tbuckley/cabot-search huggingface dataset:
Tumorgrafts as <i>In Vivo</i> Surrogates for Women with Ovarian Cancer
Authors: S. John Weroha, Marc A. Becker, Sergio Enderica-Gonzalez, Sean C. Harrington, Ann L. Oberg, Matthew J. Maurer, Sarah E. Perkins, Mariam AlHilli, Kristina A. Butler, Sarah McKinstry, Stephanie Fink, Robert B. Jenkins, Xiaonan Hou, Kimberly R. Kalli, Karin M. Goodman, Jann N. Sarkaria, Beth Y. Karlan, Amanika Kumar, Scott H. Kaufmann, Lynn C. Hartmann, Paul Haluska
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design: Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results: Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions: Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR.
Genetic Polymorphisms of Metastasis Suppressor Gene <i>NME1</i> and Breast Cancer Survival
Authors: Shimian Qu, Jirong Long, Qiuyin Cai, Xiao-Ou Shu, Hui Cai, Yu-Tang Gao, Wei Zheng
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Ample evidence supports an important role of tumor metastasis suppressor genes in cancer metastatic processes. We evaluated the association of genetic polymorphisms of metastasis suppressor gene NME1 with breast cancer prognosis in a follow-up study of patients with primary breast cancer and further investigated the functions of these polymorphisms. Experimental Design: NME1 genotypes were analyzed in a cohort of 1,134 breast cancer patients recruited as part of the Shanghai Breast Cancer Study who were followed for a median of 7.1 years. In vitro biochemical analyses were carried out to examine the function of NME1 gene polymorphisms. Results: Single nucleotide polymorphisms (SNP) in the promoter region of the NME1 gene were found to be associated with breast cancer prognosis. Patients carrying the C allele in rs16949649 were associated with higher breast cancer–specific mortality [hazard ratio (HR), 1.4; 95% confidence interval (95% CI), 1.1-1.9] compared with those carrying the wild-type allele, and the association was more evident in patients with an early-stage cancer (HR, 1.7; 95% CI, 1.2-2.5). SNP rs2302254 was also associated with breast cancer prognosis, and the association was statistically significant for the risk of breast cancer relapse, metastasis, and death (HR, 1.3; 95% CI, 1.0-1.6). In vitro biochemical analyses showed that minor alleles in rs2302254 and rs3760468, which is in strong linkage disequilibrium with rs16949646, altered nuclear proteins binding capacity and reduced NME1 promoter activity, supporting the results from an association study of these SNPs with breast cancer survival. Conclusion: Promoter polymorphisms in the NME1 gene may alter its expression and influence breast cancer survival.
A STUDY OF REPEATED ATTACKS OF EXPERIMENTAL PNEUMOCOCCUS LOBAR PNEUMONIA IN DOGS
Authors: Lowell T. Coggeshall, O. H. Robertson
Journal: The Journal of Experimental Medicine (1935)

A study has been made of repeated attacks of experimental lobar pneumonia in the dog produced by the intrabronchial injection of Pneumococcus Type I. Twenty-five individual dogs were given 78 infections in all at intervals of 3 days to 19 months. The number of attacks to which a single animal was subjected varied from two to eleven. It was found that recovery from this experimental disease conferred on the animal increased resistance against subsequent infections as shown by the fact that such animals regularly survived doses of culture which in the dog infected for the first time produced a fatal outcome. The recurrent attacks of pneumonia were uniformly mild in character; the febrile course was brief; the pulmonary lesion was usually confined to a single lobe, and bacteremia seldom occurred. There was no detectable difference between the second and the subsequent infections, which could be produced whenever desired, nor did the time intervals between attacks appear to bear any relationship to the severity of the experimental disease. Tests for acquired antipneumococcal immune substances in the blood after recovery showed their presence in some animals and not in others, yet dogs without demonstrable humoral immunity appeared to be just as resistant to reinfection as those possessing it. A comparison of the pathogenesis of these secondarily induced lesions with those of the initial infection revealed certain striking differences between the two. Secondary lesions produced in the lobe previously affected tended to evolve much more rapidly than did the primary ones. They were characterized by the early appearance of a generalized macrophage reaction and a marked diminution in the numbers of pneumococci in the tissues or their complete absence. These changes occurred more slowly in secondary lesions initiated in hitherto uninvolved lobes. The macrophage reaction, which consists of a swelling of the fixed tissue cells (histiocytes) and a subsequent liberation of macrophages into the alveolar exudate, is regarded as a significant evidence of increased antipneumococcal resistance, since it has been observed to occur regularly at the time of recovery from the first infection and is accompanied by the local disappearance of the invading microorganisms.
Specification of the Cardiac Conduction System by Transcription Factors
Authors: Cathy J. Hatcher, Craig T. Basson
Journal: Circulation Research (2009)

Abstract: Diseases of the cardiovascular system that cause sudden cardiac deaths are often caused by lethal arrhythmias that originate from defects in the cardiac conduction system. Development of the cardiac conduction system is a complex biological process that can be wrought with problems. Although several genes involved in mature conduction system function have been identified, their association with development of specific subcomponents of the cardiac conduction system remains challenging. Several transcription factors, including homeodomain proteins and T-box proteins, are essential for cardiac conduction system morphogenesis and activation or repression of key regulatory genes. In addition, several transcription factors modify expression of genes encoding the ion channel proteins that contribute to the electrophysiological properties of the conduction system and govern contraction of the surrounding myocardium. Loss of transcriptional regulation during cardiac development has detrimental effects on cardiogenesis that may lead to arrhythmias. Human genetic mutations in some of these transcription factors have been identified and are known to cause congenital heart diseases that include cardiac conduction system malformations. In this review, we summarize the contributions of several key transcription factors to specification, patterning, maturation, and function of the cardiac conduction system. Further analysis of the molecular programs involved in this process should lead to improved diagnosis and therapy of conduction system disease.
No Difference in Degree of Interstitial Sirius Red–Stained Area in Serial Biopsies from Area under Concentration-over-Time Curves–Guided Cyclosporine versus Tacrolimus-Treated Renal Transplant Recipients at One Year
Authors: Ajda T. Rowshani, Eduard M. Scholten, Frederike Bemelman, Michael Eikmans, Mirza Idu, Marian C.R. van Groningen, Janto S. Surachno, Marko J.K. Mallat, Leendert C. Paul, Johan W. de Fijter, Ingeborg M. Bajema, Ineke ten Berge, Sandrine Florquin
Journal: Journal of the American Society of Nephrology (2005)

Interstitial fibrosis is the main characteristic of chronic allograft nephropathy and long-term graft failure. Cyclosporin (CsA) is thought to be more fibrogenic than tacrolimus. In a prospective, randomized, multicenter trial using a calcineurin-sparing regimen, renal interstitial volume was compared in CsA- and tacrolimus-treated renal transplant recipients by image analysis of Sirius red (SR)-stained cortical areas in protocol biopsies obtained at 6 mo (n = 94) and 12 mo (n = 97) after transplantation. Immunosuppression consisted of CsA or tacrolimus, CD25 mAb, mycophenolate mofetil, and prednisolone. CsA therapy increased the 6-mo risk for subclinical rejection. The prevalence of subclinical rejection was 38.8% in the CsA-treated and 15.2% in the tacrolimus-treated patient group (P = 0.012). Strikingly, no difference in the degree of interstitial SR–stained area was detectable between the two treatment groups. In particular, previous subclinical rejection episodes did not influence the degree of interstitial volume. Also, no difference in GFR occurred at 1 yr, when the mean GFR mounted 63 ml/min. No significant differences in the degree of interstitial SR–stained area could be observed at 6 and 12 mo between CsA- and tacrolimus-treated renal transplant recipients. Although CsA-treated patients developed significantly more subclinical rejections at 6 mo, this did not influence the degree of SR staining or the change in renal function at 1 yr.
Effect of natural allergen exposure during the grass pollen season on airways inflammatory cells and asthma symptoms.
Authors: R Djukanovic, I Feather, C Gratziou, A Walls, D Peroni, P Bradding, M Judd, P H Howarth, S T Holgate
Journal: Thorax (1996)

BACKGROUND: Bronchial challenge with allergen causes a specific form of airways inflammation consisting of an influx of neutrophils, eosinophils, and T cells. Because the relevance of the challenge model to clinical asthma is uncertain, the cellular changes that occur in the lungs of asthmatic subjects during natural seasonal allergen exposure were investigated. METHODS: Seventeen grass pollen sensitive asthmatic subjects with previously reported seasonal exacerbations of asthma kept records of symptoms and underwent fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy before and during the peak of the grass pollen season. The BAL cells were analysed for differential cell counts and by flow cytometry for T cell subsets and surface activation markers. The biopsy samples were processed into glycol methacrylate resin and immunohistochemical analysis was performed for mast cells, activated eosinophils, T cells and interleukin 4 (IL-4), a cytokine with a pivotal role in allergen-induced inflammation. RESULTS: In the pollen season there was an increase in T lymphocyte activation in the BAL fluid as identified by increased expression of interleukin 2 receptor (IL-2R). In the submucosa these changes were paralleled by an increase in CD4+ T cells. By contrast, the numbers of metachromatic cells in BAL fluid staining with toluidine blue were reduced, possibly because of degranulation following allergen stimulation. In keeping with mast cell activation, the number of mucosal mast cells staining for secreted IL-4 increased during the season. In comparison with the period shortly before the onset of the season, all but two subjects experienced an asthma exacerbation which followed the rise in pollen counts but, compared with the period preceding the first bronchoscopic examination, asthma symptoms were not increased during the pollen season. CONCLUSIONS: The data suggest that natural allergen exposure, leading to a clinical exacerbation of asthma, may induce an inflammatory response involving T cells, mast cells and eosinophils. The relationship between allergen exposure, cellular infiltration and activation, and clinical symptoms appears to be complex, with factors other than allergen also contributing to asthmatic activity.
Wnt-5a Protein Expression in Primary Dukes B Colon Cancers Identifies a Subgroup of Patients with Good Prognosis
Authors: Janna Dejmek, Annika Dejmek, Annette Säfholm, Anita Sjölander, Tommy Andersson
Journal: Cancer Research (2005)

Oncogenic Wnt/beta-catenin signaling occurs in a majority of colorectal cancers. In contrast, very little is known about the role of the nontransforming Wnt protein family member Wnt-5a in those tumors. In the most common of the three colon cancer stages, Dukes B or lymph node-negative, the outcome is the hardest to predict. We searched for a predictive marker in this group and observed loss of or reduced Wnt-5a expression in 50% of Dukes B tumors. Such Wnt-5a negativity was a strong predictor of adverse outcome, with a relative risk of death of 3.007 (95% confidence interval, 1.336-6.769; P = 0.008) after 5 years in Wnt-5a-negative patients. Furthermore, the median survival time after diagnosis was 109.1 months for patients with Wnt-5a-positive primary tumors but only 58 months for those with Wnt-5a-negative primary tumors. To find a possible biological explanation for these results, we studied the invasive and poorly differentiated human colon cancer cell line, SW480, which does not express Wnt-5a protein and the Wnt-5a-expressing and moderately differentiated Caco2 colon cancer cell line. We found that the addition of recombinant/purified Wnt-5a significantly reduced the migratory capacity of SW480 cells. By comparison, equivalent treatment did not significantly alter migration in the Wnt-5a-expressing Caco2 colon cancer cell line. These findings indicate that the expression of Wnt-5a in primary Dukes B colon cancer tissue constitutes a good prognostic marker for longer survival, which can be explained by the ability of Wnt-5a to impair tumor cell migration and thus reduce invasiveness and metastasis.
Rare diseases bullet 5: Primary pulmonary hypertension
Authors: A J Peacock
Journal: Thorax (1999)

Primary pulmonary hypertension (PPH) is a rare disorder with an incidence of one to two cases per million people per year in Western populations. It is a progressive disease usually affecting the arterial side of the pulmonary circulation and, if untreated, progresses to severe pulmonary hypertension and, finally, right heart failure. Characteristically, and because of the vague nature of the symptoms, PPH may take up to 18 months to diagnose and, following diagnosis, the median survival is under two years. The disease is most common in women (ratio 1.7:1) and the mean age at the time of diagnosis is in the mid 30s. This bleak picture of PPH has been transformed over the last decade, partly because of better diagnostic techniques allowing earlier diagnosis and also because of new treatments, in particular the use of continuous intravenous prostacyclin. It is now realised that vasoconstriction of the pulmonary vascular bed is not the primary cause of PPH but occurs in association with marked histological changes. These histological changes are seen not only in PPH but also in severe pulmonary hypertension in association with other disorders such as HIV infection, connective tissue disease, and the use of appetite suppressant drugs. The realisation that primary or unexplained pulmonary hypertension was the end of a spectrum of several diseases causing severe pulmonary hypertension has lent a new impetus to the understanding of the disease and prompted a major symposium sponsored by the World Health Organisation held in Evian, France, in September 1998. At this symposium were gathered clinical scientists from all over the world with an interest in pulmonary hypertension and the result was a consensus about classification of pulmonary hypertension, the pathobiological methods of screening, risk assessment, and treatment. The first part of this review considers the clinical aspects of pulmonary hypertension, in …
Against all odds: anti-IgE for intrinsic asthma?
Authors: Marek Lommatzsch, Stephanie Korn, Roland Buhl, Johann Christian Virchow
Journal: Thorax (2013)

For many years, pathogenetic concepts and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. However, there is now growing clinical and mechanistic evidence suggesting that treatment with the anti-IgE antibody omalizumab can be effective in patients with intrinsic asthma. Therefore, large and well-controlled clinical trials with anti-IgE are urgently warranted in patients with intrinsic asthma. In addition, there is a need to find new biomarkers which can identify patients with asthma who respond to anti-IgE treatment.
Maintenance bevacizumab–pemetrexed after first-line cisplatin–pemetrexed–bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial
Authors: F. Barlesi, A. Scherpereel, V. Gorbunova, R. Gervais, A. Vikström, C. Chouaid, A. Chella, J.H. Kim, M.J. Ahn, M. Reck, A. Pazzola, H.T. Kim, J.G Aerts, C. Morando, A. Loundou, H.J.M. Groen, A. Rittmeyer
Journal: Annals of Oncology (2014)
Orexins in the Regulation of the Hypothalamic-Pituitary-Adrenal Axis
Authors: Raffaella Spinazzi, Paola G. Andreis, Gian Paolo Rossi, Gastone G. Nussdorfer
Journal: Pharmacological Reviews (2006)

Orexin-A and orexin-B are hypothalamic peptides that act via two G protein-coupled receptors, named orexin type 1 and type 2 receptors (OX1-Rs and OX2-Rs). The most studied biological functions of orexins are the central control of feeding and sleep, but in the past few years findings that orexin system modulates the hypothalamic-pituitary-adrenal (HPA) axis, acting on both its central and peripheral branches, have accumulated. Orexins and their receptors are expressed in the hypothalamic paraventricular nucleus and median eminence and orexin receptors in pituitary corticotropes, adrenal cortex, and medulla. Whereas the effects of orexins on adrenal aldosterone secretion are doubtful, compelling evidence indicates that these peptides enhance glucocorticoid production in rats and humans. This effect involves a 2-fold mechanism: 1) stimulation of the adrenocorticotropin-releasing hormone-mediated pituitary release of adrenocorticotropin, which in turn raises adrenal glucocorticoid secretion; and 2) direct stimulation of adrenocortical cells via OX1-Rs coupled to the adenylate cyclase-dependent cascade. The effects of orexins on catecholamine release from adrenal medulla are unclear and probably of minor relevance, but there are indications that orexins can stimulate in vitro secretion of human pheochromocytoma cells via OX2-Rs coupled to the phospholipase C-dependent cascade. Evidence is also available that orexins enhance the growth in vitro of adrenocortical cells, mainly acting via OX2-Rs. Moreover, findings suggest that the orexin system may favor HPA axis responses to stresses and play a role in the pathophysiology of cortisol-secreting adrenal adenomas.
Radiation Pneumonitis: A Possible Lymphocyte-mediated Hypersensitivity Reaction
Authors: C. Michael Roberts
Journal: Annals of Internal Medicine (1993)

Objective: To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields. Design: A prospective, nonrandomized study. Patients: Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis. Measurements: History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis. Results: After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies. Conclusion: In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.
Mechanisms of fever induced by recombinant human interferon.
Authors: C A Dinarello, H A Bernheim, G W Duff, H V Le, T L Nagabhushan, N C Hamilton, F Coceani
Journal: Journal of Clinical Investigation (1984)

Since the early trials using human interferon (hIFN) derived from blood leukocytes or cell lines, fever has been a prominent component of IFN therapy. Human protein impurities might account for the fever to cell-derived hIFN, but recombinant hIFN, free of extraneous human proteins, has produced fever in nearly all recipients during clinical trials. Our present studies were carried out to determine the mechanisms of fever due to recombinant hIFN currently being used in humans. Because recombinant hIFN is produced in Escherichia coli, in these experiments we considered contaminating endotoxin as the cause of fever. Polymyxin B, which blocks endotoxin, had no effect on the pyrogenicity of hIFN in rabbits. In addition, hIFN injected into an endotoxin-resistant strain of mice produced fever. The pyrogenicity of hIFN does not appear to involve production of leukocytic pyrogen (LP), since no circulating LP was detected in rabbits during IFN fever. Furthermore, human mononuclear cells incubated with hIFN in vitro at 10(4)-10(6) U/ml did not release LP. However, hIFN stimulated prostaglandin E2 (PGE2) release from rabbit hypothalamic tissue in vitro. Intracerebroventricular injection of hIFN into the awake cat also produced fever and a rise in PGE2 levels in the cerebrospinal fluid; both effects were reversed by treatment with indomethacin. We conclude that the fever of recombinant hIFN is not due to endotoxin but that hIFN is intrinsically pyrogenic by inducing PGE2 in the hypothalamus.