tbuckley/cabot-search huggingface dataset:
Genetic interactions: the missing links for a better understanding of cancer susceptibility, progression and treatment
Authors: Christopher A Maxwell, Víctor Moreno, Xavier Solé, Laia Gómez, Pilar Hernández, Ander Urruticoechea, Miguel Angel Pujana
Journal: Molecular Cancer (2008)

It is increasingly clear that complex networks of relationships between genes and/or proteins govern neoplastic processes. Our understanding of these networks is expanded by the use of functional genomic and proteomic approaches in addition to computational modeling. Concurrently, whole-genome association scans and mutational screens of cancer genomes identify novel cancer genes. Together, these analyses have vastly increased our knowledge of cancer, in terms of both "part lists" and their functional associations. However, genetic interactions have hitherto only been studied in depth in model organisms and remain largely unknown for human systems. Here, we discuss the importance and potential benefits of identifying genetic interactions at the human genome level for creating a better understanding of cancer susceptibility and progression and developing novel effective anticancer therapies. We examine gene expression profiles in the presence and absence of co-amplification of the 8q24 and 20q13 chromosomal regions in breast tumors to illustrate the molecular consequences and complexity of genetic interactions and their role in tumorigenesis. Finally, we highlight current strategies for targeting tumor dependencies and outline potential matrix screening designs for uncovering molecular vulnerabilities in cancer cells.
Heterogeneous Nuclear Ribonucleoprotein G Shows Tumor Suppressive Effect against Oral Squamous Cell Carcinoma Cells
Authors: Ki-Hyuk Shin, Mo K. Kang, Reuben H. Kim, Russell Christensen, No-Hee Park
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Heterogeneous nuclear ribonucleoproteins (hnRNP) are nucleic acid binding proteins involved in RNA processing. We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC). The current study was designed to test the hypothesis that hnRNP G is a tumor suppressor. Experimental Design: We investigated the expression levels of hnRNP G protein in normal, precancerous, and malignant oral tissues by in situ immunohistochemistry. In addition, wild-type or mutant hnRNP G was ectopically overexpressed in HOSCC cells and their effects on cellular replication kinetics, colonogenic efficiency, anchorage-independent growth, and in vivo tumorigenicity were determined. Results: In situ immunohistochemical staining showed robust presence of hnRNP G in the basal cell layers of normal oral epithelium but the level of its staining was markedly reduced in dysplastic or cancerous tissues. Ectopic expression of wild-type hnRNP G in cancer cells lacking hnRNP G expression or containing mutant hnRNP G resulted in severe retardation of proliferation, reduction of colonogenic efficiency, loss of anchorage-independent growth, and reduction of in vivo tumorigenicity in immunocompromised mice. In addition, hnRNP G overexpression led to up-regulation of the expression of TXNIP, a cell cycle inhibitory gene, and significantly reduced the expression of the genes that promote cellular proliferation, such as EGR1, JUND, JUNB, FOS, FOSL1, ROS, and KIT. Conclusions: These results indicate that hnRNP G is a tumor suppressor against HOSCC but its mechanisms of action remain to be further investigated.
Effects of Montelukast sodium on development and differentiation of human mast cells and eosinophils
Authors: D. Morgan, E.S. Schulman
Journal: Journal of Allergy and Clinical Immunology (2005)

RATIONALE: Inhibitors of the CysLT1 receptor (CysLT1R) are beneficial in asthma management. The effects of inhibition of the CysLT1R on the development and differentiation of human eosinophils and mast cells (MC), two crucial effector cells in asthma, are unknown. METHODS: CD34+ cells were isolated from umbilical cord blood and cultured in the presence of IL-3 to promote eosinophil, or in the presence of SCF+IL-6 for MC generation. The CysLT1R antagonist Montelukast (ML, 10-4-10-6M) or vehicle control were added to cultures either on day 0 (pure stem cell phase), or on day 7-11, after lineage-specific progenitors differentiate. Enumeration of viable cells in was performed weekly for 4 weeks to evaluate proliferation. RESULTS: ML-supplemented cultures failed to consistently influence viable cell numbers in eosinophil (n=3) or mast cell (n=5) committed cultures at all time points. In three cultures, immunocytochemical staining for the mast cell proteases tryptase and chymase was performed at four weeks. ML cultured MC (n=3) showed only weak tryptase staining by light microscopy; control cultures showed strong staining. Too few chymase positive cells were generated under these culture conditions to evaluate stain intensity. CONCLUSION: Addition of ML failed to show consistent modulation of eosinophil or MC-committed CD34+ stem cell cultures over 28 days. No differences were observed when ML was added at day 0 of culture, a pure stem cell phase, or delayed until after the first week of culture, after lineage-specific differentiation. Strong modulation of tryptase staining was observed in ML cultures and suggests a potential in vivo influence on allergic reactivity.
Spanish doctors set to carry out first double leg transplant in the world
Authors: M. de Lago
Journal: BMJ (2010)

The Spanish National Transplant Organization has given the go ahead to La Fe Hospital in Valencia, Spain, to carry out the world’s first double leg transplant. 

The procedure will be carried out by Pedro Cavadas and a team of around 35 health professionals on a young man who lost both his legs in a car crash.

Dr Cavadas performed Spain’s first face transplant last August and the country’s first hand transplant in 2006. The intention is to …
The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2
Authors: Tien-Shun Yeh, Chew-Wun Wu, Kai-Wen Hsu, Wan-Jung Liao, Min-Chieh Yang, Anna Fen-Yau Li, An-Ming Wang, Min-Liang Kuo, Chin-Wen Chi
Journal: Cancer Research (2009)

Gastric carcinoma is one of the most common cancers and lethal malignancies worldwide. Thus far, the regulatory mechanisms of its aggressiveness are still poorly understood. To understand the pathogenesis and to develop new therapeutic strategies, it is essential to dissect the molecular mechanisms that regulate progression of gastric cancer. Herein, we sought to address whether Notch1 signal pathway is involved in the control of progression in gastric cancer. We found that expression of Notch ligand Jagged1 was correlated with aggressiveness of human gastric cancer. Patients with Jagged1 expression in gastric cancer tissues had a poor survival rate compared with those without Jagged1 expression. The Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor, promoted the colony-forming ability and xenografted tumor growth of human stomach adenocarcinoma SC-M1 cells. Migration and invasion abilities of SC-M1 cells were enhanced by N1IC. Furthermore, N1IC and C promoter-binding factor 1 (CBF1) bound to cyclooxygenase-2 (COX-2) promoter and elevated COX-2 expression in SC-M1 cells through a CBF1-dependent manner. The colony-forming, migration, and invasion abilities enhanced by N1IC were suppressed in SC-M1 cells after treatment with the COX-2 inhibitor NS-398 or knockdown of COX-2. These cellular processes inhibited by Notch1 knockdown were restored by prostaglandin E(2) or exogenous COX-2. Taken together, these results suggest that activation of Notch1 signal pathway promotes progression of gastric cancer, at least in part through COX-2.
Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study
Authors: G. Bertelli, M. Venturini, L. Del Mastro, M. Bergaglio, P. Sismondi, N. Biglia, S. Venturini, G. Porcile, P. Pronzato, M. Costantini, R. Rosso
Journal: Annals of Oncology (2002)
ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)
Authors: M. Ghielmini, U. Vitolo, E. Kimby, S. Montoto, J. Walewski, M. Pfreundschuh, M. Federico, P. Hoskin, C. McNamara, F. Caligaris-Cappio, S. Stilgenbauer, R. Marcus, M. Trneny, P. Dreger, E. Montserrat, M. Dreyling, Claudio Agostinelli, Luca Arcaini, Federico Caligaris-Cappio, Elias Campo, Bertrand Coiffier, Paolo Corradini, Francesco D'Amore, Peter Dreger, Martin Dreyling, Massimo Federico, Andrea Gallamini, Philippe Gaulard, Christian H. Geisler, Michele Ghielmini, Christian Gisselbrecht, Maria Gomes da Silva, John Gribben, Olivier Hermine, Peter Hoskin, Emilio Iannitto, Won Seog Kim, Eva Kimby, Hanneke C. Kluin-Nelemans, Peter Koch, Marco Ladetto, Steven Le Gouill, Armando Lopez-Guillermo, Robert Marcus, Christopher McNamara, Carlos Montalban, Silvia Montoto, Emili Montserrat, Michael Pfreundschuh, Markus Raderer, José Rodriguez, Gilles Salles, Claude Bernard, Norbert Schmitz, Ofer Shpilberg, Stephan Stilgenbauer, Catherine Thieblemont, Hervé Tilly, Olivier Tournilhac, Lorenz Trümper, Umberto Vitolo, Jan Walewski, Andrew Wotherspoon, Emanuele Zucca
Journal: Annals of Oncology (2012)
Washout of transplanted cells from the heart: A potential new hurdle for cell transplantation therapy
Authors: J DOW, B SIMKHOVICH, L KEDES, R KLONER
Journal: Cardiovascular Research (2005)

The number of viable transplanted cells in the heart is sharply decreased shortly after cell injection. The exact mechanics of cell loss are unclear. We hypothesized that immature cardiac cells transplanted directly into rat heart could be washed out via the cardiac vasculature, and carried to other organs.Female Fischer rats were subjected to 60 min of coronary artery occlusion followed by 3 h of reperfusion (OR group) or 4 h or permanent coronary artery occlusion (PO group). Neonatal rat cardiac cells (5x10(6)) were injected directly into the free wall of the left ventricle at either 15 min post-reperfusion (OR group) or 75 min after occlusion (PO group). At the end of the protocol, a histological analysis for transplanted cells in the heart (i.e. microscopic examination for cells in approximately 790 histogic fields within each heart) and polymerase chain reaction (PCR)-based determination of the Sry gene (a male cell marker) in the heart and other organs were performed.In the OR group, only 3.39+/-0.69% fields contained immature cells compared to 6.57+/-1.33% fields in the PO group (p<0.05). Cardiac blood vessels contained round, immature cardiomyocytes. PCR analysis revealed that 100% of the animals (5 of 5) in both groups had cells present in their hearts and lungs, 40% of the OR group and 60% of the PO group demonstrated cells in the liver and kidneys, and 40% of the PO group had cells in the spleen.Neonatal cardiomyocytes injected directly into the area at risk of the heart escape acutely from the infract to other organs through the vascular system of the heart; loss of cells is more prominent with reperfusion.
A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease
Authors: J A van Noord
Journal: Thorax (2000)

<h3>BACKGROUND</h3> A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD). <h3>METHODS</h3> 288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV<sub>1</sub>) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 μg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 μg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV<sub>1</sub>and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV<sub>1</sub> and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92. <h3>RESULTS</h3> During treatment tiotropium achieved a significantly greater improvement than ipratropium (p&lt;0.05) in trough, average, and peak FEV<sub>1</sub>levels and in trough and average FVC levels. The trough FEV<sub>1</sub> response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI –0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0.07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV<sub>1</sub>than ipratropium starting three hours after inhalation (p&lt;0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p&lt;0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p&lt;0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients). <h3>CONCLUSIONS</h3> Tiotropium in a dose of 18 μg inhaled once daily using the HandiHaler was significantly more effective than 40 μg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD.
The vascular bed as the primary target in the destruction of skin grafts by antiserum. II. Loss of sensitivity to antiserum in long-term xenografts of skin.
Authors: S V Jooste, R B Colvin, H J Winn
Journal: The Journal of Experimental Medicine (1981)

Rat skin that survives for long periods of time on immunosuppressed mice becomes resistant to anti-graft serum and remains so for as long as it survives. When long-standing grafts are removed and placed on new immunosuppressed mice, they remain resistant to antiserum for as long as they survive. The acquired resistance to antiserum seems, therefore, to be due to changes in the grafts rather than to changes in their hosts. Furthermore, it was found that the acquisition of resistance is correlated with replacement of graft endothelium by host cells, as demonstrated by the use of immunofluorescent techniques in conjunction with mouse anti-rat serum and rat anti-mouse serum. Evidently, humoral antibodies are able to cause acute damage to skin grafts, and presumably to grafts to other organized tissues, only if they react with antigens of graft endothelium. Long-term grafts that are retransplanted to their original donors or to rats syngeneic with those donors are in most cases rejected, whereas 14-d-old grafts similarly regrafted are in no case rejected. Apparently, the responses of the secondary recipients to the mouse endothelial antigens in long-term grafts lead to destruction of the entire grafts. When long-standing rat skin xenografts are removed and placed on untreated mice syngeneic with the primary hosts, they are in every case rejected, although they survive slightly longer than skin taken directly from rat donors. Rejection is accompanied by a mononuclear infiltrate and is qualitatively indistinguishable from the rejection of freshly prepared rat skin. Clearly, sensitized cells are more efficient than humoral antibody in destroying grafted tissues.
Bronchoalveolar lavage cytology resembles sarcoidosis in a subgroup of granulomatous CVID
Authors: Florian Kollert, Nils Venhoff, Sigune Goldacker, Claudia Wehr, Niklas Lützen, Reinhard E. Voll, Antje Prasse, Klaus Warnatz
Journal: European Respiratory Journal (2014)

have recently became commercially available for noninvasive measurements [3].These developments can be helpful to further explore the role of neonatal lung function in the development of respiratory diseases in later life.
Platelets and Chemokines in Atherosclerosis
Authors: Christian Weber
Journal: Circulation Research (2005)

It becomes increasingly evident that blood platelets do not only exert important functions in hemostasis and thrombus formation but are also involved in atherosclerotic vascular disease. A major portion of the underlying mechanisms is related to an intricate functional interaction of platelets with chemokines, which have also been implicated in atherogenesis and neointima formation: (1) Platelets can induce the secretion of chemokines in different cells of the vascular wall; (2) In combination with primary agonists, certain chemokines can potentiate platelet aggregation and adhesion; (3) Activated platelets can release and deposit chemokines and precursors on vascular cell surfaces, which trigger atherogenic recruitment of vascular cells or modulate crucial processes such as angiogenesis and lipoprotein metabolism; (4) Surface-adherent platelets can bind and present vascular cell-derived chemokines to trigger arrest of circulating mononuclear cells. The close linkage between platelets and chemokines as culprits in the pathogenesis of vascular diseases may provide a valuable target for selective interventions.
Clinical Responsiveness of Glioblastoma Multiforme to Chemotherapy after Vaccination
Authors: Christopher J. Wheeler, Asha Das, Gentao Liu, John S. Yu, Keith L. Black
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Although the development of immune-based therapies for various cancers including malignant glioma has been heralded with much hope and optimism, objective clinical improvements in most vaccinated cancer patients have not been realized. To broaden the search for vaccine-induced benefits, we examined synergy of vaccines with conventional chemotherapy. Experimental Design: Survival and progression times were analyzed retrospectively in 25 vaccinated (13 with and 12 without subsequent chemotherapy) and 13 nonvaccinated de novo glioblastoma (GBM) patients receiving chemotherapy. Immune responsiveness and T-cell receptor excision circle (TREC) content within CD8+ T cells (CD8+ TRECs) was determined in vaccinated patients. Results: Vaccinated patients receiving subsequent chemotherapy exhibited significantly longer times to tumor recurrence after chemotherapy relative to their own previous recurrence times, as well as significantly longer postchemotherapy recurrence times and survival relative to patients receiving isolated vaccination or chemotherapy. Patients exhibiting objective (&amp;gt;50%) tumor regression, extremely rare in de novo GBM, were also confined to the vaccine + chemotherapy group. Prior tumor behavior, demographic factors, other treatment variables, distribution of vaccine responders, and patients with high CD8+ TRECs all failed to account for these differences in clinical outcome. Within all GBM patients receiving post-vaccine chemotherapy, however, CD8+ TRECs predicted significantly longer chemotherapeutic responses, revealing a strong link between the predominant T-cell effectors in GBM and tumor chemosensitivity. Conclusions: We propose that therapeutic vaccination synergizes with subsequent chemotherapy to elicit tangible clinical benefits for GBM patients.
Pregnancy and Cholelithiasis: Pathogenesis and Natural Course of Gallstones Diagnosed in Early Puerperium
Authors: Vicente Valdivieso, Carmen Covarrubias, Freddy Siegel, Francisco Cruz
Journal: Hepatology (1993)

Several recent reports have indicated an increased prevalence of gallstones in association with pregnancy. If these reports are true, the early puerperium should be a favorable time to detect the disease in its initial stages and follow its natural course. Accordingly, the gallbladder was examined by ultrasound in 980 women during the immediate postpartum period and in 150 nulliparous, age-matched healthy volunteers. Gallstones were detected in 12.2% of the puerperal women and in 1.3% of the control group. In 70 patients who had stones in a functioning gallbladder, 22 (31%) had had attacks of biliary colic. The history of pain was more common in patients with stones greater than 10 mm in diameter. Forty-one women with small stones (&lt;10 mm) were followed clinically and ultrasonographically for between 6 and 24 (mean = 8.7) mo. All remained pain-free, and in twelve subjects (29%) the stones disappeared. Gallbladder bile was examined in 11 normal volunteers (controls) immediately after delivery and in 19 women with small stones 39 ± 6 days postpartum. Bile was saturated with cholesterol in the controls and was unsaturated in patients with gallstones. We conclude that in our population pregnancy is a very important pathogenetic factor favoring gallstone formation. Attacks of biliary colic appear early and frequently in young Chilean women with this disease. Unexplained disappearance of small stones frequently occurs: in some cases it is likely to be the result of spontaneous dissolution because bile becomes unsaturated within a few weeks of delivery. (Hepatology 1993;17:1-4.)
Crohn's Disease Risk Alleles on the NOD2 Locus Have Been Maintained by Natural Selection on Standing Variation
Authors: S. Nakagome, S. Mano, L. Kozlowski, J. M. Bujnicki, H. Shibata, Y. Fukumaki, J. R. Kidd, K. K. Kidd, S. Kawamura, H. Oota
Journal: Molecular Biology and Evolution (2012)

Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions.