tbuckley/cabot-search huggingface dataset:
Phase I Studies of CBP501, a G2 Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors
Authors: Geoffrey I. Shapiro, Raoul Tibes, Michael S. Gordon, Bryan Y. Wong, Joseph Paul Eder, Mitesh J. Borad, David S. Mendelson, Nicholas J. Vogelzang, Bruno R. Bastos, Glen J. Weiss, Cristian Fernandez, William Sutherland, Hitoshi Sato, William E. Pierceall, David Weaver, Scott Slough, Ernesto Wasserman, Donald W. Kufe, Daniel Von Hoff, Takumi Kawabe, Sunil Sharma
Journal: Clinical Cancer Research (2011)

Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G(2) checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/D15, q4w, from 0.9 mg/m(2)), or with cisplatin (both on D1, q3w, from 3.6 mg/m(2) CBP501, 50 mg/m(2) cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles.In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m(2) CBP501 and 75 mg/m(2) cisplatin, with two patients at the highest dose (36.4 mg/m(2) CBP501, 75 mg/m(2) cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G(3) rise of troponin in one patient. Grade 3 to 4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease.CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients.
Sphingosine 1-Phosphate Receptor 2 Negatively Regulates Neointimal Formation in Mouse Arteries
Authors: Takuya Shimizu, Tatsu Nakazawa, Aesim Cho, Frank Dastvan, Dustin Shilling, Günter Daum, Michael A. Reidy
Journal: Circulation Research (2007)

Neointimal lesion formation was induced in sphingosine 1-phosphate (S1P) receptor 2 (S1P2)-null and wild-type mice by ligation of the left carotid artery. After 28 days, large neointimal lesions developed in S1P2-null but not in wild-type arteries. This was accompanied with a significant increase in both medial and intimal smooth muscle cell (SMC) replication between days 4 to 28, with only minimal replication in wild-type arteries. S1P2-null SMCs showed a significant increase in migration when stimulated with S1P alone and together with platelet-derived growth factor, whereas both wild-type and null SMCs migrated equally well to platelet-derived growth factor. S1P increased Rho activation in wild-type but not in S1P2-null SMCs, and inhibition of Rho activity promoted S1P-induced SMC migration. Plasma S1P levels were similar and did not change after surgery. These results suggest that activation of S1P2 normally acts to suppress SMC growth in arteries and that S1P is a regulator of neointimal development.
Snoring and excessive daytime somnolence among Polish middle-aged adults
Authors: J. Zieliński, A. Zgierska, M Polakowska, L Finn, P Kurjata, W Kupść, T Young
Journal: European Respiratory Journal (1999)

There is considerable interest in the association of snoring and health consequences that have been linked to more severe sleep-disordered breathing, including obstructive sleep apnoea syndrome. The goal of this investigation was to assess the independent association of heavy, habitual snoring and daytime sleepiness. For this, a cross-sectional, population based study of snoring, sleepiness and other factors was conducted using the Warsaw sample of the Multinational Monitoring of Trends and Determinants of Cardiovascular Diseases (MONICA) study, a population-based multicentre study of cardiovascular disease. The well-defined MONICA sample of middle-aged males and females also allowed estimation of age- and sex-specific prevalences of habitual snoring in Polish adults. Data on self-reported snoring frequency and loudness, and daytime sleepiness using the Epworth Sleepiness Scale (ESS) and other questions, were collected with a postal questionnaire. Seventy-nine per cent of the MONICA sample completed the questionnaire, yielding a total of 1,186 participants. Of the total sample, 27% of the females and 48% of the males reported habitual snoring ("often" or "always"). There was an independent association of habitual snoring and excessive daytime sleepiness (EDS), sleepiness that interfered with work and with increasing ESS scores. Habitual snorers were 5.8 and 3.1 times more likely to report EDS in active and passive situations, respectively, compared to nonsnorers (all p&lt;0.01). It is concluded that habitual snorers, most of whom are probably unlikely to have frank sleep apnoea syndrome, are at substantial risk for daytime sleepiness. These findings add support to the hypothesis that simple snoring is not benign and underscores the need for further research on health outcomes associated with this prevalent condition.
Phase III, Double-Blind, Controlled Trial of Atamestane Plus Toremifene Compared With Letrozole in Postmenopausal Women With Advanced Receptor-Positive Breast Cancer
Authors: Paul Goss, Igor N. Bondarenko, Georgiy N. Manikhas, Kelly B. Pendergrass, Wilson H. Miller, Peter Langecker, Dennis Blanchett
Journal: Journal of Clinical Oncology (2007)

Purpose To compare time to progression (TTP) with a steroidal aromatase inhibitor (AI) atamestane (ATA) combined with toremifene (TOR; complete estrogen blockade) versus letrozole (LET) in receptor-positive advanced breast cancer (ABC). Patients and Methods Eligibility included postmenopausal receptor-positive ABC and adjuvant hormonal therapy completed more than 12 months prior to study entry. Participants received daily ATA 500 mg with TOR 60 mg (ATA + TOR), or letrozole 2.5 mg (LET). The primary end point was TTP, whereas secondary objectives included objective response (OR), overall survival (OS), and time to treatment failure (TTF). The study had 80% power to detect a 25% increase in TTP assuming a TTP of 9.4 months in the LET population. Results A total of 865 patients were randomly assigned (434 to ATA + TOR and 431 to LET) in 60 centers in the United States, Canada, Russia, and Ukraine. Baseline characteristics were balanced. Median TTP was identical in the two arms at 11.2 months (P &lt; .92). Median TTF was similar at 9.24 months (ATA + TOR) versus 10.44 months (LET). The hazard ratios (LET/ATA + TOR) were 1.00 (95% CI, 0.92 to 1.08) for TTP, 0.99 (95% CI, 0.92 to 1.06) for TTF, and 0.98 (95% CI, 0.87 to 1.11) for OS. OR occurred in 30% of patients receiving ATA + TOR and in 36% of patients receiving LET (P &lt; .1). Adverse events (AEs) were similar for patients receiving ATA + TOR versus LET, and serious AEs were 10% v 11%, respectively. Conclusion TTP for patients receiving ATA + TOR was identical to that for patients receiving LET, representing the first endocrine therapy comparable to LET in ABC. Unlike in the Anastrozole, Tamoxifen, and Combined trial, addition of an antiestrogen did not decrease efficacy of the AI. Future studies of AIs in combination with more effective selective estrogen receptor modulators or selective receptor downregulators is warranted.
Clinical and molecular analysis of combined hepatocellular-cholangiocarcinomas
Authors: Dominique Cazals-Hatem, Sandra Rebouissou, Paulette Bioulac-Sage, Olivier Bluteau, Hélène Blanché, Dominique Franco, Geneviève Monges, Jacques Belghiti, Antonio Sa Cunha, Pierre Laurent-Puig, Claude Degott, Jessica Zucman-Rossi
Journal: Journal of Hepatology (2004)
Shaping, channelling, and distributing testosterone in social systems
Authors: Dov Cohen
Journal: Behavioral and Brain Sciences (1998)

Culture and social structure may affect the testosterone–behavior link by shaping the way we construe events; by muting, channelling, or amplifying the drives that testosterone produces; and by affecting the distribution and level of testosterone in various parts of the population. Research on testosterone, culture, and social class has produced suggestive results, opening broad areas for research.
Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells
Authors: Nicola J. Jordan, George Kolios, Stewart E. Abbot, Michael A. Sinai, Darren A. Thompson, Kalliopi Petraki, John Westwick
Journal: Journal of Clinical Investigation (1999)

In addition to their role as regulators of leukocyte migration and activation, chemokines and their receptors also function in angiogenesis, growth regulation, and HIV-1 pathogenesis — effects that involve the action of chemokines on nonhematopoietic cells.To determine whether chemokine receptors are expressed in human colonic epithelium, HT-29 cells were examined by RT-PCR for the expression of the chemokine receptors for lymphotactin, fractalkine, CCR1-10, and CXCR1-5. The only receptor consistently detected was CXCR4 (fusin/LESTR), although HT-29 cells did not express mRNA for its ligand, stromal cell–derived factor (SDF-1α). Flow cytometric analysis with anti-CXCR4 antibody indicated that the CXCR4 protein was expressed on the surface of roughly half of HT-29 cells. CXCR4 was also expressed in colonic epithelial cells in vivo as shown by immunohistochemistry on biopsies from normal and inflamed human colonic mucosa. The mRNA for SDF-1α and other CC and CXC chemokines was present in normal colonic biopsies. The CXCR4 receptor in HT-29 cells was functionally coupled, as demonstrated by the elevation in [Ca2+ ]i, which occurred in response to 25 nM SDF-1α and by the SDF-1α–induced upregulation of ICAM-1 mRNA. Sodium butyrate downregulated CXCR4 expression and induced differentiation of HT-29 cells, suggesting a role for CXCR4 in maintenance and renewal of the colonic epithelium. This receptor, which also serves as a coreceptor for HIV, may mediate viral infection of colonic epithelial cells.
Role of a nonimmunoglobulin cell surface determinant in the activation of B lymphocytes by thymus-independent antigens.
Authors: B Subbarao, D E Mosier, A Ahmed, J J Mond, I Scher, W E Paul
Journal: The Journal of Experimental Medicine (1979)

Lyb 5 is a B-cell alloantigen which is expressed on 50-60% of B cells. It was defined originally on the basis of cytotoxicity. We have described a new reactivity within the anti-Lyb 5 serum on the basis of selective inhibition of antibody responses in vitro by this antiserum in the absence of complement. This inhibitory activity of anti-Lyb 5.1 serum appears to be due to recognition of antigenic determinants different from the prototype antigens detected in the cytotoxicity assay. Anti-Lyb 5 serum incorporated into spleen cell cultures selectively inhibits antibody responses to a class of thymus-independent antigens (TI-2) previously characterized by their failure to elicit antibody formation in immature mice or in the defective CBA/N strain. Responses to optimal concentrations of TI-1 antigens, which can induce antibody synthesis in these mice, are unaffected by the addition of anti-Lyb 5.1 serum. The B-cell alloantigen defined by this functional assay is designated tentatively Lyb 7 and it is shown to be distinct from cell surface immunoglobulins. Lyb 7 appears to have a role in the activation of B lymphocytes by the TI-2 class of thymus-independent antigens.
Prevalence and Clinical Outcomes for Patients With ALK-Positive Resected Stage I to III Adenocarcinoma: Results From the European Thoracic Oncology Platform Lungscape Project
Authors: Fiona H. Blackhall, Solange Peters, Lukas Bubendorf, Urania Dafni, Keith M. Kerr, Henrik Hager, Alex Soltermann, Kenneth J. O'Byrne, Christoph Dooms, Aleksandra Sejda, Javier Hernández-Losa, Antonio Marchetti, Spasenija Savic, Qiang Tan, Erik Thunnissen, Ernst-Jan M. Speel, Richard Cheney, Daisuke Nonaka, Jeroen de Jong, Miguel Martorell, Igor Letovanec, Rafael Rosell, Rolf A. Stahel
Journal: Journal of Clinical Oncology (2014)

The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population.Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment.Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS).In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.
The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion
Authors: Catherine Haluszczak, Adovi D. Akue, Sara E. Hamilton, Lisa D.S. Johnson, Lindsey Pujanauski, Lenka Teodorovic, Stephen C. Jameson, Ross M. Kedl
Journal: The Journal of Experimental Medicine (2009)

Memory T cells exhibit superior responses to pathogens and tumors compared with their naive counterparts. Memory is typically generated via an immune response to a foreign antigen, but functional memory T cells can also be produced from naive cells by homeostatic mechanisms. Using a recently developed method, we studied CD8 T cells, which are specific for model (ovalbumin) and viral (HSV, vaccinia) antigens, in unimmunized mice and found a subpopulation bearing markers of memory cells. Based on their phenotypic markers and by their presence in germ-free mice, these preexisting memory-like CD44hi CD8 T cells are likely to arise via physiological homeostatic proliferation rather than a response to environmental microbes. These antigen-inexperienced memory phenotype CD8 T cells display several functions that distinguish them from their CD44lo counterparts, including a rapid initiation of proliferation after T cell stimulation and rapid IFN-γ production after exposure to proinflammatory cytokines. Collectively, these data indicate that the unprimed antigen-specific CD8 T cell repertoire contains antigen-inexperienced cells that display phenotypic and functional traits of memory cells.
Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis.
Authors: B Baggio, G Gambaro, S Zambon, F Marchini, A Bassi, L Bordin, G Clari, E Manzato
Journal: Journal of the American Society of Nephrology (1996)

Anomalies in the erythrocyte transport of anions and cations have been described in idiopathic calcium oxalate nephrolithiasis and seem to play a pathogenetic role in this disease. In consideration of the hypothesis that the complex array of ion flux cell abnormalities is an epiphenomenon of an anomaly in the composition of cell membranes, this study investigated cell-membrane lipid composition. In idiopathic calcium oxalate renal stone formers, in which ion transport abnormalities were present, and in healthy control subjects, plasma and erythrocyte membrane lipid composition, the erythrocyte oxalate exchange, and Na/K/2Cl cotransport activity were evaluated. Furthermore, in stone formers, the effect of a 30-day fish-oil diet supplementation on plasma lipids, erythrocyte oxalate exchange, oxaluria, and calciuria was investigated. The effect of archidonic acid released by phospholipase A2 on anion-carrier phosphorylation and activity in erythrocytes was evaluated as well. Patients had a lower content of linoleic and higher concentration of archidonic acids in both plasma and erythrocyte membrane phospholipids, and an increased archidonic/linoleic acid ratio. The archidonic acid level correlated with the erythrocyte oxalate exchange and sodium cotransport activity. Fish-oil supplementation lowered calcium and oxalate urine excretion, and normalized the erythrocyte oxalate exchange. Phospholipase A2 increased the erythrocyte anion-carrier protein phosphorylation and the oxalate exchange. This study shows that idiopathic calcium nephrolithiasis in the patient group reported here is characterized by a systemic defect in phospholipid archidonic acid levels that might provide an answer to the link between genetic background, dietary habits, and renal lithiasis.
Prevalence, Clinical Pattern, and Outcome of CNS Involvement in Childhood and Adolescent Non-Hodgkin's Lymphoma Differ by Non-Hodgkin's Lymphoma Subtype: A Berlin-Frankfurt-Münster Group Report
Authors: Janina Salzburg, Birgit Burkhardt, Martin Zimmermann, Olga Wachowski, Wilhelm Woessmann, Ilske Oschlies, Wolfram Klapper, Hans-Heinrich Wacker, Wolf-Dieter Ludwig, Felix Niggli, Georg Mann, Helmut Gadner, Hansjoerg Riehm, Martin Schrappe, Alfred Reiter
Journal: Journal of Clinical Oncology (2007)

Purpose We analyzed the prevalence, clinical pattern, and prognostic impact of CNS involvement in a large cohort of children and adolescents diagnosed with non-Hodgkin's lymphoma (NHL), with special attention to differences according to NHL subtype. Patients and Methods From October 1986 to December 2002, 2,381 patients (median age, 9.37 years; range, 0.2 to 23.8 years; female-to-male ratio, 1:2.7) from Germany, Austria, and Switzerland were registered. A total of 2,086 patients were eligible for the consecutive multicenter protocols NHL–Berlin-Frankfurt-Münster [BFM] -86, NHL-BFM-90, and NHL-BFM-95, and could be evaluated for outcome. Results CNS involvement was diagnosed in 141 (5.9%) of 2,381 patients and was associated with an advanced stage of NHL. The percentage of CNS-positive patients was 8.8% for Burkitt's lymphoma/Burkitt's leukemia (BL/B-ALL), 5.4% for precursor B–lymphoblastic lymphoma (pB-LBL), 3.3% for anaplastic large-cell lymphoma, 3.2% for T-cell–LBL, 2.6% for diffuse large B-cell lymphoma, and 0% for primary mediastinal large B-cell NHL (P &lt; .001). Most CNS-positive patients with pB-LBL, T-LBL, or BL/B-ALL had meningeal disease. The probability of event-free survival (pEFS; ± SE) at 5 years was 85% ± 1% for the 2,086 protocol patients (median follow-up, 6.5 years; range, 0.3 to 17.7 years). For the 112 CNS-positive patients, pEFS was 64% ± 5%, compared with 86% ± 1% for the 1,927 CNS-negative patients (P &lt; .001). Although CNS disease had no impact on pEFS for advanced-stage T-LBL patients, CNS-positive patients with BL/B-ALL had a worse average outcome than CNS-negative patients with stage IV BL/B-ALL (60% ± 5% v 81% ± 3%; P &lt; .001). In multivariate analysis, CNS disease was the strongest predictor for relapse in BL/B-ALL patients with advanced-stage disease. Conclusion Six percent of childhood/adolescent NHL patients were CNS positive. However, the prevalence, pattern, and prognostic impact of CNS involvement differed among NHL subtypes.
Prostate-Specific Antigen Kinetics During Follow-Up Are an Unreliable Trigger for Intervention in a Prostate Cancer Surveillance Program
Authors: Ashley E. Ross, Stacy Loeb, Patricia Landis, Alan W. Partin, Jonathan I. Epstein, Anna Kettermann, Zhaoyong Feng, H. Ballentine Carter, Patrick C. Walsh
Journal: Journal of Clinical Oncology (2010)

To assess the predictive ability of prostate-specific antigen (PSA) velocity (PSAV) and doubling time (PSADT) for biopsy progression and adverse pathology at prostatectomy among men with low-risk prostate cancer enrolled on an active-surveillance program.We evaluated 290 men who met criteria for active surveillance (ie, PSA density < 0.15 ng/mL/cm(3) and Gleason score < or = 6 with no pattern > or = 4, involving < or = 2 cores with cancer, and < or = 50% involvement of any core by cancer) with two or more serial PSA measurements after diagnosis from 1994 to 2008. Follow-up included twice-yearly digital rectal exam and PSA measurements and yearly surveillance biopsy. Treatment was recommended for biopsy progression (ie, Gleason score > or = 7, or > 2 positive cores, or > 50% core involvement). Sensitivity and specificity of postdiagnostic PSAV and PSADT were explored by using receiver operating characteristic (ROC) analysis.Overall, 188 (65%) men remained on active surveillance, and 102 (35%) developed biopsy progression at a median follow-up of 2.9 years. PSADT was not significantly associated with subsequent adverse biopsy findings (P = .83), and PSAV was marginally significant (P = .06). No PSAV or PSADT cut point had both high sensitivity and specificity (area under the curve, 0.61 and 0.59, respectively) for biopsy progression. In those who eventually underwent radical prostatectomy, PSAV (P = .79) and PSADT (P = .87) were not associated with the presence of unfavorable surgical pathology.Postdiagnostic PSA kinetics do not reliably predict adverse pathology and should not be used to replace annual surveillance biopsy for monitoring men on active surveillance.
Secrets of Drug Resistance in NSCLC Exposed by New Molecular Definition of EMT
Authors: Dana S. Neel, Trever G. Bivona
Journal: Clinical Cancer Research (2012)

Non-small cell lung carcinoma (NSCLC) metastasis and drug resistance has been associated with epithelial-to-mesenchymal transition (EMT). This study reports the development of a robust gene expression signature of EMT in NSCLC and reveals new insights into the key molecular events that underlie EMT and drug resistance in NSCLC.
Moderate Pericardial Effusion Early After Myocardial Infarction
Authors: L. Køber, J.E. Møller, C. Torp-Pedersen
Journal: Circulation (2010)

P ericardial effusion (PE) associated with myocardial in- farction (MI) is considered to be associated with anterior ST-segment elevation MI (STEMI), with large infarcts, and when heart failure is present.When PE is associated with cardiac tamponade, it is usually due to cardiac rupture, hemorrhagic pericarditis, or aortic dissection involving the right coronary artery.However, the majority of PE does not cause hemodynamic compromise, and a small to moderate PE may often be viewed as a benign reaction to the MI.In 1986, Galve et al 1 demonstrated in a study of 138 consecutive patients with acute MI that 28% of patients had a PE.The study was meticulously performed with repeated echocardiographic evaluations, and there were no cases of cardiac tamponade.However, these data may no longer be valid because the treatment of acute MI has changed dramatically since 1986.In a large study in the modern era of reperfusion from 25 French hospitals including 908 patients with MI, a PE was detected in only 6.6% of the patients. 2Patients had an echocardiogram performed at admission and again at discharge, and 0.8% developed left ventricular free wall rupture (FWR).This incidence of FWR is similar to that of a larger registry that did not search meticulously for rupture.