tbuckley/cabot-search huggingface dataset:
ATPS-24MULTI-COMPARTMENTAL TARGETING OF GLIOBLASTOMA THROUGH THE EphA3 RECEPTOR
Authors: Denise Herpai, Sara Ferluga, Waldemar Debinski
Journal: Neuro-Oncology (2015)

Glioblastoma (GBM) is an aggressive primary brain tumor of dismal prognosis. We have been developing targeted cytotoxic therapies relying on differences primarily between tumor and normal cells. We hypothesize that to make this approach even more efficacious it needs to include other tumor environment compartments. To this end, we further explored EphA3, a protein receptor tyrosine kinase which plays a role in development and is present in GBM stem-like cells. We found high levels of EphA3 protein expression in the majority (8/10) of GBM specimens and GBM cells in culture express (6/9), and the EphA3 presence on the cell surface was demonstrated by flow cytometry. EphA3 receptor was up-regulated nearly 20 fold in GBM explant cells grown under tumorsphere-forming conditions. As GBM is heavily infiltrated by cells of myeloid origin, we examined whether EphA3 is present in those cells. By using confocal microcopy in situ we found that EphA3 co-stains with CD45+ leukocyte cells and also with CD68-expressing (pan-macrophage marker) cells. Nonetheless, the EphA3 receptor was not detected in the hippocampus in mice, but was clearly detected in an orthotropic GBM mouse model. EphrinA5 (eA5), the naturally occurring ligand for EphA3, binds two other Eph receptors; EphB2 and EphA2, and analysis of 10 GBM tumor lysates compared to normal brain confirmed over-expression of at least one of these three receptors in tumor samples. We generated a cytotoxin composed of eA5 chemically conjugated to PE38QQR, a modified Pseudomonas exotoxin A, which effectively killed GBM cells, but did not affect normal endothelial cells and mature dendritic cells. Therefore, EphA3 is an attractive candidate for molecular targeting as it is present on GBM tumor cells, immune cells of myeloid origin in the tumor microenvironment and glioma stem-like cells; while virtually absent in normal brain, mature dendritic cells and the hippocampus.
Case 6-2014
Authors: Phoebe H. Yager, Lynn M. Luginbuhl, John P. Dekker
Journal: New England Journal of Medicine (2014)

A 35-day-old boy was admitted to the pediatric intensive care unit because of fever, vomiting, and severe anemia. On admission, he had signs of respiratory distress and tachycardia, with a heart rate of 176 beats per minute. A diagnosis was made.
NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem–Like Cells in Adenoid Cystic Carcinoma
Authors: Alex Panaccione, Michael T. Chang, Beatrice E. Carbone, Yan Guo, Christopher A. Moskaluk, Renu K. Virk, Luis Chiriboga, Manju L. Prasad, Benjamin Judson, Saral Mehra, Wendell G. Yarbrough, Sergey V. Ivanov
Journal: Clinical Cancer Research (2016)

Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation.To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, andin vitro/in vivoassays for CSC viability and tumorigenicity.We identified in ACC CD133-positive CSC that expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. CD133(+)ACC cells produced activated NOTCH1 (N1ICD) and generated CD133(-)cells that expressed JAG1 as well as neural differentiation factors NR2F1, NR2F2, and p27Kip1. Knockdowns ofNOTCH1, SOX10, and their common effectorFABP7had negative effects on each other, inhibited spheroidogenesis, and induced cell death pointing at their essential roles in CSC maintenance. Downstream effects ofFABP7knockdown included suppression of a broad spectrum of genes involved in proliferation, ribosome biogenesis, and metabolism. Among proliferation-linked NOTCH1/FABP7 targets, we identified SKP2 and its substrate p27Kip1. A γ-secretase inhibitor, DAPT, selectively depleted CD133(+)cells, suppressed N1ICD and SKP2, induced p27Kip1, inhibited ACC growthin vivo, and sensitized CD133(+)cells to radiation.These results establish in the majority of ACC the presence of a previously uncharacterized population of CD133(+)cells with neural stem properties, which are driven by SOX10, NOTCH1, and FABP7. Sensitivity of these cells to Notch inhibition and their dependence on SKP2 offer new opportunities for targeted ACC therapies.
A phase II study testing the safety and activity of AGS-003 as an immunotherapeutic in subjects with newly diagnosed advanced stage renal cell carcinoma (RCC) in combination with sunitinib.
Authors: A. Amin, A. Dudek, T. Logan, R. S. Lance, J. M. Holzbeierlein, W. L. Williams, R. Jain, T. G. Chew, C. A. Nicolette, R. A. Figlin
Journal: Journal of Clinical Oncology (2010)

4588 Background: AGS-003 is an autologous immunotherapy prepared from matured monocyte-derived dendritic cells co-electroporated with the subject's own amplified tumor and synthetic CD40L RNA. Based on previous trial results with AGS-003 and the emergence of tyrosine kinase inhibitors as the standard of care, AGS-003 was evaluated in combination with sunitinib for treatment of advanced RCC. Methods: AGS-003-006 is an open label phase II trial enrolling subjects with newly diagnosed clear cell RCC. Post-nephrectomy, subjects received sunitinib (4wk on, 2wk off) and then concomitant AGS-003 injections (every 3wk × 5 doses, then every 3mo until progressive disease [PD] or end of study). AGS-003 was dosed as 3 intradermal injections containing 1 × 107 cells (targeted to a single lymph node basin). The 1o endpoint was to evaluate clinical activity as measured by the complete response (CR) rate. 2o endpoints included safety; clinical activity via estimates of progression free survival (PFS), overall survival (OS), stable disease (SD), partial response (PR), and CR rates; and measurement of immune response. Results: 25 subjects were enrolled and 21 dosed (intent to treat [ITT]). 3 subjects discontinued before the first dose of AGS-003 and 8 discontinued during treatment due to PD. Baseline characteristics for ITT subjects included median age=56yr (22-68); ECOG performance status, 0=71%, 1=29%; and MSKCC, intermediate risk=15, poor risk=6. Interim results demonstrated that 62% (13/21 subjects) experienced clinical benefit (2 PR, 11 SD). Preliminary median PFS from registration date for the ITT population=12.5 months (95% confidence interval 7.2, N/A). Conclusions: AGS-003 is well tolerated with no immunotherapy-related SAEs or grade 3/4 AEs reported. Promising interim data indicate that AGS-003 in combination with sunitinib yields a median PFS of 12.5 months in subjects with intermediate or poor risk factors. Updated PFS and OS data will be presented. No significant financial relationships to disclose.
A systems pathology approach to predict prostate cancer progression, post radical prostatectomy, at the time of diagnosis: Interim results from a multi-center study
Authors: M. J. Donovan, R. Mesa-Tejada, M. Teverovskiy, F. Khan, T. Gaffey, R. J. Karnes, C. Busch, M. Haggmanm, S. Freedland, P. C. Albertsen, C. Cordon-Cardo
Journal: Journal of Clinical Oncology (2008)

5062
Clinical Implications of Sickle-Cell Trait and Glucose-6-Phosphate Dehydrogenase Deficiency in Hospitalized Black Male Patients
Authors: Paul Heller, William R. Best, Rodney B. Nelson, Jack Becktel
Journal: New England Journal of Medicine (1979)

To determine whether sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency influence the course and fatality rates of certain diseases requiring hospitalization, especially those associated with thrombotic phenomena, we conducted a co-operative study of 65,154 consecutively admitted, black male patients in 13 Veterans Administration hospitals. The overall frequency of sickle-cell trait was 7.8 per cent and of glucose-6-phosphate dehydrogenase dificiency 11.2 per cent. Both conditions were present in 0.9 per cent of those examined. There were regional, but no age-dependent, differences in the frequency of sickle-cell trait. Sickle-cell trait had no effect on average age at hospitalization or death, overall mortality, length of hospitalization on medical and surgical wards and frequency of any diagnosis, except essential hematuria and pulmonary embolism. Although statistically significant (P less than 0.001), the differences for the latter were small (1.5 per cent of all patients with normal hemoglobin and 2.2 per cent of patients with sickle-cell trait). Glucose-6-phosphate dehydrogenase deficiency had no adverse effect.
Complications of Smallpox Vaccination
Authors: John M. Neff, J. Michael Lane, James H. Pert, Richard Moore, J. Donald Millar, Donald A. Henderson
Journal: New England Journal of Medicine (1967)

ALTHOUGH vaccination against smallpox has been practiced in the United States since 1800, little is known in this country regarding the frequency of resulting complications. Greenberg's1 review of complications observed after the mass vaccination program in New York in 1947 constitutes essentially the only published American data concerning the frequency of complications associated with vaccination. Even in this study, however, no estimates are available regarding the numbers associated with primary vaccination and with revaccination. Published reports from several European countries have recorded such striking differences in the frequencies of complications from country to country2 3 4 5 6 that it appears that each nation's . . .
Fetal Alloimmune Thrombocytopenia
Authors: James B. Bussel, Marcia R. Zabusky, Richard L. Berkowitz, Janice G. McFarland
Journal: New England Journal of Medicine (1997)

Alloimmune thrombocytopenia is a serious fetal disorder resulting from platelet-antigen incompatibility between the mother and fetus. The diagnosis is usually made after the discovery of unexpected neonatal thrombocytopenia. Approximately 10 to 20 percent of affected fetuses have intracranial hemorrhages, one quarter to one half of which occur in utero. We studied the correlates of thrombocytopenia in affected fetuses.
Vincristine Therapy of Idiopathic and Secondary Thrombocytopenias
Authors: Yeon S. Ahn, William J. Harrington, Robert C. Seelman, Charles S. Eytel
Journal: New England Journal of Medicine (1974)

Idiopathic thrombocytopenia refractory to glucocorticoids and splenectomy remains a serious problem. Prompt benefit was obtained from vincristine in six of seven patients not splenectomized who were refractory to glucocorticoids and in nine of 13 patients refractory to both glucocorticoids and splenectomy. Five of the nine were also refractory to cyclophosphamide or azathioprine or both. Vincristine also benefited 10 of 10 patients with thrombocytopenia and serologic evidence of lupus erythematosus or its variants, some patients with various forms of bone-marrow insufficiency, and three of three with thrombocytopenia due to lymphocytic leukemia. Vincristine accordingly appears to be indicated in the management of several forms of thrombocytopenia refractory to splenectomy and glucocorticoids. Its value as compared to vinblastine, azathioprine, and cyclophosphamide remains to be determined. (N Engl J Med 291:376–380, 1974)
Case 8-1995
Authors: H.R. Jones, M.A. Edgar
Journal: New England Journal of Medicine (1995)

Presentation of CaseA 75-year-old man was admitted to the hospital because of cranial-nerve deficits and a footdrop.The patient had been well until the age of 74 years and 3 months, when an erythematous, nonpruritic rash developed on the scalp, accompanied by anorexia, after an insect bite; the rash and anorexia resolved over a period of several weeks. Three months later he had Bell's palsy on the left side, with preauricular pain, which resolved partially after three weeks. Two weeks thereafter Bell's palsy developed on the right side, with preauricular pain. During the next few weeks there was the . . .
PTOV1 gene expression in prostate cancer
Authors: A. Wang-Gillam, R. Dennis, M. Kohli, V. Phooshkooru
Journal: Journal of Clinical Oncology (2005)

9632 Background: Identification of molecular markers for prostate cancer progression is critical for prognosis and therapeutic targeting. PTOV1 (prostate tumor over expressed) expression has recently been identified as a novel gene involved in promoting prostate cell proliferation by driving cells to enter S phase with an associated increase in cyclin D expression. PTOV1 levels are undetectable in normal prostate tissue and in prostate adenoma, but high in prostate carcinoma and prostate intraepithelial carcinoma. Additionally, PTOV1 has been correlated with PSA levels, making PTOV1 a potential marker for early disease detection and progression. However, PTOV1 levels did not correlate with low p27 levels or high Gleason score, both indicators of aggressive disease. Methods: In order to further characterize the association between PTOV1 and different stages of prostate cancer, we obtained fresh prostate tissue specimens from six advanced prostate carcinoma patients undergoing transurethral resection of prostate due to bladder outlet obstruction. All patients were receiving androgen deprivation. Tissue was also collected from nine patients with newly local stage cancer undergoing prostatectomy. mRNA was isolated from each specimen, and PTOV1 expression was measured by quantitative real-time RT-PCR. Results: All specimens analyzed in both groups expressed PTOV1. The mean expression level of PTOV1 (relative to normalized control, 18s) was lower (p<0.001) in the advanced prostate cancer group (3.75±0.45) compared to the early stage prostate cancer group (6.37±0.37). Conclusion: This study provides direct evidence that PTOV1 expression is decreased in advanced prostate cancer and may not correlate with later events in prostate carcinogenesis. It is not clear whether decreased expression in advanced stage disease is secondary to down-regulation of expression pathways associated with disease progression or due to the effect of androgen deprivation. To define this, further studies will focus on expression analysis in early stage disease patients undergoing neo-adjuvant androgen deprivation followed by prostatectomy to better define the role of hormonal influences on PTOV1 expression. No significant financial relationships to disclose.
Norepinephrine and Epinephrine Release and Adrenergic Mediation of Smoking-Associated Hemodynamic and Metabolic Events
Authors: Philip E. Cryer, Morey W. Haymond, Julio V. Santiago, Suresh D. Shah
Journal: New England Journal of Medicine (1976)

We studied the effects of cigarette smoking, sham smoking and smoking during adrenergic blockade in 10 subjects to determine whether smoking released the sympathetic neurotransmitter norepinephrine, as well as the adrenomedullary hormone epinephrine, and whether smoking-associated hemodynamic and metabolic changes were mediated through adrenergic mechanisms. Smoking-associated increments in mean (±S.E.M.) plasma norepinephrine (227±23 to 324±39 pg per milliliter, P<0.01) and epinephrine (44±4 to 113±27 pg per milliliter, P<0.05) were demonstrated. Smoking-associated increments in pulse rate, blood pressure, blood glycerol and blood lactate/pyruvate ratio were prevented by adrenergic blockade; increments in plasma growth hormone and cortisol were not. Since significant smoking-associated increments, in pulse rate, blood pressure and blood lactate/pyruvate ratio, preceded measurable increments in plasma catecholamine concentrations, but were adrenergically mediated, these changes should be attributed to norepinephrine released locally from adrenergic axon terminals within the tissues rather than to increments in circulating catecholamines. (N Engl J Med 295:573–577, 1976)
Epstein-Barr Virus Infections in Brazil. II. Hodgkin's Disease2
Authors: Alfred S. Evans, Renato P. S. Carvalho, Patricia Frost, Michel Jamra, Diana H. B. Pozzi
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Epstein-Barr Virus Infections in Brazil. II. Hodgkin's Disease Get access Alfred S. Evans, Alfred S. Evans 3World Health Organization Reference Bank, Department of Epidemiology and Public Health, School of Medicine, Yale University, 60 College St., New Haven, Conn. 06510. Search for other works by this author on: Oxford Academic PubMed Google Scholar Renato P. S. Carvalho, Renato P. S. Carvalho 4Departamento de Microbiologia e Imunologia do Instituto de Ciências Biomédicas e Instituto de Medicina Tropical de São Paulo da Universidade de São Paulo, São Paulo, Brazil. Search for other works by this author on: Oxford Academic PubMed Google Scholar Patricia Frost, Patricia Frost 5Research Corporation, New York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar Michel Jamra, Michel Jamra 6Faculdade de Medicina da Universidade de São Paulo. Search for other works by this author on: Oxford Academic PubMed Google Scholar Diana H. B. Pozzi Diana H. B. Pozzi 4Departamento de Microbiologia e Imunologia do Instituto de Ciências Biomédicas e Instituto de Medicina Tropical de São Paulo da Universidade de São Paulo, São Paulo, Brazil. 7We thank the São Paulo Cancer Registry for their help in this study and for data on Hodgkin's disease. We also thank Mrs. Betty Olson, Miss Joan Wanat, Miss Linda Cenabre, Miss Maria José de Oliviera Angelo, Mrs. Wanda A. U. F. Souza, Miss Lucy Nogueira Santos, and Miss Beth Soybel for technical assistance; Miss Virginia Richards for statistical analyses; and Dr. J. D. Niederman, Yale University, for his assistance in reading Epstein-Barr virus antibody tests and in attempts to isolate Epstein-Barr virus from the throat. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 1, July 1978, Pages 19–26, https://doi.org/10.1093/jnci/61.1.19 Published: 01 July 1978 Article history Received: 25 June 1976 Revision received: 11 January 1978 Accepted: 14 February 1978 Published: 01 July 1978
Comparison of acetorphan with clonidine for opiate withdrawal symptoms
Authors: F Hartmann, M F Poirier, M C Bourdel, H Loo, J M Lecomte, J C Schwartz
Journal: American Journal of Psychiatry (1991)

The authors compared the effects of acetorphan, an enkephalinase inhibitor, with those of clonidine for the treatment of the opioid withdrawal syndrome. Nineteen patients addicted to heroin or synthetic opiates who were undergoing drug withdrawal and displayed a withdrawal syndrome according to DSM-III criteria were studied for 5 days in a hospital setting. In a double-blind trial, 10 subjects were given acetorphan intravenously and nine were given clonidine; objective signs and subjective symptoms of withdrawal were recorded.On several objective signs, the effect of acetorphan was more marked than that of clonidine, whereas the two drugs exhibited similar efficacy with respect to the subjective components of withdrawal. No side effect was noted in the subjects who received acetorphan.Enkephalinase inhibition may constitute a novel and safe therapeutic approach to the opioid withdrawal syndrome.
Variegated RHOA mutations in adult T-cell leukemia/lymphoma
Authors: Yasunobu Nagata, Kenji Kontani, Terukazu Enami, Keisuke Kataoka, Ryohei Ishii, Yasushi Totoki, Tatsuki R. Kataoka, Masahiro Hirata, Kazuhiro Aoki, Kazumi Nakano, Akira Kitanaka, Mamiko Sakata-Yanagimoto, Sachiko Egami, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Yusuke Shiozawa, Tetsuichi Yoshizato, Hiromichi Suzuki, Ayana Kon, Kenichi Yoshida, Yusuke Sato, Aiko Sato-Otsubo, Masashi Sanada, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Satoru Miyano, Osamu Nureki, Tatsuhiro Shibata, Hironori Haga, Kazuya Shimoda, Toshiaki Katada, Shigeru Chiba, Toshiki Watanabe, Seishi Ogawa
Journal: Blood (2015)
A Hospital Study of Congestive Heart Failure
Journal: BMJ (1959)

Pulmonary heart failure, or cor pulmonale, is common in some parts of Britain, and Flint (1954) found that it accounted for a quarter of the cases of heart failure admitted to one Sheffield hospital (the City General Hospital). Yet, as was pointed out by Wood (1956), there are few comparative figures, and in the mortality statistics quoted by Southwood (1959) it receives scant mention. During 1954 to 1956 a study was made in hospitals of the Sheffield Hospital Region in order to compare the relative frequency of the various causes of heart failure in Sheffield and in other areas. A secondary purpose of the study was to compare the symptoms and signs, personal habits, occupation, and residence in the patients suffering from various forms of heart failure.
The Physiology of Parathyroid Hormone–Related Protein
Authors: Gordon J. Strewler
Journal: New England Journal of Medicine (2000)

Parathyroid hormone–related protein was identified in the 1980s as a tumor product that had the ability to activate parathyroid hormone receptors and cause hypercalcemia.1 Parathyroid hormone–related protein resembles parathyroid hormone not only in terms of its genetic sequence but also in terms of its genetic structure and is thus a second member of the parathyroid hormone family.2 As expected of a protein that activates the parathyroid hormone receptor, parathyroid hormone–related protein causes hypercalcemia by increasing bone resorption and renal tubular resorption of calcium.3,4 Like parathyroid hormone, it also has phosphaturic action.Parathyroid Hormone–Related Protein and HypercalcemiaParathyroid hormone–related protein . . .
P37 Frailty and its relationship to mortality in patients receiving acute non-invasive ventilation (NIV) for respiratory failure in a district general hospital
Authors: M Hatton, D Daley, L Hughes, BC Creagh-Brown, BC Creagh-Brown
Journal: Thorax (2015)

<h3>Introduction</h3> NIV is a treatment for acute respiratory acidosis in patients admitted with exacerbations of COPD. BTS audits have demonstrated that NIV is frequently used for other conditions, functional dependency is common and in-hospital mortality is high. Tools to prognosticate outcome from acute use of NIV tend to be disease-specific. Targeting the use of NIV to those who are most likely to benefit from it should be a clinical and ethical priority. Frailty relates to patient outcome in clinical settings including elderly patients with COPD and critical care admissions. We hypothesised that patients with higher frailty scores who receive NIV for acute respiratory failure have inferior outcomes, compared to those assessed as being less frail. <h3>Methods</h3> Prospective study of patients receiving acute NIV for respiratory failure; over 15 months. The respiratory physiotherapists manage all such patients and collect data into the EPR. An additional item of data was collected – the Clinical Frailty Scale (CFS). All analyses were by episode apart from demographics and mortality which were by individual. <h3>Results</h3> 89 patients received 110 episodes of acute NIV, median age 79, (range 23–97) years. Diagnoses: COPD (56%), Pneumonia and ‘other’ (30%), cardiogenic pulmonary oedema (4%), obesity-related (4%), chest wall/neuromuscular (7%). At initiation of NIV: median pH 7.26, PaCO2 9.8 kPa, PaO2 8.5 kPa. Duration of hospital stay, median 16.5 days, in-hospital mortality (28%). CFS median score 6, range (2–8). There was no correlation between CFS and age. CFS was statistically significantly higher in those who died (either during their index admission or during follow-up) than in those who survived – see Figure 1. Patients with a CFS of 7 or 8 had an in-hospital mortality of 40% and a total mortality of 80%. By contrast those with a CFS of less than 7 had an in-hospital mortality of 24% and a total mortality of 46%. <h3>Conclusions</h3> Patients receiving acute NIV who are very frail (CFS 7 or 8) are less likely to experience a mortality benefit. These data should inform discussions and decision-making about use of NIV.