tbuckley/cabot-search huggingface dataset:
Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure
Authors: Thomas Prébet, Steven D. Gore, Benjamin Esterni, Claude Gardin, Raphael Itzykson, Sylvain Thepot, François Dreyfus, Odile Beyne Rauzy, Christian Recher, Lionel Adès, Bruno Quesnel, C.L. Beach, Pierre Fenaux, Norbert Vey
Journal: Journal of Clinical Oncology (2011)

Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described.Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program).The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care.Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.
Pathology of low-grade gliomas: An update of emerging concepts
Authors: Arie Perry
Journal: Neuro-Oncology (2003)

Although the term low-grade glioma (LGG) is useful for its connotation of a slow-growing, better prognosis CNS primary neoplasm typically occurring in a young patient, it also serves as a potential diagnostic wastebasket, occasionally leading to conceptual errors, therapeutic uncertainty, or misinterpretation of clinical data. For example, the LGG designation is occasionally invoked as a justification for lumping together biologically unrelated entities such as pilocytic astrocytoma and diffuse astrocytoma. Whereas the former represents a benign and potentially surgically curable neoplasm that virtually never undergoes malignant transformation, the latter is a surgically incurable low-grade malignancy, prone to further malignant progression and eventual fatality. Therefore, although rare cases lacking a clear distinction may be encountered, the term LGG should be abandoned for a more specific diagnosis whenever possible. The primary goals of this paper are to review practical surgical pathology issues related to the diagnosis of diffuse LGGs and to update the reader on emerging clinicopathologic and molecular genetic concepts. Also discussed are current controversies of classification/grading and the role of ancillary testing via immunohistochemical and genetic techniques.
Differentiation of Vascular Smooth Muscle Cells and the Regulation of Protein Kinase C-α
Authors: Hermann Haller, Carsten Lindschau, Petra Quass, Armin Distler, Friedrich C. Luft
Journal: Circulation Research (1995)

Abstract Dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs) are important features of atherosclerosis. The molecular mechanisms are largely unclear; however, protein kinase C (PKC) is a key enzyme in the intracellular signaling pathways that mediate this process. We studied the activity and immunoreactivity of PKC-α in primary cultures of VSMCs from rat aortas under different conditions of growth and differentiation. PKC-α was determined under the following conditions: (1) during the growth phase and after confluence of cultured (passages 1 through 3) VSMCs, (2) before and after induction of differentiation in VSMCs by retinoic acid, and (3) in primary cultures of VSMCs from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats during early passages. PKC activity was measured by in vitro substrate phosphorylation. PKC-α immunoreactivity was assessed by Western blot using specific polyclonal antibodies and by immunostaining with confocal microscopy. Cell proliferation was measured by direct count. The cell phenotype was characterized by immunostaining and Western blot for α-actin and desmin. PKC-α expression and PKC activity during VSMC growth showed a decrease during rapid growth and an increase in confluent cells. This pattern was associated with the respective changes in cell differentiation. Retinoic acid induced an increase in PKC-α expression together with a more differentiated phenotype. Subcultured, rapidly growing VSMCs from SHR showed a decreased PKC-α expression compared with cells from WKY rats. To establish cause and effect, we next microinjected either PKC-α or inactivated material directly into dedifferentiated cells. We found that cells injected with active PKC-α expressed increased amounts of actin compared with control cells. We identified a close correlation between PKC-α and actin immunofluorescence. We conclude that PKC-α is downregulated in rapidly growing VSMCs. Our findings demonstrate an inverse association between PKC-α expression and VSMC differentiation. They suggest a role for downregulation of PKC-α in the proliferative response of these cells.
An Investigation into the Lymphatic and Vascular Spread of Carcinoma of the Bronchus
Authors: H. C. Nohl
Journal: Thorax (1956)

Thepresent investigation wascarried outbecauselittle workhasbeendonetoelucidate the problemsconcerning thelymphatic spreadof bronchogenic carcinoma. Thequestion, whether thetreatment ofcarcinoma ofthebronchus by lobectomy ratherthanby pneumonectomy is basedon soundpathological principles, needed clarification. Itwasalsofelt thattheestablishmentofa surgical-pathological classification for thepurpose ofprognosis andassessment ofvarious formsoftreatment, ashasbeendonzforcancer atothersites, waslongoverdue. Furthermore, theanatomyof theintrapulmonary lymphatic pathways described inthepastareno longer tenable inthelight ofourpresent knowledge of thebronchial andsegmental anatomyofthelungs. Rouviere (1932), inhisclassic Anatomiedes Lymphatiques de l'Homme,givesan excellent description ofthemediastinal lymphatic pathwaysandnodes, butthatoftheinterlobar and intrapulmonary nodesisinaccurate andhiswork doesnotdivide thelymphflowintolobar orsegmentaldistribution. Sincethattimefewcontributions havebeenmadeinthis field; papers by McCortandRobbins(1951), Weinberg (1951), Borrie (1952), andthatbyBrockandWhytehead (1955) havetouched onthissubject. Butallof theseauthors, withtheexception of Borrie, reiterate, onthewhole, Rouviere's statements on either thelymphatic anatomyorthedrainage of thelungs.
Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies
Authors: A. Hauschild, E. Stockfleth, G. Popp, F. Borrosch, H. Brüning, R. Dominicus, H. Mensing, U. Reinhold, K. Reich, A.C.E. Moor, M. Stocker, C. Ortland, M. Brunnert, R.-M. Szeimies
Journal: British Journal of Dermatology (2009)

Photodynamic therapy (PDT) is increasingly used for treatment of actinic keratoses (AKs) but is a cumbersome procedure. A thin self-adhesive patch (PD P 506 A) containing 5-aminolaevulinic acid (5-ALA) was developed to facilitate PDT.To investigate efficacy and safety of the patch in comparison with placebo-PDT (superiority design, observer-blinded; study AK 03) and standard therapy, cryosurgery (noninferiority design, open; study AK 04).Two separate confirmatory randomized parallel-group phase III studies were set up. In total, 449 patients with up to eight mild to moderate AK study lesions located on the head were treated in 29 German study centres (study AK 03: 103 patients; study AK 04: 346 patients).Twelve weeks after treatment, 5-ALA patch-PDT proved to be superior to placebo-PDT (P < 0.001) and cryosurgery (P = 0.007). Efficacy rates on a lesion basis were 82% (AK 03) and 89% (AK 04) for PDT, 77% for cryosurgery and 19% (AK 03) and 29% (AK 04) for placebo-PDT. Local reactions at the treatment site occurred in almost all patients treated with 5-ALA patch-PDT or cryosurgery. Headache was the only side-effect not related to the treatment site which occurred in more than one patient.PD P 506 A is an innovative, easy-to-handle 5-ALA patch for PDT of mild to moderate AK lesions. Compared with current PDT procedures, pretreatment (e.g. curettage) is not needed and handling is considerably facilitated. A single PDT treatment results in efficacy rates being statistically significantly superior to placebo and cryosurgery.
Dose-Dependent Delay of the Hypoglycemic Effect of Short-Acting Insulin Analogs in Obese Subjects With Type 2 Diabetes
Authors: Maude Gagnon-Auger, Patrick du Souich, Jean-Patrice Baillargeon, Elisabeth Martin, Pascal Brassard, Julie Ménard, Jean-Luc Ardilouze
Journal: Diabetes Care (2010)

OBJECTIVE Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption. Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects, healthy or with type 1 diabetes. In obese patients, however, daily dosages are larger and ATBF is decreased. This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS Euglycemic clamps after subcutaneous lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 ± 7.0 kg/m2) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the 133Xe-washout technique. RESULTS ATBF was 64% lower in subjects with type 2 diabetes than in control subjects. After 10 units injection, time to lispro plasma peak (Tmax) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (Cmax)/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIRmax: 9.0 vs. 0.6 mg/kg/min, P &amp;lt; 0.0001, 69 vs. 130 min, P &amp;lt; 0.0001, respectively). After 30- and 50-unit injections, Tmax (88.6 and 130.0 min, respectively) and time to GIRmax (175 and 245 min) were further delayed and dose related (r2 = 0.51, P = 0.0004 and r2 = 0.76, P &amp;lt; 0.0001, respectively). CONCLUSIONS Absorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes.
Thromboxane synthesis by sources other than platelets in association with complement-induced pulmonary leukostasis and pulmonary hypertension in sheep.
Authors: J W McDonald, M Ali, E Morgan, E R Townsend, J D Cooper
Journal: Circulation Research (1983)

Infusion into sheep of plasma containing zymosan-activated complement produces leukopenia, pulmonary leukostasis, and pulmonary artery hypertension. We previously demonstrated a close relationship between the pulmonary vascular response and elevations of plasma thromboxane. We have investigated the source of thromboxane synthesis in this model. Plasma containing zymosan-activated complement added to whole blood did not stimulate thromboxane synthesis. This observation suggested that leukocytes do not synthesize thromboxane directly in response to complement added to whole blood did not stimulate thromboxane synthesis. This observation suggested that leukocytes do not synthesize thromboxane directly in response to complement. Sheep rendered severely thrombocytopenic by the administration of antiplatelet serum responded to complement infusion in the usual way. Pretreatment with aspirin (10 mg/kg) protected sheep against the pulmonary vascular response and completely blocked thromboxane synthesis. Transfusion of functional platelets did not restore these responses. Twenty-four hours after aspirin treatment, in vivo thromboxane synthesis was significantly greater than platelet thromboxane synthesis in vitro. Thromboxane is synthesized by a tissue which recovers cyclooxygenase enzyme activity at a rate that is more rapid than platelet turnover. Sheep lung synthesizes thromboxane actively in vitro. It is postulated that leukocytes exposed to activated complement components damage pulmonary vascular endothelial cells and stimulate synthesis of thromboxane A2 which causes pulmonary vasoconstriction.
Differential Regulation of Noxa in Normal Melanocytes and Melanoma Cells by Proteasome Inhibition: Therapeutic Implications
Authors: Yolanda Fernández, Monique Verhaegen, Thomas P. Miller, Jenny L. Rush, Philipp Steiner, Anthony W. Opipari, Scott W. Lowe, María S. Soengas
Journal: Cancer Research (2005)

Abstract Melanoma is the most aggressive form of skin cancer and advanced stages are invariably resistant to conventional therapeutic agents. Using bortezomib as a prototypic proteasome inhibitor, we have identified a novel and critical role of the proteasome in the maintenance of the malignant phenotype of melanoma cells that could have direct translational implications. Thus, melanoma cells from early, intermediate, and late stages of the disease could not sustain proteasome inhibition and underwent an effective activation of caspase-dependent and -independent death programs. This effect was tumor cell selective, because under similar conditions, normal melanocytes remained viable. Intriguingly, and despite of interfering with a cellular machinery in charge of controlling the half-life of the vast majority of cellular proteins, bortezomib did not promote a generalized disruption of melanoma-associated survival factors (including NF-κB, Bcl-2, Bcl-xL, XIAP, TRAF-2, or FLIP). Instead, we identified a dramatic induction in vitro and in vivo of the BH3-only protein Noxa in melanoma cells (but not in normal melanocytes) in response to proteasome inhibition. RNA interference validated a critical role of Noxa for the cytotoxic effect of bortezomib. Notably, the proteasome-dependent regulation of Noxa was found to extend to other tumor types, and it could not be recapitulated by standard chemotherapeutic drugs. In summary, our results revealed Noxa as a new biomarker to gauge the efficacy of bortezomib specifically in tumor cells, and provide a new strategy to overcome tumor chemoresistance.
ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis
Authors: Cinzia Martinengo, Teresa Poggio, Matteo Menotti, Maria Stella Scalzo, Cristina Mastini, Chiara Ambrogio, Elisa Pellegrino, Ludovica Riera, Roberto Piva, Domenico Ribatti, Fabio Pastorino, Patrizia Perri, Mirco Ponzoni, Qi Wang, Claudia Voena, Roberto Chiarle
Journal: Cancer Research (2014)

Rearrangements involving the anaplastic lymphoma kinase (ALK) gene are defining events in several tumors, including anaplastic large-cell lymphoma (ALCL) and non-small cell lung carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared with other types of T-cell lymphoma or EGFR- and K-RAS-mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC, we found that under hypoxic conditions, ALK directly regulated the abundance of hypoxia-inducible factors (HIF), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF1α and HIF2α in hypoxic conditions required ALK activity and its downstream signaling proteins STAT3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF2α, but not HIF1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF1α and HIF2α. In conclusion, we uncovered an ALK-specific regulation of the hypoxia response across different ALK(+) tumor types and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.
Major Histocompatibility Complex Class I Molecules Modulate Activation Threshold and Early Signaling of T Cell Antigen Receptor–γ/δ Stimulated by Nonpeptidic Ligands
Authors: Ilaria Carena, Abdijapar Shamshiev, Alena Donda, Marco Colonna, Gennaro De Libero
Journal: The Journal of Experimental Medicine (1997)

Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompatibility complex class I-specific inhibitory receptors expressed by natural killer cells, T cell antigen receptor (TCR)-gamma/delta cells, and a subset of TCR-alpha/beta cells. We studied the functional interaction between TCR-gamma/delta and CD94, this inhibitory receptor being expressed on the majority of gamma/delta T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR-gamma/delta by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 zeta chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.
NEAR-TERM POST-TEST TREATMENT, FUNCTIONAL STATUS AND RESOURCE UTILIZATION IN INTERMEDIATE RISK INDIVIDUALS WITH STABLE CHEST PAIN SYNDROME UNDERGOING 64-DETECTOR ROW CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY VERSUS MYOCARDIAL PERFUSION SPECT: A PROSPECTIVE MULTICENTER RANDOMIZED TRIAL
Authors: Fay Lin, Sunaina Koduru, Jason H. Cole, Jerome L. Hines, Troy M. Labounty, Jonathan W. Weinsaft, Tracy Q. Callister, Leslee J. Shaw, Daniel S. Berman, James K. Min
Journal: Journal of the American College of Cardiology (2010)
Patterns of Cancer Incidence, Mortality, and Prevalence Across Five Continents: Defining Priorities to Reduce Cancer Disparities in Different Geographic Regions of the World
Authors: Farin Kamangar, Graça M. Dores, William F. Anderson
Journal: Journal of Clinical Oncology (2006)

Efforts to reduce global cancer disparities begin with an understanding of geographic patterns in cancer incidence, mortality, and prevalence. Using the GLOBOCAN (2002) and Cancer Incidence in Five Continents databases, we describe overall cancer incidence, mortality, and prevalence, age-adjusted temporal trends, and age-specific incidence patterns in selected geographic regions of the world. For the eight most common malignancies-cancers of lung, breast, colon and rectum, stomach, prostate, liver, cervix, and esophagus-the most important risk factors, cancer prevention and control measures are briefly reviewed. In 2002, an estimated 11 million new cancer cases and 7 million cancer deaths were reported worldwide; nearly 25 million persons were living with cancer. Among the eight most common cancers, global disparities in cancer incidence, mortality, and prevalence are evident, likely due to complex interactions of nonmodifiable (ie, genetic susceptibility and aging) and modifiable risk factors (ie, tobacco, infectious agents, diet, and physical activity). Indeed, when risk factors among populations are intertwined with differences in individual behaviors, cultural beliefs and practices, socioeconomic conditions, and health care systems, global cancer disparities are inevitable. For the eight most common cancers, priorities for reducing cancer disparities are discussed.
CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung
Authors: Berber Piet, Godelieve J. de Bree, Barbara S. Smids-Dierdorp, Chris M. van der Loos, Ester B.M. Remmerswaal, Jan H. von der Thüsen, Jan M.W. van Haarst, Jan P. Eerenberg, Anja ten Brinke, Wim van der Bij, Wim Timens, René A.W. van Lier, René E. Jonkers
Journal: Journal of Clinical Investigation (2011)

The human lung T cell compartment contains many CD8+ T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8+ T cells expressing CD103 (αE integrin) resides. Here, we determined the specificity and function of CD103+CD8+ T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103+CD8+ T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8+ T cells specific for influenza but not in those specific for EBV or CMV. CD103+ and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8+ T cell cytotoxic function. In contrast to CD103–CD8+ T cells, most CD103+CD8+ cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier.
Diastolic Geometry and Sarcomere Lengths in the Chronically Dilated Canine Left Ventricle
Authors: JOHN ROSS, EDMUND H. SONNENBLICK, ROGER R. TAYLOR, HENRY M. SPOTNITZ, JAMES W. COVELL
Journal: Circulation Research (1971)

In 10 dogs left ventricular geometry and ultrastructure were examined 3 to 12 weeks after chronic ventricular dilatation was induced by means of a large arteriovenous shunt. Following cardiac catheterization, the hearts were arrested and fixed in diastole at the left ventricular end-diastolic pressures (LVEDP) which existed in the beating heart. Transmural LVEDP were increased in all animals (avg. 27 mm Hg). The diastolic pressure-volume relationship was shifted to the right, the average end-diastolic volume of the chronically dilated ventricles (avg. 103 ml) being larger than that of previously studied acutely dilated ventricles (avg. 72 ml, P &lt;.01), but calculated diastolic wall stress values were not different. Sarcomere lengths in the chronically dilated hearts averaged 2.19±.02 µ ( SE ) (range 2.11 to 2.27), a value near the apex of the sarcomere length-tension curve, but not significantly different from sarcomere lengths in acutely dilated ventricles. Slippage between myofibrils, reflected by a loss of normal alignment of the Z lines, appeared to be one mechanism underlying this adaptation. The findings indicate that sarcomeres in the canine left ventricular wall are remarkably resistant to chronic as well as to acute overstretch. They further imply that little or no Frank-Starling reserve mechanism was available in these ventricles and raise the possibility that a descending limb of the heart's performance as a pump need not reflect a descending limb at the sarcomere level.