tbuckley/cabot-search huggingface dataset:
QL-16 * COST EFFECTIVENESS ANALYSIS OF GLIOBLASTOMA MULTIFORME THERAPIES
Authors: K. Kimmell, D. Sanchez, N. Marko
Journal: Neuro-Oncology (2014)

BACKGROUND: Standard of care for glioblastoma multiforme (GBM) involves surgical resection plus chemoradiation. We recently published a survival model demonstrating personalized estimates of median survival that vary with patient-specific characteristics. We wished to build an econometric model to assess the costs of therapies for GBM. METHODS: Cost data from publicly available sources were used to construct a cost model based on our personalized predictor of GBM patient survival. We used the model to estimate median survival and cost of therapy for patients of various ages (40-90 years), Karnofsky Performance Scores (50-90), and extents of resection (0-100%). We analyzed surgery plus several adjuvant therapies (steroids, radiotherapy [XRT], temozolamide [TMZ], and XRT + TMZ). Cost effectiveness was calculated as cost per week of survival and cost per quality adjust life year (QALY). RESULTS: For surgery plus steroids, mean survival was 113 days (range 34-291), mean cost was $21,892 (range $15,167-23,782), mean cost per week of therapy was $1,614 (range $572-3,666), and mean cost/QALY was $130,149 (range $33,144-382,305). For surgery + XRT, mean survival was 155 days (range 46-399), mean cost was $35,017 (range $23,702-37,040), mean cost per week of therapy was $1,923 (range $552-4,283), and mean cost/QALY was $155,010 (range $32,009-446,611). For surgery + TMZ, mean survival was 184 days (range 48-476), mean cost was $58,732 (range $33,157-103,840), mean cost per week of therapy was $2,489 (range $1,527-5,440), and mean cost/QALY was $197,842 (range $88,472-472,753). For surgery + XRT + TMZ, mean survival was 253 days (range 76-653), mean cost was $82,018 (range $50,711-143,670), mean cost per week of therapy was $2,542 (range $1,541-4,695), and mean cost/QALY was $202,089 (range $89,283-489,670). CONCLUSION: Cost effectiveness of treatments for GBM is influenced by patient age, functional status, and extent of surgical resection. For many patients the estimated cost/QALY exceeds commonly-stated thresholds for cost-effective care, a finding that may inform future debate on GBM therapy.
Abstract 1653: Highly effective treatment of HER2-amplified breast cancers through the complete inactivation of the HER2-HER3 tumorigenic driver
Authors: Dhara N. Amin, Natalia Sergina, Deepika Ahuja, Martin McMahon, Donghui Wang, Byron Hann, Kevan Shokat, Mark M. Moasser
Journal: Cancer Research (2010)

Abstract Approximately 25% of breast cancers are driven by amplification of the HER2 oncogene and over-activity of the HER2-HER3 signaling complex. It is a promising hypothesis that the pharmacologic inactivation of HER2-HER3 signaling with tyrosine kinase inhibitors (TKIs) in patients will be a highly effective treatment for this disease. Treatment of HER2 amplified breast cancers with HER2 targeting agents shows that the HER2-HER3 complex is endowed with a two-log signal buffering capacity, making drug potency a critical and potentially limiting variable. The buffering capacity is mediated through Akt driven negative feedback signaling, which has the ability to amplify HER2-HER3 signaling and protect it against incomplete inhibition of HER2 kinase. The concomitant use of downstream inhibitors induces compound sensitizing and desensitizing mechanisms and incremental anti-tumor effects. The HER2-HER3 signal buffering mechanisms cannot ultimately compensate for the total loss of HER2 catalytic activity, and at fully inactivating doses of TKI, the failure to phosphorylate HER3 and the dual loss of MAPK and Akt pathway signaling leads to apoptotic tumor cell death. Such HER2-inactivating dosing is not tolerable in vivo using continuous schedules but is feasible and highly effective using intermittent dosing. We show that continuous dosing of the HER2 TKI, lapatinib, at its maximum tolerated dose in mice bearing HER2-amplified tumors produces modest growth inhibitory effects. However, a five day repeated intermittent schedule allows eight fold higher dosing and produces much more profound tumor regression and durable anti-tumor effects. Therefore high dose intermittent TKI therapy is an imminently testable clinical treatment hypothesis that can fully inactivate HER2-HER3 signaling by overpowering its signal buffering capacity, revealing a monotherapy potential in HER2-targeting TKIs that may surpass many of the combination therapy approaches currently being explored. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1653.
Serum antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease are mainly associated with ulcerative colitis. A correlation study between perinuclear antineutrophil cytoplasmic autoantibodies and clinical parameters, medical, and surgical treatment.
Authors: M Oudkerk Pool, P M Ellerbroek, B U Ridwan, R Goldschmeding, B M von Blomberg, A S Pena, K M Dolman, H Bril, W Dekker, J J Nauta
Journal: Gut (1993)

Perinuclear antineutrophil cytoplasmic antibodies have recently been demonstrated in the sera of patients with inflammatory bowel disease. Three hundred and sixty six sera obtained from 120 patients with ulcerative colitis, 105 patients suffering from Crohn's disease and 49 non-inflammatory bowel disease controls were tested in two laboratories, using an indirect immunofluorescence assay. In addition, a fixed-neutrophil enzyme linked immunoadsorbent assay (ELISA) was evaluated in one of the two laboratories. The results in the immunofluorescence test showed a high degree of correlation between the two laboratories (Kappa coefficient = 0.8). Ninety five of the 120 (79%) ulcerative colitis patients had a positive test whereas only 14 of the 105 (13%) patients with Crohn's disease were positive. Sera from four patients suffering from primary sclerosing cholangitis were positive as well as four of the 45 control sera (9%). The sensitivity of the perinuclear antineutrophil cytoplasmic antibody immunofluorescence test for the diagnosis of ulcerative colitis was 0.75 with a specificity of 0.88 and a positive predictive value of 0.88 (all sera). In the ELISA technique 37 of 94 ulcerative colitis sera and one of the 68 Crohn's disease sera were positive. In the control group only one of the patients suffering from primary sclerosing cholangitis reacted positively (32 non-inflammatory bowel disease sera tested). The ELISA technique had a high specificity (0.97), but a low sensitivity (0.39). There was no relation of perinuclear antineutrophil cytoplasmic antibodies in ulcerative colitis patients or in Crohn's disease patients with disease activity, duration of illness, localisation, extent of disease, previous bowel operations or medical treatment. The clinical significance of perinuclear antineutrophil cytoplasmic antibody positive and negative subsets in both groups of patients thus remains unexplained. Our study confirms that determination of serum antineutrophil cytoplasmatic antibodies in patients with inflammatory bowel disease may differentiate ulcerative colitis from Crohn's disease. Further immunological studies are needed to explain the absence of these antibodies in a subset of ulcerative colitis patients and their role in the pathogenesis of the disease.
Efficient Tet-Dependent Expression of Human Factor IX in Vivo by a New Self-Regulating Lentiviral Vector
Authors: Elisa Vigna, Mario Amendola, Fabrizio Benedicenti, Andrew D. Simmons, Antonia Follenzi, Luigi Naldini
Journal: Molecular Therapy (2005)

Regulation of gene expression represents a long-sought goal of gene therapy. However, most viral vectors pose constraints on the incorporation of drug-dependent transcriptional regulatory systems. Here, by optimizing the design of self-regulating lentiviral vectors based on the tetracycline system, we have been able to overcome the limitations of previously reported constructs and to reach both robust expression and efficient regulation from a single vector. The improved performance allows us to report for the first time effective long-term in vivo regulation of a human clotting Factor IX (hF.IX) transgene upon systemic administration of a single vector to SCID mice. We showed that hF.IX expression in the plasma could be expressed to therapeutically significant concentrations, adjusted to different set levels by varying the tetracycline dose, rapidly turned off and on, and completely recovered after each treatment cycle. The new vector design was versatile, as it successfully incorporated a tissue-specific promoter that selectively targeted regulated expression to hepatocytes. Robust transgene expression in the systemic circulation coupled to the ability to switch off and even adjust the expression level may open the way to safer gene-based delivery of therapeutics.
Arterial Drug Infusion: Pharmacokinetic Problems and Pitfalls
Authors: R. L. Dedrick
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article Arterial Drug Infusion: Pharmacokinetic Problems and Pitfalls Get access Robert L. Dedrick Robert L. Dedrick 2Biomedical Engineering and Instrumentation BranchDivision of Research Services, Building 13, Room 3W13, National Institutes of Health, Bethesda, MD 20892 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 2, 16 March 1988, Pages 84–89, https://doi.org/10.1093/jnci/80.2.84 Published: 16 March 1988 Article history Revision received: 10 November 1987 Accepted: 27 November 1987 Published: 16 March 1988
Response to Letter Regarding Article, “Comprehensive Use of Cardiopulmonary Exercise Testing Identifies Adults With Congenital Heart Disease at Increased Mortality Risk in the Medium Term”
Authors: Ryo Inuzuka, Gerhard-Paul Diller, Francesco Borgia, Leah Benson, Edgar LW Tay, Rafael Alonso-Gonzalez, Margarida Silva, Menelaos Charalambides, Lorna Swan, Konstantinos Dimopoulos, Michael A. Gatzoulis
Journal: Circulation (2012)

We thank Guazzi et al for their thoughtful comments regarding our article. 1Exertional oscillatory breathing (EOB) is recognized as an abnormal cardiopulmonary response in patients with heart failure.Although the precise pathophysiologic mechanism of EOB remains somewhat unclear, it is considered to reflect the deregulation of mechanical and neural feedback control mechanisms of the cardiopulmonary system.Several studies have demonstrated that EOB is a strong, effort-independent predictor of unfavorable outcome in patients with acquired heart failure.Abnormal breathing patterns at rest are reported in the setting of congenital heart disease, particularly so in the presence of cyanosis or right heart failure. 2 Moreover, increased ventilatory response to exercise (eg, VE/VCO 2 slope) is extreme among patients with cyanosis; the precise mechanisms by which cyanosis affects ventilation in these patients, however, is not well understood. 3A recent study reported that up to 58% of patients who have received a Fontan procedure had evidence of EOB. 4 It is possible that EOB is prevalent among adults with congenital heart disease and may relate to abnormal hemodynamics and physiology, including the effects of chronic cyanosis.When revisiting our study data, it seems that a significant proportion of patients (15.7%) demonstrated an EOB pattern, defined as 3 consecutive, regular oscillations in minute ventilation during exercise, with minute ventilation oscillation amplitude 25% of average minute ventilation persisting for 60% of exercise duration. 5We agree with Guazzi et al that the pathophysiology and clinical implications of EOB in the spectrum of adults with congenital heart disease needs to be elucidated in future studies.
beta2-glycoprotein-I (apolipoprotein H) and beta2-glycoprotein-I-phospholipid complex harbor a recognition site for the endocytic receptor megalin.
Authors: S K Moestrup, I Schousboe, C Jacobsen, J R Leheste, E I Christensen, T E Willnow
Journal: Journal of Clinical Investigation (1998)

Screening of serum by using a surface plasmon resonance analysis assay identified beta2-glycoprotein-I/apolipoprotein H as a plasma component binding to the renal epithelial endocytic receptor megalin. A calcium-dependent megalin-mediated beta2-glycoprotein-I endocytosis was subsequently demonstrated by ligand blotting of rabbit renal cortex and uptake analysis in megalin-expressing cells. Immunohistochemical and immunoelectron microscopic examination of kidneys and the presence of high concentrations of beta2-glycoprotein-I in urine of mice with disrupted megalin gene established that megalin is the renal clearance receptor for beta2-glycoprotein-I. A significant increase in functional affinity for purified megalin was observed when beta2-glycoprotein-I was bound to the acidic phospholipids, phosphatidylserine and cardiolipin. The binding of beta2-glycoprotein-I and beta2-glycoprotein-I- phospholipid complexes to megalin was completely blocked by receptor-associated protein. In conclusion, we have demonstrated a novel receptor recognition feature of beta2-glycoprotein-I. In addition to explaining the high urinary excretion of beta2-glycoprotein-I in patients with renal tubule failure, the data provide molecular evidence for the suggested function of beta2-glycoprotein-I as a linking molecule mediating cellular recognition of phosphatidylserine-exposing particles.
Leucocyte function in ulcerative colitis. Quantitative leucocyte mobilisation to skin windows and in vitro function of blood leucocytes.
Authors: J H Wandall, V Binder
Journal: Gut (1982)

Leucocyte function was evaluated by the in vivo mobilisation to skin windows with chambers and by the chemotactic, phagocytic, and nitro blue tetrazolium reducing capacity of blood leucocytes from 20 patients with ulcerative colitis. The total number of leucocytes mobilised to the chambers after 12 hours did not differ from those in 21 healthy volunteers. After 24 and 48 hours reduced number of leucocytes were mobilised by patients with ulcerative colitis (p less than 0.01). Correspondingly, the leucocyte migration rates were normal initially but were reduced after 18 hours Mobilisation in vivo was positively correlated to the blood neutrophil count (Rho:0.5549 po less than 0.02) but unrelated to clinical activity. Blood leucocytes showed reduced random migration in vitro as well as chemotactic response to casein (p less than 0.01). Serum independent and dependent phagocytosis did not differ from healthy volunteers. Nitro blue tetrazolium reduction by resting leucocytes was increased (p less than 0.01) in ulcerative colitis compared with controls. Our findings suggest altered in vivo mobilisation and in vitro migration of leucocytes in ulcerative colitis with increased spontaneous nitro blue tetrazolium reduction reflecting increased generation of potentially tissue damaging agents. The findings probably reflect changes secondary to the disease but which may be important in maintaining the inflammatory process.
Gastric flora in chronically mechanically ventilated patients. Relationship to upper and lower airway colonization.
Authors: L B Palmer, S V Donelan, G Fox, E Bellemore, W H Greene
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The oropharynx, stomach, and trachea are all potential reservoirs for gram-negative organisms in mechanically ventilated patients. The pathogenic importance of each site in respiratory infection may differ between mechanically ventilated patients who are medically stable and the critically ill, and these differences may be important in understanding the pathogenesis of nosocomial infection. We prospectively studied seven patients requiring chronic ventilatory assistance who were otherwise medically stable to determine the pattern of gram-negative colonization of these three sites. Serial weekly oropharyngeal, gastric, and tracheal cultures were taken over a 6-mo period in our Respiratory Care Unit for chronically ventilator-dependent patients. Pseudomonas aeruginosa (PA) was present more frequently and persistently in the trachea than the oropharynx and stomach (p < 0.01) and members of the family Enterobacteriaceae (Ent. species) were also observed more commonly in the trachea than the oropharynx (p < 0.01). PA was seen in 6.7% of gastric specimens whereas Ent. species were found in 40% of gastric specimens. Six identical strains from a total of 53 gastric isolates and 128 oropharyngeal isolates were cultured coincidentally from these two sites. Coincidental isolation of 11 strains was observed in 177 tracheal isolates and 53 gastric samples. Documented transfers from stomach to oropharynx ascertained by sequential isolation occurred in one of 118 cultures and transfer from stomach to trachea occurred in three of 134 cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
Suppressor of Cytokine Signaling-1 Is a Critical Regulator of Interleukin-7-Dependent CD8+ T Cell Differentiation
Authors: Mark M.W Chong, Ann L Cornish, Rima Darwiche, Edouard G Stanley, Jared F Purton, Dale I Godfrey, Douglas J Hilton, Robyn Starr, Warren S Alexander, Thomas W.H Kay
Journal: Immunity (2003)
Angiotensin II Type 2 Receptor Mediates Vascular Smooth Muscle Cell Apoptosis in Cystic Medial Degeneration Associated With Marfan’s Syndrome
Authors: Hirotaka Nagashima, Yasunari Sakomura, Yoshikazu Aoka, Kenta Uto, Kin-ichi Kameyama, Motoko Ogawa, Shigeyuki Aomi, Hitoshi Koyanagi, Naoko Ishizuka, Mitsuhide Naruse, Masatoshi Kawana, Hiroshi Kasanuki
Journal: Circulation (2001)

Cystic medial degeneration (CMD) is a histological abnormality that is common in the aortic diseases associated with Marfan's syndrome (MFS). Although little known about the mechanism underlying CMD, several recent reports have demonstrated that vascular smooth muscle cell (VSMC) apoptosis could play a substantial role in CMD. On the other hand, angiotensin II (Ang II) has been reported to play an important role in the regulation of VSMC growth and apoptosis via the Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R).To elucidate the role of Ang II signaling via the Ang II receptors in CMD, we investigated AT1R and AT2R mRNA expression and tissue concentration of Ang II in MFS aortas (n=10) and control aortas (n=12). Furthermore, we examined the effects of an ACE inhibitor, an AT1R blocker, and an AT2R blocker on serum deprivation-induced VSMC apoptosis by organ culture system. AT1R expression was significantly decreased (P<0.01) and AT2R expression was significantly increased (P<0.001) in MFS aortas compared with control aortas, and tissue Ang II concentration was significantly higher in CMD than in the control condition (P<0.01). Both the ACE inhibitor and AT2R blocker significantly inhibited serum deprivation-induced VSMC apoptosis (P<0.05), although the AT1R blocker did not inhibit apoptosis in cultured aortic media from MFS patients.Accelerated ACE-dependent Ang II formation and signaling via upregulated AT2R play a pivotal role in VSMC apoptosis in CMD, and the ACE inhibitor could have clinical value in the prevention and treatment of CMD.
Nodules and hyperthyroidism
Authors: B. Bury
Journal: BMJ (2009)

Pathologic α-syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD. <h3>Abstract:</h3> Pathological α-synuclein (α-syn) plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic α-syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the α-syn preformed fibril (PFF) and <i>Drosophila</i> α-syn transgenic models of pathologic α-syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic α-syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.
Antibody levels to parainfluenza, herpes simplex, varicella-zoster, cytomegalo virus, and measles virus in patients with connective tissue diseases.
Authors: J.L Kalliomäki, P Halonen
Journal: Annals of the Rheumatic Diseases (1972)

From the Departmetit of Medicinie anid the Departmenit of Virology, Uniiversity of Tuirkii, Tzrh-ki,, Finlanid Phillips and Christian (1969) reported that measles antibody titres are higher in patients with systemic lupus erythematosus (SLE) than in controls.Later (1970) they also found increased levels of antibody titres to parainfluenza type I virus in patients with SLE and in six patients with Reiter's syndrome, but the mean titres of patients with rheumatoid arthritis (RA) were not significantly different than those of normal subjects.The present report describes the antibody titres to parainfluenza type 1, herpes simplex, varicella-zoster, cytomegalo virus and measles virus in 48 patients with connective tissue diseases and in 48 normal subjects.The antibody survey of measles virus was carried out with complement fixation (CF), haemag- glutination inhibition (HI), and inhibition of salt- dependent haemagglutination (SDI).
Transplantation of livers from donors positive for antibody to hepatitis B core antigen: transmission of hepatitis B infection and clinical course
Authors: L. Castells, V. Vargas, J.F. Sanchez-Avila, F. Rodriguez, H. Allende, T. Pumarola, C. Margarit, R. Esteban, J. Guardia
Journal: Journal of Hepatology (2001)
Application of Clinical Indicators in the Emergency Department
Authors: Margaret R. O'Leary
Journal: JAMA (1989)

Clinical indicators were developed and used to assess the quality of patient care resulting from the system of shared responsibility between emergency department (ED) and radiology department faculty physicians for interpretation of ED roentgenograms. The first indicator—all discrepancies in roentgenogram interpretation between ED and radiology department faculty—measured an overall discrepancy rate of 3.3% (776 films). Three hundred fifty-two apparent discrepancies were not related to the accuracy with which ED faculty interpreted films, resulting in a revised overall discrepancy rate of 1.8%. The second indicator— undesirable patient care outcomes as a result of delayed accurate radiological diagnosis—measured an occurrence rate of 0 after clinical reevaluation of more than 99% of patients within 24 hours of initial ED evaluation. Aspects of the development and use of clinical indicators are discussed in relationship to the broader monitoring and evaluating process necessary for the continuous improvement of patient care. (<i>JAMA</i>. 1989;262:3444-3447)