tbuckley/cabot-search huggingface dataset:
SINE (selective inhibitor of nuclear export) – translational science in a new class of anti-cancer agents
Authors: John Gerecitano
Journal: Journal of Hematology & Oncology (2014)

Regulation of protein trafficking between the nucleus and cytoplasm represents a novel control point for antineoplastic intervention. Several proteins involved with cellular growth and survival depend on precise and timely positioning within the cell to fulfill their functions, and the nuclear membrane defines one of the most important compartmental barriers. Chromosome Region Maintenance 1, or exportin-1 (CRM1/XPO1), is involved with the export of more than 200 nuclear proteins, and has intriguingly been shown to have an increased expression in several tumor cell types. Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (SINE) to be developed for clinical use. Preclinical data has demonstrated antineoplastic activity of SINE compounds in many human solid and hematologic malignancies. The clinical development of Selinexor provides an excellent model for translational research.
Association of Serum Leptin Levels With Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes
Authors: Ko Hanai, Tetsuya Babazono, Michino Mugishima, Naoshi Yoshida, Izumi Nyumura, Kiwako Toya, Ryotaro Bouchi, Nobue Tanaka, Yasuko Uchigata
Journal: Diabetes Care (2011)

To clarify the association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes (T2D).This was an observational cohort study of 668 patients with T2D. Patients were classified into three groups by sex-specific tertile of leptin levels. Outcome measurements were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria.Patients with low or high leptin levels had a steeper eGFR decline (-2.07 and -2.14 mL/min/1.73 m(2)/year) than those with midrange leptin levels (-0.82 mL/min/1.73 m(2)/year; P < 0.01), whereas patients with low leptin levels had an elevated risk of progression of albuminuria as compared with those with high leptin levels (hazard ratio 3.125 [95% CI 1.302-7.499]).Both low and high serum leptin levels were risk factors for kidney function decline. Meanwhile, lower serum leptin levels were associated with progression of albuminuria.
Development of chimeric molecules for recognition and targeting of antigen-specific B cells in pemphigus vulgaris
Authors: C.M. Proby, T. Ota, H. Suzuki, S. Koyasu, S. Gamou, N. Shimizu, J.K. Wahl, M.J. Wheelock, T. Nishikawa, M. Amagai
Journal: British Journal of Dermatology (2000)

Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3). The purpose of this study was to develop chimeric molecules for specific recognition and elimination of autoimmune B cells in PV. Mouse hybridoma cell lines producing anti‐Dsg3 antibody (5H10, 12A2) were developed as an in vitro model system for targeting B cells. Dsg3‐GFP, a baculoprotein containing the entire extracellular domain of Dsg3 fused with green fluorescence protein, recognized and targeted the hybridoma cells through their surface immunoglobulin receptors in an antigen‐specific way. The epitopes of these monoclonal antibodies were mapped on the amino terminal EC1 and part of EC2, a region considered functionally important in cadherins. Chimeric toxin molecules containing the mapped region (Dsg3ΔN1) and modified Pseudomonas exotoxin were produced in bacteria (Dsg3ΔN1‐PE40‐KDEL, PE37‐Dsg3ΔN1‐KDEL) and tested in vitro on hybridoma cell lines. The chimeric toxins, but not Dsg3ΔN1 alone, showed dose‐dependent toxic activity with a reduction in hybridoma cell number to 40–60% of toxin‐negative control cultures, compared with little or no effect on anti‐Dsg3‐negative hybridoma cells. Furthermore, these toxins showed toxic effects on anti‐Dsg3 IgG‐producing B cells from Dsg3ΔN1‐immunized mice, with a 60% reduction in cell number compared with Dsg3ΔN1 alone. Thus, specific recognition and targeting of antigen‐specific B cells in PV was demonstrated; this strategy may hold promise as a future therapeutic option for PV and other autoimmune diseases.
MicroRNA-195 suppresses tumorigenicity and regulates G<sub>1</sub>/S transition of human hepatocellular carcinoma cells
Authors: Teng Xu, Ying Zhu, Yujuan Xiong, Yi-Yuan Ge, Jing-Ping Yun, Shi-Mei Zhuang
Journal: Hepatology (2009)

Abstract Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G 1 /S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G 1 /S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G 1 arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G 1 /S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (Hepatology 2009.)
490 HIGHLY EXPRESSED CCL-2 IN SEVERE FORM OF ALCOHOLIC HEPATITIS: A POTENTIAL ENHANCER OF THE IL-17-NEUTROPHIL LIVER RECRUITMENT PATHWAY
Authors: P. Degré, A. Lemmers, T. Gustot, E. Trépo, R. Ouziel, P. Demetter, L. Verset, E. Quertinmont, V. Vercruysse, O. Le Moine, J. Devière, C. Moreno
Journal: Journal of Hepatology (2011)
Verbal working memory and sentence comprehension
Authors: David Caplan, Gloria S. Waters
Journal: Behavioral and Brain Sciences (1999)

This target article discusses the verbal working memory system used in sentence comprehension. We review the concept of working memory as a short-duration system in which small amounts of information are simultaneously stored and manipulated in the service of accomplishing a task. We summarize the argument that syntactic processing in sentence comprehension requires such a storage and computational system. We then ask whether the working memory system used in syntactic processing is the same as that used in verbally mediated tasks that involve conscious controlled processing. Evidence is brought to bear from various sources: the relationship between individual differences in working memory and individual differences in the efficiency of syntactic processing; the effect of concurrent verbal memory load on syntactic processing; and syntactic processing in patients with poor short-term memory, patients with poor working memory, and patients with aphasia. Experimental results from these normal subjects and patients with various brain lesions converge on the conclusion that there is a specialization in the verbal working memory system for assigning the syntactic structure of a sentence and using that structure in determining sentence meaning that is separate from the working memory system underlying the use of sentence meaning to accomplish other functions. We present a theory of the divisions of the verbal working memory system and suggestions regarding its neural basis.
Comparative Effectiveness of Weight-Loss Interventions in Clinical Practice
Authors: Lawrence J. Appel, Jeanne M. Clark, Hsin-Chieh Yeh, Nae-Yuh Wang, Janelle W. Coughlin, Gail Daumit, Edgar R. Miller, Arlene Dalcin, Gerald J. Jerome, Steven Geller, Gary Noronha, Thomas Pozefsky, Jeanne Charleston, Jeffrey B. Reynolds, Nowella Durkin, Richard R. Rubin, Thomas A. Louis, Frederick L. Brancati
Journal: New England Journal of Medicine (2011)

Obesity and its cardiovascular complications are extremely common medical problems, but evidence on how to accomplish weight loss in clinical practice is sparse.
CaMKII Is Essential for the Proasthmatic Effects of Oxidation
Authors: Philip N. Sanders, Olha M. Koval, Omar A. Jaffer, Anand M. Prasad, Thomas R. Businga, Jason A. Scott, Patrick J. Hayden, Elizabeth D. Luczak, David D. Dickey, Chantal Allamargot, Alicia K. Olivier, David K. Meyerholz, Alfred J. Robison, Danny G. Winder, Timothy S. Blackwell, Ryszard Dworski, David Sammut, Brett A. Wagner, Garry R. Buettner, Robert M. Pope, Francis J. Miller, Megan E. Dibbern, Hans Michael Haitchi, Peter J. Mohler, Peter H. Howarth, Joseph Zabner, Joel N. Kline, Isabella M. Grumbach, Mark E. Anderson
Journal: Science Translational Medicine (2013)

Ca 2+ /calmodulin-dependent protein kinase (CaMKII) transduces oxidative stress into asthma-related diseases.
Overexpression of Functionally Coupled Cyclooxygenase-2 and Prostaglandin E Synthase in Symptomatic Atherosclerotic Plaques as a Basis of Prostaglandin E <sub>2</sub> -Dependent Plaque Instability
Authors: Francesco Cipollone, Cesaria Prontera, Barbara Pini, Matteo Marini, Maria Fazia, Domenico De Cesare, Annalisa Iezzi, Sante Ucchino, Gianfranco Boccoli, Vittorio Saba, Francesco Chiarelli, Franco Cuccurullo, Andrea Mezzetti
Journal: Circulation (2001)

Studies have implicated a role for prostaglandin (PG) E(2)-dependent matrix metalloproteinase (MMP) biosynthesis in the rupture of atherosclerotic plaque. Cyclooxygenase-2 (COX-2) and PGE synthase (PGES) are coregulated in nucleated cells by inflammatory stimuli. The aim of this study was to characterize the expression of COX-2 and PGES in carotid plaques and to correlate it with the extent of inflammatory infiltration and MMP activity and with clinical features of patients' presentation.Plaques were obtained from 50 patients undergoing carotid endarterectomy and divided into 2 groups (symptomatic and asymptomatic) according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, PGES, MMP-2, and MMP-9 by immunocytochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunocytochemistry was used to identify CD68+ macrophages, CD3+ T lymphocytes, and HLA-DR+ cells. The percentage of macrophage-rich areas was larger (P<0.0001) in symptomatic plaques. COX-2, PGES, and MMPs were detected in all specimens; enzyme concentration, however, was significantly higher in symptomatic plaques. COX-2, PGES, and MMPs were especially noted in shoulders of symptomatic plaques, colocalizing with HLA-DR+ macrophages. All symptomatic plaques contained activated forms of MMPs. Finally, inhibition of COX-2 by NS-398 was accompanied by decreased production of MMPs that was reversed by PGE(2).This study demonstrates the colocalization of COX-2 and PGES in symptomatic lesions and provides evidence that synthesis of COX-2 and PGES by activated macrophages is associated with acute ischemic syndromes, possibly through metalloproteinase-induced plaque rupture.
A role for microRNA in cystic liver and kidney diseases
Authors: Andrew S. Chu, Joshua R. Friedman
Journal: Journal of Clinical Investigation (2008)

The polycystic liver and kidney diseases are a family of disorders with heterogeneous etiologies. Proposed mechanisms of disease include ciliary dysfunction, excess cell proliferation, and altered cell-cell or cell-matrix interactions. In this issue of the JCI, Lee and colleagues provide data to support a novel mechanism for cystogenesis involving microRNA (miRNA) (see the related article beginning on page 3714). They demonstrate that levels of the miRNA miR15a are decreased in livers of patients with autosomal recessive and autosomal dominant polycystic kidney disease (ARPKD and ADPKD, respectively) and congenital hepatic fibrosis as well as in the PKC rat model of ARPKD. This results in increased expression of the cell-cycle regulator Cdc25A, which is a direct target of miR15a, and increased cellular proliferation and cystogenesis in vitro. These findings suggest that other miRNAs may also participate in the molecular pathogenesis of cystic liver and kidney diseases.
TWO-YEAR CLINICAL OUTCOMES OF SECOND GENERATION VERSUS FIRST GENERATION CORONARY DRUG-ELUTING STENTS: AN ANALYSIS FROM ADAPT-DES
Authors: Puja Parikh, Ajay Kirtane, Giora Weisz, Thomas Stuckey, Ke Xu, Bernhard Witzenbichler, Michael Rinaldi, Franz-Josef Neumann, D. Christopher Metzger, Timothy Henry, David Cox, Peter Duffy, Bruce Brodie, Ernest Mazzaferri, Ecaterina Cristea, Helen Parise, Roxana Mehran, Gregg Stone
Journal: Journal of the American College of Cardiology (2014)
Organizational structures and practices are better predictors of suicide terror threats than individual psychological dispositions
Authors: Hector Qirko
Journal: Behavioral and Brain Sciences (2014)

Abstract Terror organizations tend to rely on a limited number of practices to reinforce commitment to suicide on the part of recruits. Therefore, given the many difficulties associated with identifying individuals willing to become suicide terrorists, understanding the organizational contexts in which most suicide terrorism takes place is likely to be more useful than psychological profiling for predicting future attacks.
Optic pathway gliomas in adolescence--time to challenge treatment choices?
Authors: A. Lee Chong, J. D. Pole, K. Scheinemann, J. Hukin, U. Tabori, A. Huang, E. Bouffet, U. Bartels
Journal: Neuro-Oncology (2013)

Optimal management of optic pathway/hypothalamic glioma (OPHG) remains an ongoing challenge. Little is known about the natural history, management strategies, and outcomes in adolescents. Carboplatin-based chemotherapy is a useful modality in younger children, delaying radiation to their immature brains. National trials have focused on younger children and excluded adolescents from studies evaluating the role of chemotherapy. This retrospective study describes clinical characteristics, treatment regimens, and outcomes in adolescents (aged ≥10 years) with OPHG (diagnosis during 1990–2006). Progression-free survival was compared with that in a cohort of younger children (aged <10 years). Thirty-three adolescents (19 females, 6 with neurofibromatosis type 1) with OPHG were identified within 2 Canadian pediatric oncology institutions. The majority presented with visual symptoms (82%). More than 55% (18 of 33) involved the posterior tract and/or hypothalamus (modified Dodge classification 3/4). Seventeen were initially observed; 8 remained progression free. Of the 25 of 33 adolescents who required active treatment, 9 (36%) needed second-line therapy. The progression-free survival for any first active treatment at age <10 years (52 of 102) or ≥10 years (25 of 33) was similar (46.9 vs 46.8 months; P = .60). In those who received chemotherapy as first-line treatment or after prior nonchemotherapy treatment failure, the progression-free survival trend was superior (62.9 vs 38.9 months) in those aged ≥10 years although not statistically significant (P = .16). Chemotherapy is a valuable treatment modality for the achievement of disease control even in adolescents; their progression-free survival compares favorably with that in younger children. We propose that chemotherapy be considered as a first-line modality in adolescents, avoiding potential radiation-associated morbidities.
<i>TP53</i> Mutation and Survival in Chronic Lymphocytic Leukemia
Authors: Thorsten Zenz, Barbara Eichhorst, Raymonde Busch, Tina Denzel, Sonja Häbe, Dirk Winkler, Andreas Bühler, Jennifer Edelmann, Manuela Bergmann, Georg Hopfinger, Manfred Hensel, Michael Hallek, Hartmut Döhner, Stephan Stilgenbauer
Journal: Journal of Clinical Oncology (2010)

The precise prognostic impact of TP53 mutation and its incorporation into treatment algorithms in chronic lymphocytic leukemia (CLL) is unclear. We set out to define the impact of TP53 mutations in CLL.We assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a randomized prospective trial (n = 375) with a follow-up of 52.8 months (German CLL Study Group CLL4 trial; fludarabine [F] v F + cyclophosphamide [FC]).We found TP53 mutations in 8.5% of patients (28 of 328 patients). None of the patients with TP53 mutation showed a complete response. In patients with TP53 mutation, compared with patients without TP53 mutation, median progression-free survival (PFS; 23.3 v 62.2 months, respectively) and overall survival (OS; 29.2 v 84.6 months, respectively) were significantly decreased (both P < .001). TP53 mutations in the absence of 17p deletions were found in 4.5% of patients. PFS and OS for patients with 17p deletion and patients with TP53 mutation in the absence of 17p deletion were similar. Multivariate analysis identified TP53 mutation as the strongest prognostic marker regarding PFS (hazard ratio [HR] = 3.8; P < .001) and OS (HR = 7.2; P < .001). Other independent predictors of OS were IGHV mutation status (HR = 1.9), 11q deletion (HR = 1.9), 17p deletion (HR = 2.3), and FC treatment arm (HR = 0.6).CLL with TP53 mutation carries a poor prognosis regardless of the presence of 17p deletion when treated with F-based chemotherapy. Thus, TP53 mutation analysis should be incorporated into the evaluation of patients with CLL before treatment initiation. Patients with TP53 mutation should be considered for alternative treatment approaches.
TACE/TGF- /EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components
Authors: J. Øvrevik, M. Refsnes, A.I. Totlandsdal, J.A. Holme, P.E. Schwarze, M. Låg
Journal: European Respiratory Journal (2011)

Airborne particulate matter (PM) may induce or exacerbate neutrophilic airway disease by triggering the release of inflammatory mediators, such as CXC chemokine ligand (CXCL)8, from the airway epithelium. It is still unclear which PM components are driving CXCL8 responses, as most candidates occur at low concentrations in the dusts. We therefore hypothesised that different PM constituents may contribute through common mechanisms to induce CXCL8. Human bronchial epithelial cells (BEAS-2B) were exposed to different PM components (Zn 2+ /Fe 2+ salts, 1-nitropyrene, lipopolysaccharide and diesel exhaust/mineral particles). Gene expression patterns were detected by real-time PCR array. CXCL8 responses were measured by real-time PCR and ELISA. CXCL8 regulation was assessed with a broad inhibitor panel and neutralising antibodies. Epidermal growth factor receptor (EGFR) phosphorylation was examined by immunoprecipitation and Western blotting. Component-induced gene expression was mainly linked to nuclear factor-κB, Ca 2+ /protein kinase C, phospholipase C, low-density lipoprotein and mitogenic signalling. Many inhibitors attenuated CXCL8 release induced by all PM components, but to varying extents. However, EGFR inhibition strongly reduced CXCL8 release induced by all test compounds and selected compounds increased EGFR phosphorylation. Interference with transforming growth factor (TGF)-α or tumour necrosis factor-α-converting enzyme (TACE), which mediates TGF-α ectodomain shedding, also attenuated CXCL8 release. Different PM constituents induced CXCL8 partly through similar signalling pathways but the relative importance of the different pathways varied. However, TACE/TGF-α/EGFR signalling appears to be a convergent pathway regulating innate immune responses of airway epithelial cells upon exposure to multiple airborne pollutants.
Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells
Authors: Lionel Franz Poulin, Mariolina Salio, Emmanuel Griessinger, Fernando Anjos-Afonso, Ligia Craciun, Ji-Li Chen, Anna M. Keller, Olivier Joffre, Santiago Zelenay, Emma Nye, Alain Le Moine, Florence Faure, Vincent Donckier, David Sancho, Vincenzo Cerundolo, Dominique Bonnet, Caetano Reis e Sousa
Journal: The Journal of Experimental Medicine (2010)

In mouse, a subset of dendritic cells (DCs) known as CD8α+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8α+ DCs in humans. Here, we characterize a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8α+ DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanized mice and report on a protocol to generate them in vitro. Like mouse CD8α+ DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8α+ DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to poly I:C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell–derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalize material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I:C. The characterization of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.
Peritoneal ultrafiltration dialysis: enhanced urea transfer using hypertonic peritoneal dialysis fluid.
Authors: L W Henderson
Journal: Journal of Clinical Investigation (1966)

Peritoneal dialysis is generally considered to be a process of diffusion down concentration gradi- ents.The passive nature of the peritoneal membrane has been well demonstrated by Boen (1) using solutions of varying compositions.In these studies solute transfer by diffusion is the only mechanism considered, and no distinction is made between solutions of differing osmolality.The present study compares the rate of urea transfer using dialyzing solutions of different os- molalities (Table I).Solutions hypertonic to plasma enhance the transfer of urea across the peritoneal membrane and result in a markedly im- proved peritoneal clearance of this solute.The data suggest that solvent drag is the probable mechanism responsible for this effect. MethodsNine uremic subjects that required treatment by peri- toneal dialysis were studied on the Clinical Research Center at the University of Pennsylvania.Disposable commercially available peritoneal dialysis equipment was used throughout.Points of difference from usual dialysis technique as described by Flanigan, Henderson, and Merrill (2) have to do with the timing of the various phases of each exchange.The time from starting inflow to the completion of drainage constitutes one exchange.This time was held as closely as possible to 70 minutes total.Each exchange was divided into inflow, dwell, and outflow time corresponding to the time required to run two bottles of dialysis fluid into the abdomen, the time *
STUDY OF TRANSFUSED BLOOD
Authors: Winifred Ashby
Journal: The Journal of Experimental Medicine (1921)

Group IV transfused blood in a recipient of unlike group is eliminated by a blood-destroying activity of the body. This blood-destroying activity is periodic both in men and women, and in women coincident with menstruation. The elimination of the transfused blood probably takes place as part of a period of blood-destroying and blood-producing activity of the body, although direct evidence to this effect is so far lacking.