smoking cessation, regular exercise, and judicious food selection.

It is reasonable to ask “Why now?” Why have these organizations (which have in the past cooperated/collaborated only intermittently and typically around more narrow, specific issues) now come together with a common purpose and a resolve to have a more enduring collaboration built around a shared comprehensive vision? The question is presented even more strongly as these organizations have often competed in the “Philanthropic Marketplace,” a phenomenon that will surely continue. Almost certainly, the answer lies in a shared recognition that each organization can move forward most effectively to meeting their respective missions by sharing efforts in education, advocacy, information, and research to provide a greater good for the people they serve.

We’re reminded of the familiar story of the “Tragedy …
Intestinal Bleeding Associated with Antiphospholipid Antibody Syndrome
Authors: P. Kornprat, H. Bacher, H. Cerwenka, A. El-Shabrawi, C. Langner, H.-J. Mischinger
Journal: Endoscopy (2005)

Antiphospholipid antibody syndrome is characterized by recurrent vascular thromboses or recurrent complications of pregnancy, including miscarriage or premature birth [1] [2] [3]. Thrombosis caused by autoantibodies directed against phospholipid-binding proteins can occur in any tissue. We present the case of a patient with antiphospholipid antibody syndrome and intestinal bleeding.
Diagnosis and treatment of systemic lupus erythematosus.
Authors: P J Venables
Journal: BMJ (1993)

Many CNS disorders involve an inflammatory response that is orchestrated by cells of the innate immune system: macrophages, neutrophils, and microglia (the endogenous CNS immune cell). Hence, there is considerable interest in anti-inflammatory strategies that target these cells. Microglia express Kv1.3 (KCNA3) channels, which we showed previously are important for their proliferation and the NADPH-mediated respiratory burst. Here, we demonstrate the potential for targeting Kv1.3 channels to control CNS inflammation. Rat microglia express Kv1.2, Kv1.3, and Kv1.5 transcripts and protein, but only a Kv1.3 current was detected. When microglia were activated with lipopolysaccharide or a phorbol ester, only the Kv1.3 transcript (but not protein) expression changed. Using a Transwell cell-culture system that allows separate drug treatment of microglia or neurons, we found that activated microglia killed postnatal hippocampal neurons through a process that requires Kv1.3 channel activity in microglia but not in neurons. A major neurotoxic molecule in this model was peroxynitrite, which is formed from superoxide and nitric oxide; thus, it is significant that Kv1.3 channel blockers reduced the respiratory burst, but not nitric oxide production, by the activated microglia. In addressing the biochemical pathway affected by Kv1.3 channel activity, we found that Kv1.3 acts via a different cellular mechanism from the broad-spectrum drug minocycline, which is often used in animal models of neuroinflammation. That is, the dose-dependent reduction in neuron killing by minocycline corresponded with a reduction in p38 mitogen-activated protein kinase activation in microglia; however, none of the Kv1.3 blockers affected p38 activation.
Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV
Authors: Sarah C. Darby, Sau Wan Kan, Rosemary J. Spooner, Paul L. F. Giangrande, Frank G. H. Hill, Charles R. M. Hay, Christine A. Lee, Christopher A. Ludlam, Michael Williams
Journal: Blood (2007)
Downregulation of RBMS3 Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma
Authors: Yan Li, Leilei Chen, Chang-jun Nie, Ting-ting Zeng, Haibo Liu, Xueying Mao, Yanru Qin, Ying-Hui Zhu, Li Fu, Xin-Yuan Guan
Journal: Cancer Research (2011)

Abstract Deletions on chromosome 3p occur often in many solid tumors, including esophageal squamous cell carcinoma (ESCC), suggesting the existence at this location of one or more tumor suppressor genes (TSG). In this study, we characterized RBMS3 gene encoding an RNA-binding protein as a candidate TSG located at 3p24. Downregulation of RBMS3 mRNA and protein levels was documented in approximately 50% of the primary ESCCs examined. Clinical association studies determined that RBMS3 downregulation was associated with poor clinical outcomes. RBMS3 expression effectively suppressed the tumorigenicity of ESCC cells in vitro and in vivo, including by inhibition of cell growth rate, foci formation, soft agar colony formation, and tumor formation in nude mice. Molecular analyses revealed that RBMS3 downregulated c-Myc and CDK4, leading to subsequent inhibition of Rb phosphorylation. Together, our findings suggest a tumor suppression function for the human RBMS3 gene in ESCC, acting through c-Myc downregulation, with genetic loss of this gene in ESCC contributing to poor outcomes in this deadly disease. Cancer Res; 71(19); 6106–15. ©2011 AACR.
Differential expression of interferon responsive genes in rodent models of transmissible spongiform encephalopathy disease
Authors: Michael J Stobart, Debra Parchaliuk, Sharon LR Simon, Jillian LeMaistre, Jozef Lazar, Richard Rubenstein, J David Knox
Journal: Molecular Neurodegeneration (2007)

The pathological hallmarks of transmissible spongiform encephalopathy (TSE) diseases are the deposition of a misfolded form of a host-encoded protein (PrPres), marked astrocytosis, microglial activation and spongiosis. The development of powerful gene based technologies has permitted increased levels of pro-inflammatory cytokines to be demonstrated. However, due to the use of assays of differing sensitivities and typically the analysis of a single model system it remained unclear whether this was a general feature of these diseases or to what extent different model systems and routes of infection influenced the relative levels of expression. Similarly, it was not clear whether the elevated levels of cytokines observed in the brain were accompanied by similar increases in other tissues that accumulate PrPres, such as the spleen.The level of expression of the three interferon responsive genes, Eif2ak2, 2'5'-OAS, and Mx2, was measured in the brains of Syrian hamsters infected with scrapie 263K, VM mice infected with bovine spongiform encephalopathy and C57BL/6 mice infected with the scrapie strain ME7. Glial fibrillary acidic expression confirmed the occurrence of astrocytosis in all models. When infected intracranially all three models showed a similar pattern of increased expression of the interferon responsive genes at the onset of clinical symptoms. At the terminal stage of the disease the level and pattern of expression of the three genes was mostly unchanged in the mouse models. In contrast, in hamsters infected by either the intracranial or intraperitoneal routes, both the level of expression and the expression of the three genes relative to one another was altered. Increased interferon responsive gene expression was not observed in a transgenic mouse model of Alzheimer's disease or the spleens of C57BL/6 mice infected with ME7. Concurrent increases in TNFalpha, TNFR1, Fas/ApoI receptor, and caspase 8 expression in ME7 infected C57BL/6 mice were observed.The identification of increased interferon responsive gene expression in the brains of three rodent models of TSE disease at two different stages of disease progression suggest that this may be a general feature of the disease in rodents. In addition, it was determined that the increased interferon responsive gene expression was confined to the CNS and that the TSE model system and the route of infection influenced the pattern and extent of the increased expression. The concurrent increase in initiators of Eif2ak2 mediated apoptotic pathways in C57BL/6 mice infected with ME7 suggested one mechanism by which increased interferon responsive gene expression may enhance disease progression.
Bone turnover in early rheumatoid arthritis. 2. Longitudinal bone density studies.
Authors: P N Sambrook, B M Ansell, S Foster, J M Gumpel, R Hesp, J Reeve
Journal: Annals of the Rheumatic Diseases (1985)

<h3>Abstract</h3> Amyotrophic Lateral Sclerosis (ALS) is an incurable fatal neurodegenerative disease for which the precise mechanisms of toxicity remain unclear despite some significant advances in our understanding of the underlying genetic basis. A holistic, integrated view of cellular changes will be critical to understanding the processes of neurodegeneration and the development of effective treatments. Mutant forms of optineurin (a ubiquitin-binding protein involved in autophagy, membrane trafficking, and NF-κB activation) are found associated with cytoplasmic inclusions containing TDP43 or SOD1 in some ALS patients. We have taken a multi-omics approach to understand the cellular response to OPTN overexpression in a yeast model of ALS. We found that genetic interaction screens and metabolomics provided parallel, highly complementary data on OPTN toxicity. Genetic enhancers of OPTN toxicity in yeast relate directly to the native function of OPTN in vesicular trafficking and intracellular transport, suggesting the human OPTN protein is functional when expressed in yeast even though there is no yeast ortholog. Crucially, we find that the genetic modifiers and the metabolic response are distinct for different ALS-linked genes expressed in yeast. This lends strong support to the use of yeast as a model system and omics platform to study ALS.
Differential Effects of Kinins on Cardiomyocyte Hypertrophy and Interstitial Collagen Matrix in the Surviving Myocardium After Myocardial Infarction in the Rat
Authors: Kai C. Wollert, Roland Studer, Kristin Doerfer, Elisabeth Schieffer, Christian Holubarsch, Hanjörg Just, Helmut Drexler
Journal: Circulation (1997)

Background Left ventricular remodeling after myocardial infarction (MI) involves the hypertrophic growth of cardiomyocytes and the accumulation of fibrillar collagen in the interstitial space. We evaluated the role of kinins in postinfarction ventricular remodeling and their potential contribution to the antiremodeling effects of ACE inhibition and angiotensin II type 1 (AT1) receptor blockade. Methods and Results Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant. Additional groups of infarcted rats were treated with the ACE inhibitor lisinopril or the AT1 receptor antagonist ZD7155, each separately and in combination with icatibant. B2 kinin receptor blockade enhanced the interstitial deposition of collagen after MI, whereas morphological and molecular markers of cardiomyocyte hypertrophy (cardiac weight, myocyte cross-sectional area, prepro–atrial natriuretic factor mRNA expression) were not affected. Chronic ACE inhibition and AT1 receptor blockade reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition and AT1 receptor blockade on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy. Conclusions (1) Kinins inhibit the interstitial accumulation of collagen but do not modulate cardiomyocyte hypertrophy after MI. (2) Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. (3) The effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy are related to a reduced generation/receptor blockade of angiotensin II.
Tackling health inequities
Authors: G. Davey Smith, N. Krieger
Journal: BMJ (2008)

WHO report calls for global action to ensure health equity within and between countries

Finally, an official report on health inequity has been published that has the honesty and courage to say that “social injustice is killing people on a grand scale.”1 The report of the World Health Organization’s Commission on Social Determinants of Health synthesises evidence from a large and disparate range of sources, while recognising that what constitutes evidence is itself contested and not value free.2 It presents a wealth of data to show the unquestionable link between economic, social, and bodily wellbeing—within and across countries. In the case of life expectancy, these embodied facts of social inequity3 can span the equivalent of a lifetime: women born in Botswana can anticipate living an average of 43 years, half that of the 86 years for women in Japan; between the poorest and most affluent parts of Glasgow life expectancy in men ranges from 54 to 82 years.

Many official reports have documented social inequalities in health over the past 170 years, from Chadwick4 to Sachs.5 Yet, in contrast to these reports, which subtly (and not so subtly) emphasised the detrimental effects of poor health induced by poverty on economic performance,6 the commission firmly draws the arrow of causality from impoverished environments to ill health, something that is clear to most …
Suppression of reperfusion induced arrhythmias in the isolated rat heart: pretreatment with 7-oxo prostacyclin in vivo
Authors: T. Ravingerova, N. Tribulova, A. Ziegelhoffer, J. Styk, L. Szekeres
Journal: Cardiovascular Research (1993)

The aim was to investigate the late effect of pretreatment with 7-oxo prostacyclin on reperfusion induced arrhythmias in the isolated rat heart.Forty eight hours after intramuscular administration of drug in vivo (50 micrograms.kg-1 body weight), isolated Langendorff perfused rat hearts were subjected to 30 minutes of regional ischaemia and 5 minutes of reperfusion. Incidence and duration of ventricular arrhythmias in both pretreated and control groups were evaluated on reperfusion. Morphological examination was also performed.In the untreated group reperfusion induced 75% of sustained ventricular fibrillation. Incidence of ventricular fibrillation, its duration, and arrhythmia score were significantly lower in the pretreated group. Pretreatment with 7-oxo prostacyclin had no effect on heart rate and coronary flow throughout the whole course of perfusion. Neither was the occluded zone size affected. Ultrastructure of ischaemic and reperfused myocardium was better preserved in the pretreated group.Antiarrhythmic action of 7-oxo prostacyclin was unrelated to changes in haemodynamics, thus suggesting the direct influence of the myocardium. The possible mechanism of action may involve maintenance of intracellular cation homeostasis (particularly of Na+ and Ca2+) due to a stimulation of sarcolemmal Na+ pump activity.
Top UCLA surgeon is demoted after failing to disclose conflicts of interests
Authors: N. Siva
Journal: BMJ (2009)

A top orthopaedic surgeon from the University of California, Los Angeles (UCLA) has been demoted after failing to disclose financial links with the medical companies whose products he was researching.

The Wall Street Journal (http://online.wsj.com, 22 Jul, “Surgeon faces probe of research”) reports that Jeffrey Wang allegedly failed to tell the university about payments of $459 500 he received between 2004 and 2007 from the companies. Charles Grassley, the US Republican senator who has pursued unreported payments by drug companies to doctors and researchers, is said to have written to …
That's the “GIST” of It: Use of Adjuvant Imatinib After Resection of a Primary GI Stromal Tumor
Authors: William D. Tap, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2014)

Article Tools ONCOLOGY GRAND ROUNDS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2013.53.5971 Journal of Clinical Oncology - published online before print March 17, 2014 PMID: 24638004 That's the “GIST” of It: Use of Adjuvant Imatinib After Resection of a Primary GI Stromal Tumor William D. TapxWilliam D. TapSearch for articles by this author , Gary K. SchwartzxGary K. SchwartzSearch for articles by this author Show More Memorial Sloan-Kettering Cancer Center, New York, NY https://doi.org/10.1200/JCO.2013.53.5971 First Page Full Text PDF Figures and Tables © 2014 by American Society of Clinical Oncology
Elevation of Receptor Tyrosine Kinase EphA2 Mediates Resistance to Trastuzumab Therapy
Authors: Guanglei Zhuang, Dana M. Brantley-Sieders, David Vaught, Jian Yu, Lu Xie, Sam Wells, Dowdy Jackson, Rebecca Muraoka-Cook, Carlos Arteaga, Jin Chen
Journal: Cancer Research (2009)

One arising challenge in the treatment of breast cancer is the development of therapeutic resistance to trastuzumab, an antibody targeting the human epidermal growth factor receptor-2 (HER2), which is frequently amplified in breast cancers. In this study, we provide evidence that elevated level of the receptor tyrosine kinase Eph receptor A2 (EphA2) is an important contributor to trastuzumab resistance. In a screen of a large cohort of human breast cancers, we found that EphA2 overexpression correlated with a decrease in disease-free and overall survival of HER2-overexpressing patients. Trastuzumab-resistant cell lines overexpressed EphA2, whereas inhibiting EphA2 restored sensitivity to trastuzumab treatment in vivo. Notably, trastuzumab treatment could promote EphA2 phosphorylation by activating Src kinase, leading in turn to an amplification of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signaling in resistant cells. Our findings offer mechanistic insights into the basis for trastuzumab resistance and rationalize strategies to target EphA2 as a tactic to reverse trastuzumab resistance.
SCREENING DATA FROM THE CANCER CHEMOTHERAPY NATIONAL SERVICE CENTER SCREENING LABORATORIES. XXII.
Authors: Joseph Leiter, B. J. Abbott, Saul A. Schepartz
Journal: Cancer Research (1965)

Data are reported on 1,755 synthetic compounds which were tested in the CCNSC primary screens. Almost all of the compounds were tested in Sarcoma 180, Carcinoma 755, Leukemia 1210, and KB cells in culture; some tests were also carried out in Friend virus leukemia and Lewis lung carcinoma. Data are reported only on compounds which have not demonstrated sufficient activity in these systems to warrant further investigation.
Advances in Inflammation Research
Authors: D. E Woolley
Journal: Annals of the Rheumatic Diseases (1986)

This pleasant, friendly, well written book gives very adequate coverage of most aspects of the pathology of bone.The selection of topics and detail has been effectively calculated to render the book useful in diagnostic work, and as a book to study.The balance favours the latter in that the author provides the groundwork that enables a diagnosis to be arrived at rather than patterns for matching.This form of approach works particularly well in bone, especially in metabolic disorders, where lies the centre of gravity of this book.Bone responds to many stimuli, local and general; to understand this thoroughly is to grasp the essentials of bone pathology.The pathological processes, as known from general pathology, all occur in bones, modified by their architecture, the tissue structure, and the bone cell responses under the control of local and general mechanisms.I'he various pathological processes are treated in turn, building up a picture of the subject.The section devoted to congenital and developmental disorders, a large topic not possible to deal with comprehensively in a book of this order, is well treated and referenced.The most lightly treated subject is neoplasia, a topic fully covered by several authoritative texts.Here the first steps in sorting tissue patterns are set out.This book has a commodious page size, a slim profile, a firm binding, and a pleasant handle.The illustrations are large and clear and make their point.There is a strikingly large number of references, of great value to further reading; and there is a very adequate index.