tbuckley/cabot-search huggingface dataset:
Venous Thromboembolic Events With Chemotherapy Plus Bevacizumab: A Pooled Analysis of Patients in Randomized Phase II and III Studies
Authors: Herbert I. Hurwitz, Leonard B. Saltz, Eric Van Cutsem, James Cassidy, Jonas Wiedemann, Florin Sirzén, Gary H. Lyman, Ulrich-Peter Rohr
Journal: Journal of Clinical Oncology (2011)

Thromboembolism is a major source of morbidity and mortality in patients with cancer. The contribution of anti-vascular endothelial growth factor therapy to these events remains controversial.Individual patient data were available for 6,055 patients in 10 randomized studies. Unadjusted and exposure-adjusted incidence of venous thromboembolisms (VTEs) was estimated for the overall population and by tumor type. Multivariate analysis was performed to identify risk factors for development of VTE. The safety of anticoagulant therapy in patients undergoing bevacizumab treatment was also examined.There were no statistically significant increases in the unadjusted or exposure-adjusted incidences of all-grade VTEs for bevacizumab versus controls in the overall population or by tumor type. The unadjusted incidence in the overall population was 10.9% with bevacizumab versus 9.8% with controls (odds ratio, 1.14; 95% CI, 0.96 to 1.35; P = .13); the rate per 100 patient-years was 18.5 for bevacizumab and 20.3 for controls (rate ratio, 0.91; 95% CI, 0.77 to 1.06; P =.23). Incidences of grade 3 to 5 events were similar in both groups. Several risk factors for VTEs were identified, including tumor type, older age, poorer performance status, VTE history, and baseline oral anticoagulant use. No interactions between bevacizumab treatment and these factors were observed. For patients who had a VTE and received full-dose anticoagulation therapy, the risk of severe bleeding was low (< 1%) and unaffected by bevacizumab treatment.The addition of bevacizumab to chemotherapy did not statistically significantly increase the risk of VTEs versus chemotherapy alone. The risk for VTEs is driven predominantly by tumor and host factors.
Inhibition of airway smooth muscle tone by Chinese herbal medicines
Authors: E. Tagaya, J. Tamaoki, K. Kawatani, M Taira, A Nagai
Journal: European Respiratory Journal (2000)

The aim of the present study was to elucidate whether Chinese traditional herbal drugs, Gorei-San (TJ-17) and Toki-Shakuyaku-San (TJ-23), affect airway smooth muscle tone and, if so, to determine what the mechanism of action is. Rabbit tracheal segments were isolated and the contractile responses to electrical field stimulation and acetylcholine were measured before and after the application of TJ-17 or TJ-23 under isometric conditions in vitro. Ouabain-sensitive rubidium-86 (86Rb) uptake by tissues in response to each drug was also measured. Each herbal medicine attenuated the contractile responses to electrical field stimulation and acetylcholine in a concentration-dependent manner, the maximal inhibition of acetylcholine-induced contraction being 37.5+/-4.9% for TJ-17 and 42.4+/-5.3% for TJ-23 (p&lt;0.05 for each). These effects were not altered by mechanical removal of the epithelium, indomethacin, the nitric oxide synthase inhibitor NG -nitro-L-arginine methyl ester, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor adenosine 3959-cyclic monophosphorothioate (Rp-cAMPS), the cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor KT5823, or the calcium (Ca2+)-activated potassium (K+) channel inhibitor charybdotoxin, but were greatly inhibited in the presence of the sodium (Na+)-K+ adenosine triphosphatase (ATPase) inhibitor ouabain. Incubation of tissues with TJ-17 and TJ-23 dose dependently increased ouabain-sensitive 86Rb uptake. The results of the study suggest that both Gorei-San and Toki-Shakuyaku-San reduce airway smooth muscle tone via a postjunctional mechanism probably through stimulation of the sodium pump and the subsequent hyperpolarization/repolarization of the cell membrane. These effects may contribute to the antiasthmatic properties of these herbal medicines.
Theoretical integration in motivational science: System justification as one of many “autonomous motivational structures”
Authors: Aaron C Kay, John T Jost
Journal: Behavioral and Brain Sciences (2014)

Abstract Recognizing that there is a multiplicity of motives – and that the accessibility and strength of each one varies chronically and temporarily – is essential if motivational scientists are to achieve genuine theoretical and empirical integration. We agree that system justification is a case of nonconscious goal pursuit and discuss implications of the fact that it conflicts with many other psychological goals.
Natural Proteolytic Processing of Hemofiltrate Cc Chemokine 1 Generates a Potent Cc Chemokine Receptor (Ccr)1 and Ccr5 Agonist with Anti-HIV Properties
Authors: Michel Detheux, Ludger Ständker, Jalal Vakili, Jan Münch, Ulf Forssmann, Knut Adermann, Stefan Pöhlmann, Gilbert Vassart, Frank Kirchhoff, Marc Parmentier, Wolf-Georg Forssmann
Journal: The Journal of Experimental Medicine (2000)

Hemofiltrate CC chemokine (HCC)-1 is a recently described human chemokine that is constitutively expressed in numerous tissues and is present at high concentrations in normal plasma. Using a cell line expressing CC chemokine receptor (CCR)5 as a bioassay, we isolated from human hemofiltrate an HCC-1 variant lacking the first eight amino acids. HCC-1[9–74] was a potent agonist of CCR1, CCR3, and CCR5 and promoted calcium flux and chemotaxis of T lymphoblasts, monocytes, and eosinophils. It also blocked entry of HIV-1 strains using CCR5 as coreceptor. Limited tryptic digestion of HCC-1 generated the active variant. Conditioned media from several tumor cell lines activated HCC-1 with a high efficiency, and this activity could be inhibited by serine protease inhibitors. Our results indicate that HCC-1 represents a nonfunctional precursor that can be rapidly converted to the active chemokine by proteolytic processing. This process represents an additional mechanism by which tumor cells might generate chemoattractant molecules and recruit inflammatory cells. It might also affect HIV-1 replication in infected individuals and play an important role in AIDS pathogenesis.
What to say to a skeptical metaphysician: A defense manual for cognitive and behavioral scientists
Authors: Don Ross, David Spurrett
Journal: Behavioral and Brain Sciences (2004)

A wave of recent work in metaphysics seeks to undermine the anti-reductionist, functionalist consensus of the past few decades in cognitive science and philosophy of mind. That consensus apparently legitimated a focus on what systems do, without necessarily and always requiring attention to the details of how systems are constituted. The new metaphysical challenge contends that many states and processes referred to by functionalist cognitive scientists are epiphenomenal. It further contends that the problem lies in functionalism itself, and that, to save the causal significance of mind, it is necessary to re-embrace reductionism. We argue that the prescribed return to reductionism would be disastrous for the cognitive and behavioral sciences, requiring the dismantling of most existing achievements and placing intolerable restrictions on further work. However, this argument fails to answer the metaphysical challenge on its own terms. We meet that challenge by going on to argue that the new metaphysical skepticism about functionalist cognitive science depends on reifying two distinct notions of causality (one primarily scientific, the other metaphysical), then equivocating between them. When the different notions of causality are properly distinguished, it is clear that functionalism is in no serious philosophical trouble, and that we need not choose between reducing minds or finding them causally impotent. The metaphysical challenge to functionalism relies, in particular, on a naïve and inaccurate conception of the practice of physics, and the relationship between physics and metaphysics.
The Stoke CNEP Saga – how it damaged all involved
Authors: Teresa Wright
Journal: Journal of the Royal Society of Medicine (2010)

After one family made allegations about the way the study of an innovative strategy for providing nursing care was conducted, staff in the neonatal unit at North Staffordshire Hospital endured 11 years of disciplinary enquiry. And, because staff are barred from talking while under investigation, it has only recently become possible to describe in detail much of what then went on.
Association Between Estrogen Receptor-β Expression and Epidermal Growth Factor Receptor Mutation in the Postoperative Prognosis of Adenocarcinoma of the Lung
Authors: Naohiro Nose, Kenji Sugio, Tsunehiro Oyama, Tadahiro Nozoe, Hidetaka Uramoto, Teruo Iwata, Takamitsu Onitsuka, Kosei Yasumoto
Journal: Journal of Clinical Oncology (2008)

Purpose Adenocarcinoma of the lung unrelated to a smoking habit occurs more frequently in women than men, thus suggesting an association between female hormones and development of these tumors. The aim of this study was to elucidate the correlation between expression of estrogen receptor (ER) and clinicopathologic factors, including a mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), and prognosis in adenocarcinoma of the lung. Patients and Methods This study evaluated 447 resected primary lung adenocarcinoma specimens. The expression of ERα and ERβ was evaluated with an immunohistochemical method. The EGFR mutation was evaluated with polymerase chain reaction. Results A strong cytoplasmic expression of ERα and nuclear expression of ERβ were detected in 49.4% and 48.5% of all patients, respectively. A strong nuclear expression of ERβ was independently associated with the EGFR mutations (odds ratio = 2.947; 95% CI, 1.97 to 4.57; P &lt; .001) and good differentiation (odds ratio = 1.84; 95% CI, 1.21 to 2.80; P = .004) and was correlated with an increasing disease-free survival in patients with EGFR mutations (hazard ratio = 2.18; 95% CI, 1.18 to 4.06; P = .014). However, no prognostic significance was identified in patients without EGFR mutations. No clinicopathologic and/or prognostic significance of a strong expression of cytoplasmic ERα was found. Conclusion A strong nuclear expression of ERβ correlates with EGFR mutations, and its favorable prognostic significance was influenced by the EGFR mutations in adenocarcinoma of the lung.
Late Recurrences of Breast Cancer
Authors: J. H. D. Webster
Journal: BMJ (1927)

<h3>Abstract</h3> In neurons, mitochondria are transported to distal regions for supplying energy and buffer Ca<sup>2+</sup>. Mitochondrial transport is mediated by Miro and TRAK adaptors that recruit kinesin and dynein-dynactin. To understand how mitochondria are transported by these opposing motors and stalled at regions with elevated Ca<sup>2+</sup>, we reconstituted the mitochondrial transport machinery in vitro. We show that the coiled-coil domain of TRAK activates dynein-dynactin motility, but kinesin requires an additional factor to efficiently transport Miro/TRAK. Unexpectedly, TRAK adaptors that recruit both motors move towards kinesin’s direction, whereas kinesin is excluded from binding TRAK transported by dynein-dynactin. The assembly and motility of the transport machinery are not affected by Ca<sup>2+</sup>. Instead, the mitochondrial docking protein syntaphilin is sufficient to oppose the forces generated by kinesin and stall the motility. Our results provide mechanistic insight into how mitochondria are transported by the coordinated action of motors and statically anchored to regions with high neuronal activity.
Arsenic Trioxide-Induced Death of Neuroblastoma Cells Involves Activation of Bax and Does Not Require p53
Authors: Jenny Karlsson, Ingrid Øra, Isabella Pörn-Ares, Sven Påhlman
Journal: Clinical Cancer Research (2004)

Abstract Purpose: On the basis of clinical studies showing that arsenic trioxide (As2O3), via an apoptotic mechanism, and with minimal toxicity induces complete remission in patients with refractory acute promyelocytic leukemia and that multidrug-resistant and p53-mutated neuroblastoma cells are sensitive to As2O3 both in vitro and in vivo, we searched for molecular mechanisms involved in the As2O3-induced neuroblastoma cell death. Experimental Design: We have studied the effect of As2O3 on the expression and cellular localization of proteins involved in drug-induced death in two neuroblastoma cell lines with intact p53 and two with mutated p53, the latter two displaying multidrug resistance. Results: As2O3 provoked Bax expression in all tested neuroblastoma cell lines, including SK-N-BE(2) cells with mutated p53 and LA-N-1 cells, which have a deleted p53. In all cell lines exposed to As2O3, p21 Bax was proteolytically cleaved in a calpain-dependent way into the more proapoptotic p18 Bax, which was detected exclusively in a mitochondria-enriched subcellular fraction. As2O3 also caused an increase of cytoplasmic cytochrome c, translocation of antiapoptosis-inducing factor to the nuclei, and a slight activation of caspase 3. However, inhibition of caspase 3 did not prevent cell death, whereas inhibition of Bax cleavage was associated with a decreased As2O3-induced cell death. Conclusions: We show that multidrug-resistant neuroblastoma cells die after exposure to As2O3, independent of functional p53, suggesting activation of a cytotoxic pathway different from that induced by conventional chemotherapeutic agents. We further propose that proteolytic activation of Bax is an important event in As2O3-induced cell death.
Specificities of serum α-fetoprotein in HBsAg+ and HBsAg− patients in the diagnosis of hepatocellular carcinoma
Authors: H S Lee, Y H Chung, C Y Kim
Journal: Hepatology (1991)

Serum α-fetoprotein level is often elevated in patients with chronic liver disease and patients with hepatocellular carcinoma. One of the most difficult problems frequently encountered in practice is differentiating hepatocellular carcinoma from chronic liver disease. This study investigated the specificity and predictive value positive of serum α-fetoprotein at various levels in the diagnosis of hepatocellular carcinoma, using 54 patients with histologically proven hepatocellular carcinoma and 200 patients with chronic liver disease (40 patients with chronic active hepatitis and 160 patients with cirrhosis) as nontumor controls. Among 254 patients, 170 (66.9%) were HBsAg + . A wide range of overlap (from 0 to 6,400 ng/ml) in the distribution of serum α-fetoprotein levels between hepatocellular carcinoma and chronic liver disease patients was observed mainly among HBsAg + patients. In contrast, the overlapping range of serum α-fetoprotein levels between HBsAg − patients with hepatocellular carcinoma and chronic liver disease was remarkably narrow (from 0 to 200 ng/ml). Therefore the specificity and predictive value positive of α-fetoprotein at a given level were significantly lower in HBsAg + than in HBsAg − patients, especially when α-fetoprotein was between 25 and 200 ng/ml. The specificities of α-fetoprotein at 200 ng/ml and 400 ng/ml in HBsAg + patients were 79.8% and 91.5%, respectively, whereas these specificities were both 100% in HBsAg + patients. The predictive values positive at 200 ng/ml and 400 ng/ml in HBsAg + patients were 53.6% and 72.5%, respectively, in contrast to 100% at both levels in HBsAg − patients. The serum α-fetoprotein level, which showed a predictive value positive of 95% in HBsAg + hepatocellular carcinoma patients, was 3,200 ng/ml, whereas that in HBsAg − hepatocellular carcinoma patients, was 200 ng/ml. We conclude that serum HBsAg status should be considered when serum α-fetoprotein is measured as an independent test to diagnose hepatocellular carcinoma, and suggest that regular serum α-fetoprotein determination may be more useful in HBsAg − patients with chronic liver disease for the early diagnosis of hepatocellular carcinoma than in HBsAg + patients. (HEPATOLOGY 1991;14:68-72.)
Representational geometry: integrating cognition, computation, and the brain
Authors: Nikolaus Kriegeskorte, Rogier A. Kievit
Journal: Trends in Cognitive Sciences (2013)

The cognitive concept of representation plays a key role in theories of brain information processing. However, linking neuronal activity to representational content and cognitive theory remains challenging. Recent studies have characterized the representational geometry of neural population codes by means of representational distance matrices, enabling researchers to compare representations across stages of processing and to test cognitive and computational theories. Representational geometry provides a useful intermediate level of description, capturing both the information represented in a neuronal population code and the format in which it is represented. We review recent insights gained with this approach in perception, memory, cognition, and action. Analyses of representational geometry can compare representations between models and the brain, and promise to explain brain computation as transformation of representational similarity structure.
Prostaglandin E2 Stimulates Human Lung Carcinoma Cell Growth through Induction of Integrin-Linked Kinase: The Involvement of EP4 and Sp1
Authors: Ying Zheng, Jeffrey D. Ritzenthaler, XiaoJuan Sun, Jesse Roman, ShouWei Han
Journal: Cancer Research (2009)

Cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) stimulates tumor cell growth and progression. However, the mechanisms by which PGE(2) increases tumor growth remain incompletely understood. In studies performed in non-small cell lung carcinoma (NSCLC) cells, we found that PGE(2) stimulates the expression of integrin-linked kinase (ILK). ILK small interfering RNA (siRNA) inhibited the mitogenic effects of PGE(2). In view of its perceived importance, we turned our attention to the mechanisms involved in PGE(2)-induced ILK expression and found that this effect was blocked by an antagonist of the PGE(2) receptor subtype EP4 and by EP4 siRNA. Furthermore, we showed that PGE(2) induction of ILK was associated with phosphorylation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt, which were abrogated by ILK siRNA. Transient transfection, gel mobility shift assays, and chromatin immunoprecipitation experiments showed that PGE(2) induced ILK promoter activity and increased Sp1, although it had no effect on nuclear factor-kappaB and AP-2 DNA-binding activity. Blockade of Sp1 abrogated the effect of PGE(2) on expression of ILK and promoter activity and on cell growth. In summary, our observations show that PGE(2) increases NSCLC cell growth through increased ILK expression, which is dependent on EP4 signaling and on induction of Sp1 protein and Sp1 DNA-binding activity in the ILK promoter. These studies suggest a novel molecular mechanism by which PGE(2) stimulates NSCLC cell growth and unveils a new molecular target for the development of therapies against NSCLC.
CXC Chemokine Receptor 3 and CC Chemokine Receptor 4 Expression in T-Cell and NK-Cell Lymphomas with Special Reference to Clinicopathological Significance for Peripheral T-Cell Lymphoma, Unspecified
Authors: Takashi Ishida, Hiroshi Inagaki, Atae Utsunomiya, Yoshifusa Takatsuka, Hirokazu Komatsu, Shinsuke Iida, Genji Takeuchi, Tadaaki Eimoto, Shigeo Nakamura, Ryuzo Ueda
Journal: Clinical Cancer Research (2004)

Abstract We recently reported expression of the chemokine receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 4 (CCR4) in adult T-cell leukemia/lymphoma and showed a preferential expression of CCR4 and its association with an unfavorable outcome. In the present study, we extend our adult T-cell leukemia/lymphoma study to other subtypes of T- and NK-cell lymphoma, to clarify whether a characteristic chemokine receptor expression pattern is obtained for each of the subtypes defined by the WHO classification. CXCR3 and CCR4 were rarely expressed in three well-defined subtypes, precursor T-lymphoblastic lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and extranodal NK/T-cell lymphoma. A CXCR3-dominant expression pattern was observed in angioimmunoblastic T-cell lymphoma, while a CCR4-dominant expression pattern was observed in mycosis fungoides in transformation and in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. CXCR3 and CCR4 were heterogeneously expressed in peripheral T-cell lymphomas, unspecified (PTCLU). We next focused on PTCLU and analyzed the clinical significance of the chemokine receptors and their association with FoxP3, a hallmark of immunoregulatory T (Treg) cells. Multivariate analysis showed that CCR4 expression was an independent and significant unfavorable prognostic factor (P &amp;lt; 0.001). A significant correlation was found between mRNA expression of CCR4 and FoxP3, suggesting a possible association of CCR4-positive tumors with Treg cells and thereby with an immunocompromised state. Chemokine receptors may be useful not only for further characterization of the T- and NK-cell lymphomas but also in predicting clinical outcomes for patients. We suggest that a specific therapy targeting the CCR4 molecule may be developed as an alternative treatment for patients with CCR4-positive tumors.
CD103 Expression Is Required for Destruction of Pancreatic Islet Allografts by CD8+ T Cells
Authors: Ye Feng, Donghua Wang, Rongwen Yuan, Christina M. Parker, Donna L. Farber, Gregg A. Hadley
Journal: The Journal of Experimental Medicine (2002)

The mechanisms by which CD8 effector populations interact with epithelial layers is a poorly defined aspect of adaptive immunity. Recognition that CD8 effectors have the capacity to express CD103, an integrin directed to the epithelial cell-specific ligand E-cadherin, potentially provides insight into such interactions. To assess the role of CD103 in promoting CD8-mediated destruction of epithelial layers, we herein examined the capacity of mice with targeted disruption of CD103 to reject pancreatic islet allografts. Wild-type hosts uniformly rejected islet allografts, concomitant with the appearance of CD8+CD103+ effectors at the graft site. In contrast, the majority of islet allografts transplanted into CD103−/− hosts survived indefinitely. Transfer of wild-type CD8 cells into CD103−/− hosts elicited prompt rejection of long-surviving islet allografts, whereas CD103−/− CD8 cells were completely ineffectual, demonstrating that the defect resides at the level of the CD8 cell. CD8 cells in CD103−/− hosts exhibited normal effector responses to donor alloantigens in vitro and trafficked normally to the graft site, but strikingly failed to infiltrate the islet allograft itself. These data establish a causal relationship between CD8+CD103+ effectors and destruction of graft epithelial elements and suggest that CD103 critically functions to promote intragraft migration of CD8 effectors into epithelial compartments.
Prosody and word production
Authors: Fernanda Ferreira
Journal: Behavioral and Brain Sciences (1999)

Any complete theory of lexical access in production must address how words are produced in prosodic contexts. Levelt, Roelofs &amp; Meyer make some progress on this point: for example, they discuss resyllabification in multiword utterances. I present work demonstrating that word articulation takes into account overall prosodic context. This research supports Levelt et al.'s hypothesized separation between metrical and segmental information.