tbuckley/cabot-search huggingface dataset:
Assessment of Methods for Tissue-Based Detection of the HER-2/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry
Authors: Giovanni Pauletti, Suganda Dandekar, HongMei Rong, Lilllian Ramos, HongJun Peng, Ram Seshadri, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2000)

To compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in detecting the HER-2/neu alteration in human breast cancer.Unselected stage I, II, and III breast cancer patients (N = 900) were tested for HER-2/neu gene amplification by FISH in paraffin-embedded, formalin-fixed archival material. Of these samples, 856 were tested for HER-2/neu overexpression by non-antigen-retrieval IHC with the polyclonal antibody R60, the sensitivity and specificity of which was preliminarily compared with the United States Food and Drug Administration-approved HercepTest (Dako Corp, Carpinteria, CA). Patient survival was analyzed in relation to the presence of the HER-2/neu alteration as determined by these two methodologies.A total of 189 (21%) of 900 patients were positive by FISH and 147 (17.2%) of 856 were positive by IHC. This discrepancy is consistent with expected loss of IHC sensitivity associated with tissue fixation/embedding. The HercepTest did not improve sensitivity and introduced false positives. Comparison of R60-based IHC with FISH demonstrates that patient survival is associated progressively to gene amplification level as determined by FISH, whereas for IHC an association is found only in the highest (3+) immunostaining group. Among FISH-negative tumors, 45 (6.6%) of 678 were IHC-positive, with a survival probability similar to that of FISH-negative/IHC-negative cases; FISH-positive/IHC-negative patients have a survival probability similar to that of FISH-positive/IHC-positive cases.IHC does not consistently discriminate patients likely to have a poor prognosis, whereas FISH provides superior prognostic information in segregating high-risk from lower-risk beast cancers. HER-2/neu protein overexpression in the absence of gene amplification occurs infrequently in breast cancer, in which case, patient outcome is similar to that of patients without the alteration.
Early onset of acute immune‐mediated lung injury in a child undergoing allogeneic peripheral blood transplantation
Authors: Julián Sevilla, Marta González‐Vicent, Luis Madero, Imelda González‐Mediero, Miguel A. Díaz
Journal: American Journal of Hematology (2001)

Abstract Animal models have recently clarified the lung injury after allogeneic hematopoietic transplantation. These works have confirmed the role of donor T lymphocytes in immune‐mediated inflammatory reactions in the lung. We report here a fatal case of a 3‐year‐old child who developed acute respiratory failure coinciding with the onset of hyper‐acute graft versus host disease (aGVHD) after allogeneic peripheral stem cell transplantation. aGVHD was refractory to treatment and the patient died on day +28. Lung necropsy showed interstitial pneumonia and peribronchial and perivascular infiltration by mononuclear cells, with no viral inclusions. These findings are not specific but have been found by some authors in animal models with acute immune‐mediated lung injury related with donor T lymphocytes. Immune‐mediated lung injury, as defined by animal models, should be considered in patients with severe signs of systemic aGVHD while excluding other known etiologies of pulmonary disease. Am. J. Hematol. 69:56‐58, 2002. © 2002 Wiley‐Liss, Inc.
A simple technique of anaesthesia for experimental open-heart surgery in the calf
Authors: M. P. Singh, R. L. Elliott, D. G. Melrose
Journal: Thorax (1971)

A safe and simple technique of anaesthesia has been developed for the calf, which is increasingly in demand for experimental testing of prosthetic heart valves and other cardiac devices. In view of the calf9s sensitivity to anaesthetics, a minimal number of short-acting agents was employed. Pulmonary complications, to which the calf is said to be so susceptible, were eliminated by a greater control over the artificial respiration. No deaths occurred due to anaesthesia in 35 calves.
Complications in Cardiothoracic Surgery
Journal: Thorax (1992)

Diagnostic value of lung clearance of SSmTc DTPA compared with other non- invasive investigations in Pneumocystis carinii pneumonia in AIDS We read with interest the paper by Dr D S Robinson and others (October 1991;46:722- 6), which reported the finding of a biphasic or biexponential DTPA clearance curve and its use in the management of patients with HIV infection and pneumocystis pneumonia.We have found the test sensitive and useful.'2There are, however, some issues raised by the method used that are worth exploring.The most crucial point is the lack of separation of the patients with pneumocystis pneumonia and those that are smokers without pneumo- cystis pneumonia.This observation makes the suggestion that an analysis of the first seven minutes of data acquisition is suffi-
Distribution and changing density of gamma-delta T cells in murine skin during the induced hair cycle
Authors: R. PAUS, U. HOFMANN, S. EICHMULLER, B.M. CZARNETZKI
Journal: British Journal of Dermatology (1994)

Journal Article Distribution and changing density of gamma‐delta T cells in murine skin during the induced hair cycle Get access R. PAUS, R. PAUS Department of Dermatology, University Hospital R.Virchow, Freie Universität Berlin, D‐13344 Berlin, Germany *Correspondence: Dr R.Paus, Hautklinik, UKRV, FU Berlin, D‐1000 Berlin 65, Germany. Search for other works by this author on: Oxford Academic Google Scholar U. HOFMANN, U. HOFMANN Department of Dermatology, University Hospital R.Virchow, Freie Universität Berlin, D‐13344 Berlin, Germany Search for other works by this author on: Oxford Academic Google Scholar S. EICHMÜLLER, S. EICHMÜLLER Department of Dermatology, University Hospital R.Virchow, Freie Universität Berlin, D‐13344 Berlin, Germany Search for other works by this author on: Oxford Academic Google Scholar B.M. CZARNETZKI B.M. CZARNETZKI Department of Dermatology, University Hospital R.Virchow, Freie Universität Berlin, D‐13344 Berlin, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 130, Issue 3, 1 March 1994, Pages 281–289, https://doi.org/10.1111/j.1365-2133.1994.tb02922.x Published: 01 March 1994 Article history Accepted: 28 July 1993 Published: 01 March 1994
DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes
Authors: Richard D. Kennedy, Alan D. D'Andrea
Journal: Journal of Clinical Oncology (2006)

Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair. Cancer cells are often defective in one of six major DNA repair pathways, namely: mismatch repair, base excision repair, nucleotide excision repair, homologous recombination, nonhomologous endjoining and translesion synthesis. The specific DNA repair pathway affected is predictive of the kinds of mutations, the tumor drug sensitivity, and the treatment outcome. The study of rare inherited DNA repair disorders, such as Fanconi anemia, has yielded new insights to drug sensitivity and treatment of sporadic cancers, such as breast or ovarian epithelial tumors, in the general population. The Fanconi anemia pathway is an example of how DNA repair pathways can be deregulated in cancer cells and how biomarkers of the integrity of these pathways could be useful as a guide to cancer management and may be used in the development of novel therapeutic agents.
A Tribute to Willem Johan Kolff, M.D., 1912–2009
Authors: Lee W. Henderson
Journal: Journal of the American Society of Nephrology (2009)

Willem J. Kolff, M.D., 97, inventor of the first artificial organ to reliably sustain life, died of congestive heart failure on February 11, 2009, in Newtown Square, PA. Dr. Kolff is widely considered the “father of artificial organs.” His rotating drum artificial kidney was initially reported in 1943 and, for the first time, offered an effective intervention for the treatment of acute renal failure.1 It was in The Netherlands during World War II at the height of German occupation that he began work on the first dialysis machine. He had moved to a small hospital in Kampen, on the Zuider Zee, to escape the Nazi sympathizers who had been put in charge of his hospital at Groningen. There, conducting bench experiments with sausage casing (Visking Casing Corporation), saline, and urea, he saw that urea moved down its concentration gradient and equilibrated across this cellulosic membrane. He then cobbled together his rotating drum artificial kidney from miscellaneous available parts including bed slats, a bathtub, and sundry tubing connectors of considerable sophistication. It is the only artificial kidney where uremic blood is circulated through tubing that itself is moving through a stationary noncirculating dialysis bath. The membrane area employed was 2 to …
Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models
Authors: Roberta Rosa, Roberta Marciano, Umberto Malapelle, Luigi Formisano, Lucia Nappi, Claudia D'Amato, Valentina D'Amato, Vincenzo Damiano, Gabriella Marfè, Silvana Del Vecchio, Antonella Zannetti, Adelaide Greco, Alfonso De Stefano, Chiara Carlomagno, Bianca Maria Veneziani, Giancarlo Troncone, Sabino De Placido, Roberto Bianco
Journal: Clinical Cancer Research (2012)

Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the "sphingolipid rheostat"-the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P)-due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described.We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro/in vivo models, and in tumor specimens from patients.SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients.
Cyclopamine cooperates with EGFR inhibition to deplete stem-like cancer cells in glioblastoma-derived spheroid cultures
Authors: Sandrine Eimer, Frédéric Dugay, Kelly Airiau, Tony Avril, Véronique Quillien, Marc-Antoine Belaud-Rotureau, Francis Belloc
Journal: Neuro-Oncology (2012)

Putative cancer stem cells have been identified in glioblastoma (GBM), associated with resistance to conventional therapies. Overcoming this resistance is a major challenge to manage this deadly brain tumor. Epidermal growth factor receptor (EGFR) is commonly amplified, over-expressed, and/or mutated in GBM, making it a compelling target for therapy. This study investigates the behavior of 3 primary neurosphere (NS) cell lines and their adherent counterparts originated from human GBM resections, when treated with EGFR–tyrosine kinase inhibitor erlotinib, associated or not with cyclopamine, a hedgehog pathway inhibitor. Adherent cells cultured in the presence of serum expressed the glial fibrillary acidic protein, whereas NS-forming cells cultured in serum-free medium expressed CD133, nestin, and Oct-4, markers of neural stem and progenitor cells. For the 3 adherent cell lines, erlotinib has a moderate effect (50% inhibitory concentration [IC50], >10 µM). Conversely, erlotinib induced a strong cell growth inhibition (IC50, <1 µM) on NS-forming cells, related to the EGFR gene amplification and EGFR protein expression. A short exposure to erlotinib reduced nestin-positive cell proliferation, but NS-initiating activity and self-renewal were not altered. EGFR pathway seems essential for GBM progenitor cell proliferation but dispensable for cancer stem-like cell self-renewal. Inhibition of hedgehog pathway with cyclopamine was evaluated in association with erlotinib on NS growth. Although each drug separately had no effect on sphere initiation, their combination significantly decreased the sphere number (P < .001). Our findings show synergic efficiency for erlotinib-cyclopamine association and provide a suitable in vitro model to explore drug combinations on GBM cells.
Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice
Authors: Timothy Kottke, Geoff Hall, Jose Pulido, Rosa Maria Diaz, Jill Thompson, Heung Chong, Peter Selby, Matt Coffey, Hardev Pandha, John Chester, Alan Melcher, Kevin Harrington, Richard Vile
Journal: Journal of Clinical Investigation (2010)

Clinical trials of oncolytic virotherapy have shown low toxicity and encouraging signs of efficacy. However, it remains critically important to develop methods for systemic viral delivery if such therapies are to be clinically implemented to treat established tumors. In this respect, much effort is being focused on combining oncolytic viruses with standard treatment modalities such as inhibitors of VEGF165 (an alternatively spliced isoform of VEGF-A) signaling, which are widely used to treat several different cancers. Here, we have demonstrated that combining VEGF165 inhibitors with systemic delivery of oncolytic viruses leads to substantial regression and cure of established tumors in immunocompetent mice. We have shown that manipulating VEGF165-mediated signaling by administering VEGF165 to mice harboring mouse melanoma cells that do not express VEGF165 and by administering a VEGF inhibitor and then withdrawing treatment to allow VEGF levels to rebound in mice harboring mouse melanoma cells expressing VEGF165 allows tumor-associated endothelial cells transiently to support viral replication. This approach led to direct tumor cell lysis and triggered innate immune-mediated attack on the tumor vasculature. It also resulted in long-term antitumor effects, even against tumors in which viral replication is poorly supported. Since this combinatorial approach targets the tumor endothelium, we believe these data have direct, wide-ranging, and immediate clinical applicability across a broad range of tumor types.
Mutations in Fibrillin-1 Cause Congenital Scleroderma: Stiff Skin Syndrome
Authors: B. L. Loeys, E. E. Gerber, D. Riegert-Johnson, S. Iqbal, P. Whiteman, V. McConnell, C. R. Chillakuri, D. Macaya, P. J. Coucke, A. De Paepe, D. P. Judge, F. Wigley, E. C. Davis, H. J. Mardon, P. Handford, D. R. Keene, L. Y. Sakai, H. C. Dietz
Journal: Science Translational Medicine (2010)

Stiff skin syndrome, an autosomal dominant congenital form of scleroderma, is caused by mutations in the domain of fibrillin-1 that mediates integrin binding.
Stressful Life Events and the Metabolic Syndrome
Authors: Antti-Jussi Pyykkönen, Katri Räikkönen, Tiinamaija Tuomi, Johan G. Eriksson, Leif Groop, Bo Isomaa
Journal: Diabetes Care (2009)

Stress may play a role in the pathogenesis of the metabolic syndrome. However, the scant evidence available is not population-based, restricting the external validity of the findings. Our aim was to test associations between stressful life events, their accumulation, and the metabolic syndrome in a large population-based cohort. We also tested associations between stress and the individual components related to the metabolic syndrome.This was a population-based, random sample of 3,407 women and men aged 18-78 years residing in Western Finland. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation criteria. The severity of 15 stressful life events pertaining to finance, work, social relationships, health, and housing was self-rated.In comparison with subjects not reporting any extremely stressful life events, those reporting work- or finance-related events had an increased odds for having the metabolic syndrome. The risk was further increased according to accumulation of stressful finance-related events and to having at least three stressful life events in any of the life domains assessed. Accumulation of stressful life events was associated with insulin resistance, obesity, and triglycerides. The associations were not confounded by sex, age, lifestyle, or family history of diabetes.Life events perceived as stressful, particularly those related to finance and work, may be a signal for poor metabolic health.
Glycolysis in the control of blood glucose homeostasis
Authors: Xin Guo, Honggui Li, Hang Xu, Shihlung Woo, Hui Dong, Fuer Lu, Alex J. Lange, Chaodong Wu
Journal: Acta Pharmaceutica Sinica B (2012)

Glycolysis, a simple pathway of glucose metabolism, critically regulates insulin secretion and metabolic functions of various cells. Depending on cell types, rates of glycolysis are determined at various steps of glycolysis that are subjected to the control of key metabolic and regulatory enzyme(s), which include glucokinase, 6-phosphofructo-1-kinase, and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. These enzymes are regulated by both nutritional and hormonal signals at the levels of transcription, translation, and post-translational modifications. In hepatocytes, glycolysis is involved in the control of hepatic glucose production. The latter, when excessive, contributes to hyperglycemia in diabetes. In pancreatic β cells, glycolysis couples glucose-stimulated insulin secretion. Absolute or relatively low levels of circulating insulin causes hyperglycemia. In adipocytes, glycolysis generates metabolites for lipogenesis and channels fatty acids from excessive oxidation to triglyceride synthesis, thereby reducing oxidative stress. With increased proinflammatory status, adipocytes produce pro-hyperglycemic factors and bring about hyperglycemia and insulin resistance. In hypothalamic neurons, glycolysis conveys nutrient sensing that is related to feeding control. Dysregulation of glycolysis occurs in conditions of insulin deficiency or resistance, and is attributable to inappropriate amount and/or activities of metabolic and regulatory enzymes of glycolysis. Targeting key metabolic and regulatory enzymes to enhance glycolysis may offer viable approaches for treatment of diabetes.
S119 UK HOT-HMV Trial: Acceptability and tolerability of high pressure domiciliary non-invasive ventilation (NIV) in COPD
Authors: P. B. Murphy, J. Moxham, M. I. Polkey, N. Hart
Journal: Thorax (2011)

<h3>Introduction</h3> Domiciliary NIV in COPD remains controversial with previous randomised controlled trials showing little clinical benefit. However, these trials have been criticised for using low pressure NIV and consequently nocturnal hypoventilation occurs. In contrast, there are genuine concerns that patients may not be able to tolerate the high pressure domiciliary NIV required to manage nocturnal hypoventilation effectively. <h3>Method</h3> Patients admitted for acute hypercapnic respiratory failure due to an exacerbation of COPD with persistent hypercapnia (PaCO<sub>2</sub>&gt;7 kPa) 2–4 weeks following resolution of acute episode were offered participation into the trial. Patients were randomised to either home oxygen therapy (HOT) or home mechanical ventilation (HMV) and followed up at 6 weeks and 3 months. Patient assessment included anthropometrics, arterial blood gases and health related quality of life measures. Sleep disruption was assessed using actigraphy (Actiwatch spectrum, Philips-Respironics, Murrysville, Pennsylvania, USA) for 7 days following the assessment. <h3>Results</h3> 36 patients have been recruited and randomised to date. Abstract S119 table 1 show the baseline data for 20 patients that have completed follow-up to 3 months. Discharge ventilator settings were IPAP 26±3 cmH<sub>2</sub>O, EPAP 5±1 cmH<sub>2</sub>O and back up rate 15±1 bpm in the HMV group. Total sleep time during the first 2 weeks of HMV was significantly shorter than in those patients receiving HOT (?88 min; 95% CI 5 to 172 min, p=0.04). However, by 6 weeks there was no difference between the groups (Δ66 min; 95% CI −62 to 194 min, p=0.3). This was sustained at 3 months (Δ51 min; 95% CI −100 to 202 min, p=0.5). There were no between group differences in wake after sleep onset, sleep efficiency or sleep latency at initial assessment or subsequent follow-up. Ventilator compliance at 6 weeks was 3 h 41 min ±1 h 41 min and at 3 months was 4 h 30 min ±1 h 44 min. <h3>Conclusion</h3> A reduction in total sleep time between patients receiving HMV compared with those receiving HOT was demonstrated during the initial period of acclimatisation to HMV. However, despite increasing ventilator usage during the follow-up period the difference in sleep duration between treatment groups reduced suggesting improved tolerability to NIV.
Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma
Authors: K. M. Schmainda, M. Prah, J. Connelly, S. D. Rand, R. G. Hoffman, W. Mueller, M. G. Malkin
Journal: Neuro-Oncology (2014)

The anti-VEGF antibody, bevacizumab, is standard treatment for patients with recurrent glioblastoma. In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response. Here we evaluate the prognostic significance of pre- and posttreatment relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI to predict response to bevacizumab.Thirty-six participants with recurrent high-grade gliomas who underwent rCBV imaging 60 days before and 20-60 days after starting bevacizumab treatment were enrolled. Tumor regions of interest (ROIs) were determined from deltaT1 maps computed from the difference between standardized post and precontrast T1-weighted images. Both pre- and posttreatment rCBV maps were corrected for leakage and standardized (stdRCBV) to a consistent intensity scale. The Kaplan-Meier method was used to determine if either the pre- or post-bevacizumab stdRCBV within the tumor ROI was predictive of overall survival (OS) or progression free survival (PFS).The OS was significantly longer if either the pre- (380d vs 175d; P=.0024) or posttreatment stdRCBV (340d vs 186d; P = .0065) was <4400. The posttreatment stdRCBV was also predictive of PFS (167d vs 78d; P = .0006). When the stdRCBV values were both above versus both below threshold, the OS was significantly worse (100.5d vs 395d; P < .0001). With a 32.5% decrease in stdRCBV, the risk of death was reduced by about 68% but increased by 140% with a 29% increase in stdRCBV.Standardized rCBV is predictive of OS and PFS in patients with recurrent high-grade brain tumor treated with bevacizumab.