tbuckley/cabot-search huggingface dataset:
A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies
Authors: David A. Rizzieri, Eric Feldman, John F. DiPersio, Nashat Gabrail, Wendy Stock, Roger Strair, Victor M. Rivera, Maher Albitar, Camille L. Bedrosian, Francis J. Giles
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies. Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed. Results: Fifty-five patients received deforolimus as follows: cohort 1 23 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus. Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.
Further experience in the use of ancrod (Arvin) to prevent thrombosis on prosthetic heart valves
Authors: M. P. Singh, W. R. Pitney, D. G. Melrose
Journal: Thorax (1971)

Intravenous administration of ancrod produces hypofibrinogenaemia, which may be prolonged by further doses. Hypofibrinogenaemia, maintained for a week, was used to prevent thrombosis on prosthetic heart valves in the calf. Thirteen calves were used in the study. Three of these were used to determine dose schedules and to test antibody formation. The calf was found to have hyperactive fibrinogenesis, and doses higher than previously reported were required to maintain prolonged hypofibrinogenaemia. Antibodies were detected in the calves treated for prolonged periods and the phenomenon was probably related to the massive dosage required. In 10 calves, the tricuspid valve was replaced with a polypropylene valve, using cardiopulmonary bypass. Two of these calves, used as controls and not treated with ancrod, showed massive thrombus formation on the valves. The remaining eight calves were treated with ancrod on different dose schedules. In four calves consistent low fibrinogen levels were not achieved. In the other four, treated by a continuous infusion of ancrod, 8-10 units/kg of body weight per day supplemented further by twice daily intravenous injections of 8·0 units/kg, it was possible to maintain sufficiently low fibrinogen levels and to prevent thrombus formation on the valves. In man, hypofibrinogenaemia is more easily maintained and antibody formation is less likely with the small dosage needed.
Relationship between obstructive sleep apnoea, driving simulator performance, and risk of road traffic accidents
Authors: P M Turkington
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Obstructive sleep apnoea (OSA) has been shown to be associated with an increased risk of road traffic accidents (RTAs). Predicting the driving ability and risk of RTAs in an individual with OSA is difficult. On-road testing is the gold standard, but this is time consuming, expensive, and potentially dangerous. Simple computer based driving simulators have been developed to help determine driving ability. Although patients with OSA have been shown to perform poorly compared with matched controls, it is not known whether these simulators can predict those at most risk of accidents. In this study we evaluated whether data derived from a simple driving simulator provided information over and above that obtained from the history and a sleep study that might be useful for advising patients about driving. <h3>METHODS</h3> We examined 150 patients admitted for routine sleep studies for investigation of OSA and snoring. Each patient performed a 20 minute driving simulation and completed a questionnaire regarding their driving history and experience. <h3>RESULTS</h3> Logistic regression analysis was used to investigate factors associated with patients9 performance on the simulator. It was found that patient characteristics, older age (OR 1.05, 95% CI 1.01 to 1.09, p&lt;0.01), female sex (OR 9.32, 95% CI 1.09 to 79.4, p&lt;0.04), and self-reported alcohol consumption (OR 1.04, 95% CI 1.01 to 1.07, p&lt;0.01) had the greatest influence; however, the number of self-reported near miss accidents was independently associated with a poor performance (OR 2.62, 95% CI 1.00 to 6.88, p&lt;0.05). A further logistic regression was used to investigate whether clinical history, sleep study results, and data from the driving simulator were useful in classifying patients with OSA as having had an RTA. The number of off-road events per hour on the simulator was independently associated with a history of previous RTA (OR 1.004, 95% CI 1.0004 to 1.008, p&lt;0.03). The Epworth score was independently associated with episodes of falling asleep at the wheel (OR 1.21, 95% CI 1.12 to 1.31, p&lt;0.00001) and near miss accidents (OR 1.15, 95% CI 1.07 to 1.23, p&lt;0.0001). Using this model, 100% of patients who did not have an accident could be identified, but only 10% of those who did. <h3>CONCLUSIONS</h3> Although factors not directly related to OSA influence performance on a driving simulator, there is an independent relationship between driving ability in patients with OSA and performance on a simple computer based simulator. When combined with clinical history, it is those not reporting hypersomnolence and not having off-road events on the simulator who appear to be at least risk of adverse driving events. Poor performance on the simulator, however, relates poorly to accident history. These data require confirmation in future studies before simple computer simulators can be used in clinical practice to advise whether an individual is safe to drive.
Activation of HIF2α in Kidney Proximal Tubule Cells Causes Abnormal Glycogen Deposition but not Tumorigenesis
Authors: Leiping Fu, Gang Wang, Maria M. Shevchuk, David M. Nanus, Lorraine J. Gudas
Journal: Cancer Research (2013)

Abstract Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1α (HIF1α) and HIF2α has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2α (P405A, P530A, and N851A, named as HIF2αM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1αM3 oncogenesis when coexpressed with constitutively active HIF1αM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), γH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2α is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2α activation is critical for ccRCC tumorigenesis. Cancer Res; 73(9); 2916–25. ©2013 AACR.
Diabetes Treatment and Measures of Glycemia
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2009)

This is the fourth of a series of six articles based on presentations at the American Diabetes Association Scientific Sessions held 6–10 June 2008 in San Francisco, California.

### Incretin treatment

Visboll et al. (abstract 1465) studied 13 women with gestational diabetes mellitus during the third trimester and 2–3 months following delivery, showing almost a doubling of the insulin secretory effect of oral glucose over that of intravenous glucose, evidence of reversibility of the reduced incretin effect of type 2 diabetes with improvement in glycemia. Yokoo et al. (abstract 1597) identified a protein, CF266, expressed in the intestine, which increased glucose-stimulated islet insulin secretion and appeared to have β-cell trophic effects—perhaps a novel incretin. (Abstract numbers refer to the ADA Scientific Sessions, Diabetes 57 [Suppl. 2], 2008).

A number of studies were presented of glucagon-like peptide-1 (GLP-1) receptor activators. Novel formulations are being explored. Asakura et al. (abstract 12) synthesized glycosylated GLP-1 by chemical and enzymatic modifications, showing resistance to degradation by dipeptidyl peptidase - 4 with preservation of GLP-1 receptor binding and functional activity and with a 10- to 100-fold increase in duration of activity and glucose-lowering potency in db/db mice. Blase et al. (abstract 195) administered 60–1,800 μg intranasal exenatide in a formulation containing an absorption enhancer to 17 type 2 diabetic patients, finding therapeutic plasma levels and reduction in glycemia after a standardized meal. Although nausea, vomiting, and sneezing occurred in 6, 5, and 2 patients, respectively, this might be an effective therapeutic approach. Costello et al. (abstract 198) administered GLP-1 adsorbed to Technosphere microparticles by inhalation in 26 healthy individuals, with a rapid increase in plasma GLP-1 to levels >100 pmol/l at 1 and 1.5 mg doses, respectively, increasing insulin and reducing glucose levels. Nausea and vomiting were not reported, although cough and headache occurred. Drucker et al. (abstact …
Evolution of Breast-Conserving Therapy for Localized Breast Cancer
Authors: Stuart J. Schnitt, Jay R. Harris
Journal: Journal of Clinical Oncology (2008)

foci of invasive carcinoma. The 5-year results for our patients treated between 1968 and 1982 are summarized in Table 1. EICpositive cancers were noted to be more common in premenopausal than postmenopausal patients. “Other” recurrences in Table 1 were predominantly at distant sites, whereas local recurrences were mainly at or near the primary site in the breast. Table 1 indicates that local recurrence was uncommon in patients with EIC-negative cancers and common in patients with EIC-positive cancers. It was interesting to note that EIC-positive cancers were not a biologically more aggressive form of breast cancer; if anything, patients with EIC-positive breast cancer had a lower rate of “other” recurrences than patients with EIC-negative cancers. Patients with EICpositive cancers also did not have a higher rate of contralateralbreast cancer than patients with EIC-negative cancers (data not shown here). This suggested to us that the problem with EICpositive cancers was in the segment of the primary disease. We eventually began to ink and microscopically evaluate the margins of resected breast specimens and encouraged our surgical colleagues to perform re-excisions if the margins were positive. We subsequently found and reported that EIC-positive cancers commonly had considerable residual DCIS on re-excision, whereas EIC-negative cancers uncommonly had considerable residual disease. 2 We also collaborated with Roland Holland, MD, who had performed whole-organ studies of mastectomy specimens in patients with breast cancer, documenting the presence, type, and extent of additional microscopic disease beyond the tumor mass. Together, we found that EIC-positive cancers frequently had extensive additional microscopic disease (mainly DCIS), whereas EIC-negative cancers uncommonly had extensive additional disease. 3 Figure 1 is taken from our 1990 JCO article, which reported
Mediastinal non-seminomatous germ cell tumours (MNSGCT) treated with cisplatin-based combination chemotherapy
Authors: M. Hidalgo, L. Paz-Ares, F. Rivera, P. Lianes, G. Huidobro, A. Ruiz, M. López-Brea, J. Sanz-Ortiz, J. López-López, H. Cortes-Funes, J.M. Tabernero
Journal: Annals of Oncology (1997)
Preferential hemolysis of immature erythrocytes in experimental iron deficiency anemia: source of erythropoietic bilirubin formation
Authors: Stephen H. Robinson, Ellen Koeppel
Journal: Journal of Clinical Investigation (1971)

Bilirubin-(14)C production was measured in rats transfused with labeled erythrocytes from animals with iron deficiency anemia, a condition associated with ineffective erythropoiesis. With labeled reticulocytes harvested 1 day after the administration of glycine-2-(14)C, conversion of hemoglobin-(14)C to bilirubin averaged 47.3% over the 3 days of observation; the corresponding value for reticulocytes from normal rats was only 1.7%. Findings were not altered by splenectomy. Bilirubin-(14)C production fell to 35.8% with iron-deficient cells harvested 3 days after glycine-(14)C administration, and declined further to a plateau averaging 25% with cells labeled 5, 7, 10, or 15 days earlier. The latter values still far exceed those for mature erythrocytes from normal animals.The findings indicate that experimental iron deficiency anemia is associated with hemolysis of red cells of various ages, but with preferential destruction of the youngest cells. Degradation of hemoglobin from reticulocytes is sufficient to account for a major fraction of the increase in erythropoietic bilirubin production found in this disorder, as has also been shown for physiologically regulated erythroid hyperplasia. However, the defect is quantitatively much more striking in experimental iron deficiency, and this and perhaps a similar defect in bone marrow cells appear to explain the decrease in net hemoglobin production that is characteristic of pathologic ineffective erythropoiesis.
Highly efficient, In-vivo Fas-mediated Apoptosis of B-cell Lymphoma by Hexameric CTLA4-FasL
Authors: Alexandra Aronin, Shira Amsili, Tatyana B Prigozhina, Kobi Tzdaka, Roy Shen, Leonid Grinmann, Fanny Szafer, Per Edebrink, Mari-Anne Rauvola, Noam Shani, Michal Dranitzki Elhalel
Journal: Journal of Hematology & Oncology (2014)

Non-Hodgkin lymphomas (NHLs) account for 4% of all malignancies. 5-year survival rate increased to 50% with new treatment modalities, however there is need for new effective treatment for the more aggressive, relapsing forms. Recently, CTLA4-FasL, that can bind to B7 and Fas receptor (Fas), was shown to induce robust apoptosis of cell lines originating from B cell lymphomas expressing both B7 and Fas, by activating pro-apoptotic signals in parallel to abrogating anti-apoptotic ones. The present study focuses on the unique properties of CTLA4-FasL as a potent apoptosis inducer of malignant cells in-vitro and in a xenograft model. CTLA4-FasL was found to naturally form a stable homo-hexamer. CTLA4-FasL induces robust apoptosis of a large variety of malignant cells while relatively sparing non-malignant ones, being more efficient when both receptors (B7 and Fas) are expressed on target cells. Even in non-B7 expressing cells, CTLA4-FasL exhibited better apoptotic activity than its parts, alone or in combination, however, only in B7 expressing cells apoptosis occurs at low concentrations and CTLA4-FasL induces activation of apoptotic signals and reduces anti-apoptotic ones. Importantly, CTLA4-FasL efficiently inhibited the growth of human B cell lineage tumors in a xenograft model, by provoking tumor cells' apoptosis. Thus, CTLA4-FasL, a natural homo-hexamer protein, induces robust apoptosis of malignant cells, in-vitro and in-vivo. In B-cell lymphoma, its potency stems from the combination of its synergistic effect of activating the caspases while abrogating the anti-apoptotic signaling, with its unique hexameric structure, making CTLA4-FasL a promising candidate for aggressive B cell lymphomas treatment.
Epidemiological Perspectives on Type 1 Diabetes in Childhood and Adolescence in Germany
Authors: Stefan Ehehalt, Klaus Dietz, Andre M. Willasch, Andreas Neu
Journal: Diabetes Care (2009)

OBJECTIVE To predict the frequency of type 1 diabetes in childhood and adolescence (&amp;lt;15 years of age) in Germany for the next 20 years. RESEARCH DESIGN AND METHODS Data on diabetes onset has been collected by means of a registry in the federal German state of Baden-Württemberg (documentation period, 1987–2006; n = 5,108; completeness of data 98.1%). RESULTS The current incidence rate (2000–2006) is 19.4 per 100,000 per year (95% CI 18.6–20.2). The annual incidence rate can be expressed as a square of a linear function of the calendar year X [y = (3.05 + 0.0778 × {X–1986})2; r2 = 0.90]. The highest increase per year was observed in the age-groups comprising 2- and 3-year-olds (12 and 13% per year, respectively). The incidence rate for the year 2026 is estimated to be 37.9 per 100,000 per year (95% CI 33.3–42.9). CONCLUSIONS The increase that we found in younger children is characteristic of a left shift toward an earlier age.
Progression of lumbar disc degeneration over a decade: a heritability study
Authors: F. M. K. Williams, M. Popham, P. N. Sambrook, A. F. Jones, T. D. Spector, A. J. MacGregor
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> Lumbar disc degeneration (LDD) is prevalent, age-related and contributes to low back pain. Cross-sectional LDD as determined by MRI scan is known to be highly heritable. The authors postulated that the rate of progression might also be controlled by genetic factors. <h3>Methods</h3> A 10-year follow-up of MRI-determined LDD was performed in 234 pairs of twin volunteers in the UK and Australia, comprising 90 monozygotic pairs and 144 dizygotic same-sex twin pairs. Of the total sample, 95% were female. The mean age at baseline was 53.3 years (range 32.3–69.5). The rate of progression was calculated and, because the effect of age was non-linear, the sample was divided into age strata and heritability estimated for each trait9s progression. <h3>Results</h3> All MRI-determined traits worsened significantly over the period of follow-up (p&lt;0.0001 for each). Change in disc height was not heritable at any age while posterior disc bulge was heritable across all age categories (range 28–53%), with higher heritability in those over 60 years. Change in disc signal intensity and anterior osteophytes were found to be heritable only in those aged under 50 years at baseline (heritability estimates 76% (95% CI 44% to 100%) and 74% (42% to 100%), respectively). <h3>Conclusions</h3> Longitudinal change in LDD traits is heritable for all traits except disc height, but there is a significant influence of age, which varies across traits. Future studies to define the genetic variants influencing LDD progression should examine MRI traits individually and in women should focus on those under 50 years of age.
Factors responsible for differences between asymptomatic subjects and patients presenting an IgE sensitization to allergens. A GA<sup>2</sup>LEN project
Authors: J. Bousquet, J. M. Anto, C. Bachert, P. J. Bousquet, P. Colombo, R. Crameri, M. Daëron, W. Fokkens, B. Leynaert, C. Lahoz, M. Maurer, G. Passalacqua, R. Valenta, M. Van Hage, R. Van Ree
Journal: Allergy (2006)

The synthesis of allergen-specific IgE is required for the development of allergic diseases including allergic rhinitis and allergic asthma (patients), but many individuals with allergen-specific IgE do not develop symptoms (asymptomatic subjects). Differences may exist between asymptomatic subjects and patients. Whether the presence of allergen-specific IgE translates into clinical allergy most likely depends on a complex interplay of multiple factors. These include a family history of atopy, the levels of total serum IgE and, allergen-specific IgE or IgG, epitope-specificity of IgE and their degree of polyclonality (mono- vs polysensitized), as yet unidentified serum factors, the balance of T regulatory cells (Treg) and Th1/Th2 cells, the polymorphisms of the high affinity receptor for IgE (FcepsilonRI) and other factors regulating the activation of FcepsilonRI-bearing cells. Asymptomatic subjects may be more often monosensitized than patients who may be more often polysensitized. There are many unanswered important questions that need to be addressed in order to better understand how IgE sensitization translates into clinical allergy. The assessment of differences between the asymptomatic and symptomatic groups of subjects represent one of the scientific programs of Global Allergy and Asthma European Network funded by the European Union and the hypotheses underlying these differences are presented in this paper.
Surgical preparative injury and neointima formation increase MMP-9 expression and MMP-2 activation in human saphenous vein
Authors: S George
Journal: Cardiovascular Research (1997)

Objectives: Injury stimulates smooth muscle cell (SMC) migration and proliferation by mechanisms that are incompletely understood. Surgical preparative injury is an important determinant of neointimal thickening in human saphenous vein bypass grafts. We investigate here whether basement-membrane-degrading metalloproteinases (MMPs) are stimulated by surgical preparation and culturing of human saphenous veins in organ culture. Methods: Secretion of MMP-2 and MMP-9 was measured by zymography and Western blotting. Sites of MMP secretion were localised by immunocytochemistry and in situ hybridisation. Results: Freshly isolated veins secreted pro-MMP-2 and much lower amounts of active MMP-2 and pro-MMP-9. MMP-2 was expressed in all cells whereas MMP-9 expression was confined to endothelial cells and at low levels to 55±10% (mean±s.e.m., n=6) of medial SMC. Surgical preparative injury increased pro-MMP-2, active MMP-2 and pro-MMP-9 secretion. MMP-9 expression 3 h after surgical preparation occurred at high levels in 89±5% of medial SMC (P<0.05 vs. freshly isolated, n=6). Culturing in serum for 12 days increased pro-MMP-2, active MMP-2 and pro-MMP-9 secretion to equal levels in freshly isolated and surgically prepared veins. MMP-9 expression was greatest in the highly proliferative neointimal SMC and was more widespread in medial SMC of surgically prepared than freshly isolated veins (89±3 vs. 67±11%, n=6, P<0.05), paralleling the differences in proliferative index (18±3 vs. 8±4 cell/mm2, P<0.05). Conclusions: The data provide new insights into the mechanisms underlying human SMC proliferation. Activation of MMP-2 and increased MMP-9 expression are shown to be important components of the response to injury in this model. Furthermore, MMP-9 expression is closely associated with medial and neointimal SMC proliferation.