tbuckley/cabot-search huggingface dataset:
Novel Tumor Suppressor Locus in Human Chromosome Region 3p14.2
Authors: K. Julicher, G. Marquitan, N. Werner, W. Bardenheuer, L. Vieten, F. Brocker, H. Topal, S. Seeber, B. Opalka, J. Schutte
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Alterations of chromosome region 3p14 are observed in numerous human malignancies. Because the pattern of allelic losses suggests the existence of at least one tumor suppressor gene within this region, we established a library of yeast artificial chromosomes (YACs) containing contiguous human 3p14 sequences to permit a search for tumor suppressor loci within the 3p14 region by use of functional complementation. METHODS: YACs specific for human chromosome region 3p14 were transduced by spheroplast fusion into cells of the human nonpapillary renal carcinoma cell line RCC-1, which shows a cytogenetically detectable 3p deletion and is tumorigenic in nude mice. RESULTS: We identified a 3p14.2-specific YAC clone, located in the vicinity of the fragile histidine triad (FHIT) gene (but toward the telomere), that is capable of inducing sustained suppression of tumorigenicity in nude mice and of activating cellular senescence in vitro . Among 23 mice given injections of RCC-1 cells containing this YAC, 16 (70%) remained tumor free for at least 6 months, whereas tumor formation occurred after a median of 6 weeks in control mice given injections of either RCC-1 parental cells or a revertant cell line (in which the YAC had lost all human sequences) or RCC-1 parental cells containing other, unrelated YACs. Similar results were obtained following microcell-mediated transfer of the entire human chromosome 3. CONCLUSION: These data provide strong evidence for the existence of a novel tumor suppressor locus adjacent to the previously identified candidate tumor suppressor gene, FHIT, in 3p14.2. Positional cloning of the novel suppressor element within the 3p14.2-specific YAC and the sequence's molecular and functional characterization should add to the understanding of the pathogenesis of renal cell carcinoma and other human tumors that exhibit 3p14 aberrations.
P1-08-25: Breast Cancer Burden, Risks and Outcomes in Latin America.
Authors: NA Justo, NE Wilking, B Jönsson
Journal: Cancer Research (2011)

Abstract BACKGROUND: Breast cancer (BC) burden and care vary substantially across Latin America (LA). Aim: Provide an overview of the epidemiology, outcomes and countries’ risk profiles in LA to identify opportunities for improvement. METHODS: Review of literature (PubMed, LILACS, SCIELO), public databases (Globocan 2002 &amp; 2008, CEPALSTAT, DIRAC, PAHO, WHOSYS, etc) and conference presentations (ASCO, ISPOR). Local experts &amp; patient organizations were surveyed. Current BC epidemiology in LAC, future trends, countries’ risk profiles and outcomes (such as mortality-to-incidence ratios — MIRs) were analyzed and compared (Sweden as benchmark). RESULTS: BC annual incidence (114,900 cases) &amp; mortality (37,000 deaths) are the highest of all cancers in LA and twice as many deaths are expected by 2030. Countries more advanced in the demographic transition, like Uruguay and Argentina, present much higher incidence and mortality but also better outcomes as observed in their MIRs. In LA women are diagnosed younger and at a more advanced stage, especially in countries with poor outcomes, such as Ecuador, Mexico or Peru. The imbalanced progress since 2002 seems to widen the gap in BC outcomes, but countries like Costa Rica are catching up. Age is the main risk factor; while the association of education and wealth with BC occurrence is less significant. Reproductive and lifestyle-related risk factors, proven at a patient level, were not significant at a country-aggregate level and the specialized literature indicates that the evidence on associations between BC and diet is inconclusive. DISCUSSION: LA's considerable variation embedded within per-countries’ averages may be masking underlying causality. Though, it can be inferred that there is no one-suit-all prevention campaign and policies aimed at reducing the risk of developing BC will succeed as long as they are properly targeted and tailored for different needs. Early diagnosis and population-wide access to treatment following evidence-based best practices remain unresolved matters that endow many of these countries with the opportunity to substantially improve the care for their women. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-25.
A Small Interfering RNA Targeting Vascular Endothelial Growth Factor as Cancer Therapeutics
Authors: Yoshifumi Takei, Kenji Kadomatsu, Yukio Yuzawa, Seiichi Matsuo, Takashi Muramatsu
Journal: Cancer Research (2004)

Abstract Vascular endothelial growth factor (VEGF) plays a critical role during normal embryonic angiogenesis and also in the pathological angiogenesis that occurs in a number of diseases, including cancer. We developed a novel VEGF blockade system using RNA interference. The small interfering RNA (siRNA) targeting human VEGF almost completely inhibited the secretion of VEGF in a human prostate cancer cell line, PC-3, whereas the control scramble siRNA showed no effects. The VEGF siRNA with atelocollagen dramatically suppressed tumor angiogenesis and tumor growth in a PC-3 s.c. xenograft model. Atelocollagen provided a beneficial delivering means by which stabilization and efficient transfection of the siRNA injected into the tumors were achieved.
Human Peripheral Blood Eosinophils Express a Functional c-kit Receptor for Stem Cell Factor that Stimulates Very Late Antigen 4 (VLA-4)–mediated Cell Adhesion to Fibronectin and Vascular Cell Adhesion Molecule 1 (VCAM-1)
Authors: Qian Yuan, K. Frank Austen, Daniel S. Friend, Matthew Heidtman, Joshua A. Boyce
Journal: The Journal of Experimental Medicine (1997)

We evaluated mature peripheral blood eosinophils for their expression of the surface tyrosine kinase, c-kit, the receptor for the stromal cell–derived cytokine, stem cell factor (SCF). Cytofluorographic analysis revealed that c-kit was expressed on the purified peripheral blood eosinophils from 8 of 8 donors (4 nonatopic and 4 atopic) (mean channel fluorescence intensity 2.0– 3.6-fold, average 2.8 ± 0.6-fold, greater than the negative control). The uniform and selective expression of c-kit by eosinophils was confirmed by immunohistochemical analysis of peripheral blood buffy coats. The functional integrity of c-kit was demonstrated by the capacity of 100 ng/ml (5 nM) of recombinant human (rh) SCF to increase eosinophil adhesion to 3, 10, and 30 μg/ml of immobilized FN40, a 40-kD chymotryptic fragment of plasma fibronectin, in 15 min by 7.7 ± 1.4-, 5.3 ± 3.3-, and 5.4 ± 0.2-fold, respectively, and their adhesion to 0.1, 0.5, and 1.0 μg/ml vascular cell adhesion molecule-1 (VCAM-1), by 12.7 ± 9.2-, 3.8 ± 2.5-, and 1.7 ± 0.6-fold, respectively. The SCF-stimulated adhesion occurred without concomitant changes in surface integrin expression, thereby indicating an avidity-based mechanism. rhSCF (100 ng/ml, 5 nM) was comparable to rh eotaxin (200 ng/ml, 24 nM) in stimulating adhesion. Cell adhesion to FN40 was completely inhibited with antibodies against the α4 and β1 integrin subunits, revealing that the SCF/c-kit adhesion effect was mediated by a single integrin heterodimer, very late antigen 4 (VLA-4). Thus, SCF represents a newly recognized stromal ligand for the activation of eosinophils for VLA-4–mediated adhesion, which could contribute to the exit of these cells from the blood, their tissue localization, and their prominence in inflammatory lesions.
A key role of TRPC channels in the regulation of electromechanical activity of the developing heart
Authors: Jessica Sabourin, Elodie Robin, Eric Raddatz
Journal: Cardiovascular Research (2011)

It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the spontaneous activity of the developing heart. TRPC isoforms were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blotting and co-immunoprecipitation, we report for the first time that TRPC1, 3, 4, 5, 6, and 7 isoforms are expressed at the mRNA and protein levels and that they can form a macromolecular complex with the α1C subunit of the L-type voltage-gated calcium channel (Cav1.2) in atria and ventricle. Using ex vivo electrocardiograms, electrograms of isolated atria and ventricle and ventricular mechanograms, we found that inhibition of TRPC channels by SKF-96365 leads to negative chrono-, dromo-, and inotropic effects, prolongs the QT interval, and provokes first- and second-degree atrioventricular blocks. Pyr3, a specific antagonist of TRPC3, affected essentially atrioventricular conduction. On the other hand, specific blockade of the L-type calcium channel with nifedipine rapidly stopped ventricular contractile activity without affecting rhythmic electrical activity. These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis.
No TGFBRII germline mutations in juvenile polyposis patients without SMAD4 or BMPR1A mutation
Authors: L A A Brosens, W A van Hattem, M C E Kools, C Ezendam, F H Morsink, W W J de Leng, F M Giardiello, G J A Offerhaus
Journal: Gut (2008)

Juvenile polyposis (JPS) is an autosomal dominant disorder characterised by the presence of multiple gastro-intestinal juvenile polyps and an increased risk of colorectal cancer (CRC).1 JPS is caused by germline mutation of SMAD4 or BMPR1 A, both involved in the transforming growth factor β/bone morphogenic protein (TGFβ/BMP) signalling pathway. A recent study by van Hattem et al , published in this journal ( Gut 2008; 57 :623–7), showed that a germline defect in one of these genes is found in approximately 50% of JPS patients, with 30–40% being a point mutation or small deletion and 10–15% a large genomic deletion. Since no germline defect is found in ∼50% of JPS patients, it is likely that other genes exist which cause JPS.2

Several candidate genes, mostly involved in TGFβ/BMP signalling, have been investigated for a role in JPS pathogenesis. No mutations have been found in these genes.3–6 (table 1) Recently, the TGFβ co-receptor endoglin was proposed as a JPS susceptibility gene, but other studies could …
Simplified method to perform CLARITY imaging
Authors: Ekaterina Poguzhelskaya, Dmitry Artamonov, Anastasia Bolshakova, Olga Vlasova, Ilya Bezprozvanny
Journal: Molecular Neurodegeneration (2014)

Imaging methods are used widely to understand structure of brain and other biological objects. However, sample penetration by light microscopy is limited due to light scattering by the tissue. A number of methods have been recently developed to solve this problem. In one approach (SeeDB) simple procedure for clarifying brain samples for imaging was described. However, this method is not compatible with immunostaining approach as SeeDB-prepared tissue is not permeable to the antibodies. Another technique for clearing brain tissue (CLARITY) was optimized for immunochemistry, but this method technically much more demanding than SeeDB. Here we report optimized protocol for imaging of brain samples (CLARITY2). We have simplified and shortened the original protocol. Following hydrogel fixation, we cut brain tissue to 1–1.5 mm thick coronal slices. This additional step enabled us to accelerate and simplify clearing, staining and imaging steps when compared to the original protocol. We validated the modified protocol in imaging experiments with brains from line M Thy1-GFP mouse and in immunostaining experiments with antibodies against postsynaptic protein PSD-95 and striatal-specific protein DARPP32. The original CLARITY protocol was optimized and simplified. Application of the modified CLARITY2 protocol could be useful for a broad range of scientists working in neurobiology and developmental biology.
Renal eicosanoids as determinants of renal function in liver disease
Authors: Murray Epstein, Meyer Lifschitz
Journal: Hepatology (1987)

The available data suggest that alterations in renal prostaglandin metabolism participate in the pathogenesis of at least two prominent renal complications of liver disease: (a) sodium retention and (b) HRS. Although the data are highly suggestive, additional studies, including experimental manipulations that augment vasodilatory prostaglandins while diminishing vasoconstrictor metabolites of arachidonic acid, will be required to establish the role of prostaglandins or other arachidonic acid metabolites in mediating these renal abnormalities. The clinical caveat emerging from these observations is that every attempt should be made to avoid prescribing drugs which possess cyclooxygenase inhibitory activity to patients with decompensated liver disease who are sodium-avid.
Measurement of lung tissue mass in Pneumocystis carinii pneumonia.
Authors: D J Seddon, P D Snashall
Journal: Thorax (1989)

Transmission-emission scanning of the thorax with a flood source of technetium-99m (99mTc), autologous 99mTc labelled red blood cells, and diethylenetriaminepenta-acetic acid (99mTc DTPA) allows measurement of thoracic tissue thickness and blood and interstitial volume per pixel of the gamma camera image. Volume of blood or interstitium per pixel divided by pixel area gives the thoracic tissue thickness for these two compartments. A measure of lung tissue thickness may be obtained by subtracting chest wall thickness as measured on a lateral chest radiograph. As part of the evaluation of this technique 13 patients were scanned before treatment for proved or presumed pneumocystis pneumonia and their results were compared with those of 12 normal young men, approximately matched for age. In the patients with pneumocystis pneumonia lung tissue thickness at the base of the right lung averaged 3.4 cm (71%) more than that in the normal subjects, and interstitial thickness was 1.2 cm (150%) more than in the normal subjects. After treatment 10 of the patients with pneumocystis pneumonia were scanned again. Lung tissue thickness remained greater than the control value by 1.2 cm and interstitial tissue thickness by 0.5 cm. Blood thickness remained unchanged. Lung tissue and interstitial tissue thickness was correlated with a numerical score of the changes in the chest radiograph. The changes in the properties of the lung tissue compartments in the patients presumably reflect the mural and intra-alveolar inflammation found in pneumocystis pneumonia. Transmission scanning alone measures the increase of lung tissue thickness as well as transmission-emission scanning. It may be of value in monitoring the progress of this condition during treatment.
ETHERINGTON-SMITH MEMORIAL
Authors: A. A. Bowlby, W. B. Close, G. A. Davis, J. H. Gibbon, W. P. Herringham, R. C. Lehmann, H. Marsh, S. D. Muttlebury, G. Nickalls, G. D. Rowe, H. T. Steward
Journal: BMJ (1913)
HEPATITIS B IMMUNISATION WITH A REDUCED NUMBER OF DOSES IN NEWBORN BABIES AND CHILDREN
Authors: M. Piazza, R. Villari, R. Orlando, V. Macchia, A. Vegnente, A. Scarcella, C. Cirillo, E. Isabella, L. Picciotto, V. Guadagnino, L. Isabella, A.M. Memoli, A.M. Borrelli, C. Cascioli, P. Coppola, G. Parisi
Journal: The Lancet (1985)
ACC/AHA 2008 Statement on Performance Measurement and Reperfusion Therapy
Authors: Frederick A. Masoudi, Robert O. Bonow, Ralph G. Brindis, Christopher P. Cannon, Jo DeBuhr, Susan Fitzgerald, Paul A. Heidenreich, Kalon K.L. Ho, Harlan M. Krumholz, Chris Leber, David J. Magid, David S. Nilasena, John S. Rumsfeld, Sidney C. Smith, Thomas P. Wharton
Journal: Circulation (2008)
Translating Pembrolizumab to Clinical Practice: Speak Immunology and Learn Fast!
Authors: Andrea van Elsas, Hans van Eenennaam, John B. Haanen
Journal: Clinical Cancer Research (2015)

Abstract T-cell checkpoint inhibitors treat the cancer patient's immune system potentially inducing significant long-term survival. Pembrolizumab demonstrates clinical activity in patients diagnosed with melanoma and other cancers. Its mode of action suggests a rationale for combination with other treatment modalities, urging oncologists to brush up their knowledge of immunology. Clin Cancer Res; 21(19); 4251–3. ©2015 AACR. See related article by Patnaik et al., p. 4286
Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells
Authors: K Herbrig
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Rheumatoid arthritis (RA) is associated with increased morbidity and mortality attributable to accelerated atherosclerosis and cardiovascular events. <b>Objective:</b> To determine the role played by endothelial progenitor cells (EPC) in the defence system against arteriosclerosis. <b>Methods:</b> The number and function of EPC in 13 young patients with RA with low disease activity (DAS28 3.5 (0.3)) and 13 healthy control subjects was studied. Endothelial function was investigated by agonist-induced, endothelium dependent vasodilatation measured by the forearm blood flow technique. Migratory activity and adhesion of EPC to tumour necrosis factor α (TNFα) activated mature endothelial cells and components of the extracellular matrix were tested in vitro. Putative precursor populations (CD34<sup>+</sup>, CD34<sup>+</sup>/CD133<sup>+</sup>, and CD34<sup>+</sup>/KDR<sup>+</sup> haematopoietic stem cells) were measured by flow cytometric analysis. <b>Results:</b> Acetylcholine-induced, endothelium dependent vasodilatation was reduced by about 50% in patients with RA, indicating endothelial dysfunction, whereas endothelium-independent vasodilatation in response to glyceryl trinitrate was at control level. Significantly reduced numbers of EPC were found in the patients compared with controls. Migratory activity of EPC was decreased in patients with RA. Adhesion to mature endothelial cells after activation with TNFα was enhanced only in controls. The adhesion to matrix proteins and the number of putative precursor cell lineages was comparable in both groups. <b>Conclusion:</b> Endothelial dysfunction in patients with RA with low grade inflammation is associated with a reduced number and partial dysfunction of EPC. Further studies are needed to explore whether interventions that potentially ameliorate the number and function of EPC also improve endothelial function in these patients.
EGFR-Mediated Chromatin Condensation Protects KRAS-Mutant Cancer Cells against Ionizing Radiation
Authors: Meng Wang, Ashley M. Kern, Marieke Hülskötter, Patricia Greninger, Anurag Singh, Yunfeng Pan, Dipanjan Chowdhury, Mechthild Krause, Michael Baumann, Cyril H. Benes, Jason A. Efstathiou, Jeff Settleman, Henning Willers
Journal: Cancer Research (2014)

Therapeutics that target the epidermal growth factor receptor (EGFR) can enhance the cytotoxic effects of ionizing radiation (IR). However, predictive genomic biomarkers of this radiosensitization have remained elusive. By screening 40 non-small cell lung cancer cell (NSCLC) lines, we established a surprising positive correlation between the presence of a KRAS mutation and radiosensitization by the EGFR inhibitors erlotinib and cetuximab. EGFR signaling in KRAS-mutant NSCLC cells promotes chromatin condensation in vitro and in vivo, thereby restricting the number of DNA double-strand breaks (DSB) produced by a given dose of IR. Chromatin condensation in interphase cells is characterized by an unexpected mitosis-like colocalization of serine 10 phosphorylation and lysine 9 trimethylation on histone H3. Aurora B promotes this process in a manner that is codependent upon EGFR and protein kinase C α (PKCα). PKCα, in addition to MEK/ERK signaling, is required for the suppression of DSB-inducible premature senescence by EGFR. Blockade of autophagy results in a mutant KRAS-dependent senescence-to-apoptosis switch in cancer cells treated with IR and erlotinib. In conclusion, we identify EGFR as a molecular target to overcome a novel mechanism of radioresistance in KRAS-mutant tumor cells, which stands in contrast to the unresponsiveness of KRAS-mutant cancers to EGFR-directed agents in monotherapy. Our findings may reposition EGFR-targeted agents for combination with DSB-inducing therapies in KRAS-mutant NSCLC.
Mortality associated with delay in operation after hip fracture: Scottish data provide additional information…
Authors: D Graham Mackenzie, Sarah Wild, Rod Muir
Journal: BMJ (2006)

EDITOR—Bottle and Aylin's study provides evidence of an association between delay to hip fracture surgery and mortality,1 a topic that has proved controversial.2 However, as their analysis depended on routinely collected data, the study had important limitations. Scottish data provide additional relevant information.

Scottish hip fracture audit data are collected prospectively,3 and records have been linked to routinely collected data for hospital admissions and mortality.4 We …
Interferon‐γ and interleukin‐4 differentially regulate ICAM‐1 and VCAM‐1 expression on human lung fibroblasts
Authors: F.M. Spoelstra, D.S. Postma, H Hovenga, J.a Noordhoek, H.f Kauffman
Journal: European Respiratory Journal (1999)

The expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and more specifically vascular adhesion molecule-1 (VCAM-1) on lung fibroblasts may be important for migration of inflammatory cells through the submucosa to the airway lumen in the asthmatic inflammatory response. This study aimed to assess which cytokines are regulating ICAM-1 and VCAM-1 expression on human lung fibroblasts. For this purpose, confluent fibroblast cultures (derived from lung tissue from a nonasthmatic donor) were stimulated for 4 h with interleukin (IL)-1beta, tumour necrosis factor (TNF)alpha, interferon (IFN)gamma, IL-4, IL-5 or transforming growth factor (TGF)beta. IL-1beta (optimal concentration (OC) 1 U x mL(-1)) and TNFalpha (OC 100 U x mL(-1)) both increased ICAM-1 and VCAM-1 expression. IFNgamma (OC 2 U x mL(-1)) increased only ICAM-1 expression and IL-4 (OC 5 ng x mL(-1)) increased only VCAM-1 expression, whereas IL-5 (20 ng x mL(-1)) and TGFbeta (10 ng x mL(-1)) did not influence ICAM-1 or VCAM-1 expression. ICAM-1 expression reached a plateau at 8-12 h after cytokine stimulation and remained constant for at least 24 h. VCAM-1 showed a transient increased expression within 24 h after IL-1beta and TNFalpha stimulation. In contrast, VCAM-1 expression did not decrease after maximal expression at 4 h upon IL-4 stimulation. It is concluded that the Helper-1T-cell, type cytokine interferon gamma and the Helper-2 T-cell type cytokine interleukin-4 differentially regulate intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on human lung fibroblasts. The proinflammatory cytokines interleukin-1beta and tumour necrosis factor alpha increase both intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, without differential regulation of the expression of these adhesion molecules.