tbuckley/cabot-search huggingface dataset:
Targeting the Fanconi Anemia/BRCA Pathway Circumvents Drug Resistance in Multiple Myeloma
Authors: Danielle N. Yarde, Vasco Oliveira, Linda Mathews, Xingyu Wang, Alejandro Villagra, David Boulware, Kenneth H. Shain, Lori A. Hazlehurst, Melissa Alsina, Dung-Tsa Chen, Amer A. Beg, William S. Dalton
Journal: Cancer Research (2009)

The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-kappaB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IkappaB kinase alpha and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-kappaB by small interfering RNA, blocking the IkappaB kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-kappaB transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients.
Gene Expression Levels and Immunolocalization of Organic Ion Transporters in the Human Kidney
Authors: Hideyuki Motohashi, Yuji Sakurai, Hideyuki Saito, Satohiro Masuda, Yumiko Urakami, Maki Goto, Atsushi Fukatsu, Osamu Ogawa, Ken-ichi Inui
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Renal excretion of organic anions and cations is mediated by the organic ion transporter family (SLC22A). In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney. The expression level of hOAT3 mRNA was the highest among the organic ion transporter family, followed by that of hOAT1 mRNA. The hOCT2 mRNA level was the highest in the human OCT family, and the level of hOCTN2 mRNA was higher than that of hOCTN1. hOCT1 mRNA showed the lowest level of expression in organic ion transporter family. hOAT1, hOAT3, and hOCT2 proteins were detected in crude membranes from the kidney of all patients by Western blot analyses, whereas hOCT1 protein could not be detected. Immunohistochemical analyses showed that both hOAT1 and hOAT3 were localized to the basolateral membrane of the proximal tubules in the cortex, and hOCT2 was localized to the basolateral membrane of the proximal tubules in both the cortex and medullary ray. Immunohistochemical analyses of serial sections indicated that hOAT1, hOAT3, and hOCT2 were coexpressed in a portion of the proximal tubules. These results suggest that hOAT1, hOAT3, and hOCT2 play predominant roles in the transport of organic ions across the basolateral membrane of human proximal tubules.
Prospective, randomized comparison in humans of a unipolar defibrillation system with that using an additional superior vena cava electrode.
Authors: G H Bardy, G L Dolack, P J Kudenchuk, J E Poole, R Mehra, G Johnson
Journal: Circulation (1994)

A unipolar defibrillation system using a single right ventricular (RV) electrode and the active shell or "CAN" of the implantable cardioverter-defibrillator itself situated in a left infraclavicular pocket has been shown to be as efficient in defibrillation as an epicardial lead system. The purpose of this study was to determine whether defibrillation efficacy can be improved further by adding a superior vena cava (SVC) electrode to this already efficient defibrillation system.We prospectively and randomly compared the defibrillation efficacy of a simplified unipolar defibrillation system, RV-->CAN, with that of one incorporating a high SVC electrode, RV-->SVC + CAN, in 15 consecutive cardiac arrest survivors undergoing implantation of a presently available transvenous defibrillation system. The RV defibrillation electrode was a 5-cm coil located on a 10.5F lead used as the anode in both lead configurations examined. The active CAN was a 108-cm2 surface area shell of a titanium alloy pulse generator used as the cathode in both configurations and placed in a left infraclavicular pocket. The SVC electrode was a 6F 5-cm-long coil and was used as an additional cathode positioned at the junction of the SVC and the left innominate vein. The defibrillation pulse used was a 65% tilt, asymmetric biphasic waveform delivered from a 120-microF capacitor. The defibrillation threshold (DFT) stored energy, leading edge voltage, current, and pulsing resistance were measured for both lead systems. The single-lead unipolar system, RV-->CAN, resulted in a stored energy DFT of 7.4 +/- 5.2 J, and the three-electrode dual pathway system, RV-->SVC + CAN, resulted in a DFT of 6.0 +/- 3.4 J (P = .20). There was no difference in defibrillation efficacy with the more complicated three-electrode system over the unipolar system despite a decrease in pulsing resistance to 48.6 +/- 3.5 omega compared with 61.2 +/- 5.9 omega for the unipolar system (P < .0001) and a slight rise in delivered current to 6.3 +/- 1.8 A compared with 5.5 +/- 2.0 A for the unipolar system (P = .062).The unipolar single-lead transvenous defibrillation system provides defibrillation at energy levels comparable to that reported with present epicardial lead systems. Coupling of this lead system to a third SVC electrode increases system complexity but offers little defibrillation advantage despite a large decrease in pulsing resistance and a modest increase in delivered current.
Methodological problems in the epidemiological study of osteoarthritis.
Authors: T D Spector, M C Hochberg
Journal: Annals of the Rheumatic Diseases (1994)

In conclusion, though there are numerous opportunities and different approaches to studying the epidemiology of OA, we have concentrated on some of the methodological problems and difficulties inherent in these methods. We think it is important that researchers are aware of these problems before undertaking such studies. In addition, readers of published studies need to be aware of these potential pitfalls before being able to make valid judgements on research papers. We hope, however, that stressing these problems does not dissuade present and future investigators from participating in this area of research. Despite difficulties inherent in the epidemiology of chronic diseases and OA in particular, studies may uncover modifiable risk factors for the development and progression of OA which could lead to important preventive strategies.
Ultrafast computed tomography analysis of regional radius-to-wall thickness ratios in normal and volume-overloaded human left ventricle.
Authors: A J Feiring, J A Rumberger
Journal: Circulation (1992)

BACKGROUND This study tested two hypotheses: 1) regional left ventricular radius-to-wall thickness ratios (R/T) are uniform in normal subjects, and 2) patients with left ventricular hypertrophy secondary to compensated volume overload normalize global and regional R/T. METHODS AND RESULTS Ultrafast computed tomography was used to measure regional short-axis ventricular R/T in 11 normal subjects and 13 patients with compensated aortic insufficiency (AI) of moderate severity (regurgitant fraction, greater than or equal to 25%). Radius and wall thickness dimensions were calculated by two different methods. In method 1, the average radius and wall thickness were determined for each planimetric transaxial tomographic image. In method 2, the left ventricle was three-dimensionally reconstructed; then, new radii and wall thickness were recalculated as if all the images were acquired orthogonal to the endocardial surface at each tomographic level. In normals, the mean R/T ratio was 1.75 +/- 0.11 (SEM) with method 1 and 1.80 +/- 0.07 with method 2. The R/T ratios varied as a function of the relative apex-to-base position. R/T ratios at the basal four levels were relatively uniform, whereas R/T at the lower three tomographic levels were significantly less than those at the base (p less than 0.01). Patients with AI had a mean regurgitant fraction of 44 +/- 3.8% (range, 25-63%). The mean R/T ratio was 2.18 +/- 0.16 with method 1 and 2.55 +/- 0.18 with method 2. Similar to the pattern observed in normals, the regional R/T ratios at the lower three or four levels were significantly less than the basal R/T ratios (p less than 0.01). Regional comparison of the normal to the volume-overloaded ventricles demonstrated that R/T ratios in the AI patients were significantly greater at the upper five levels with method 1 and at all eight levels with method 2 (p less than 0.01-0.001, AI versus normal). CONCLUSIONS These findings demonstrate that regional R/T ratios are heterogeneous in both normals and patients with left ventricular hypertrophy secondary to compensated aortic insufficiency. Furthermore, these findings challenge the accepted hypothesis that global and regional R/T ratios normalize in patients with compensated volume-overload hypertrophy.
Positron Emission Tomography (PET) Imaging with [11C]-Labeled Erlotinib: A Micro-PET Study on Mice with Lung Tumor Xenografts
Authors: Ashfaque A. Memon, Steen Jakobsen, Frederik Dagnaes-Hansen, Boe S. Sorensen, Susanne Keiding, Ebba Nexo
Journal: Cancer Research (2009)

Erlotinib (Tarceva) targets the epidermal growth factor receptor (EGFR), which is commonly overexpressed in human cancers, including lung cancer. We show that erlotinib can be labeled with [(11)C] by reacting the normethyl precursor with [(11)C]-methyl iodide. By using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, two lung cancer cell lines (A549 and NCI358) were shown to be less sensitive to erlotinib compared with the lung cancer cell line HCC827. This correlated with higher expression and activity of the EGFR in HCC827 cells as compared with the less sensitive cell lines. Micro-positron emission tomography (PET) and biodistribution of erlotinib was performed with [(11)C]-erlotinib in nude mice bearing xenografts of A549, NCI358, and HCC827 cells. Dynamic micro-PET showed that HCC827 tumors had the highest [(11)C]-erlotinib uptake and retained the activity significantly longer as compared with A549 and NCI358 tumors. Biodistribution of [(11)C]-erlotinib in the xenograft models of lung cancer showed the highest accumulation in the liver. In mice carrying the sensitive cancer cells, the accumulation of [(11)C]-erlotinib was higher in tumors than in the other organs. In contrast, the drug accumulated to a comparable extent in tumors from the less sensitive cancer cells and the other organs. Uptake of [(11)C]-erlotinib in the tumors was 1.6%, 0.7%, and 3.7% (percentage of injected dose/g), in A549, NCI358, and HCC827 cells, respectively. We show for the first time that [(11)C]-erlotinib identifies erlotinib-sensitive tumors. These results pave the road for studies examining the benefit of [(11)C]-erlotinib PET in patients with lung tumors or other tumors overexpressing EGFR.
The role of nonclassical Fc receptor-associated, Ag-B antigens (Ia) in rat allograft enhancement.
Authors: J P Soulillou, C B Carpenter, A J d'Apice, T B Strom
Journal: The Journal of Experimental Medicine (1976)

The ability of a hyperimmune Lew anti-BN serum (HIS) to induce enhancement of (Lew/BN)F1 kidneys transplanted into Lew recipients was compared to that of the same antiserum that had been depleted of hemagglutinating anti-Ag-B antibodies by absorption with Brown-Norway (BN) RBC-absorbed sera (RAS) or platelet-absorbed sera (PAS). The RAS and PAS were as effective as the unabsorbed HIS in abrogating early rejection as assessed by renal function and promotion of long-term survival. The absorbed sera retained the capacity to block the mixed lymphocyte culture (MLC) between Lew and BN lymphocytes and to a lesser degree the MLC between Lew and BUF, WF, AUG, and ACI lymphocytes; however, strain specificity was clearly evident at high antiserum dilutions. Similarly, these absorbed sera retained the capacity to block the Fc receptor of BN lymphocytes, and this effect was completely strain specific. In contrast, hemagglutinating and cytotoxic antibodies eluted from platelets used for antiserum absorption did not react with Fc receptors as assessed by rabbit antisheep (IgG)-coated SRBC (EA) rosette formation. F(Ab')2 fragments of PAS also blocked EA rosettes. On the other hand, complement rosettes (EAC) were not inhibited by the HIS. The antibodies were therefore directed against the Fc receptor itself or a structure spatially or functionally closely related to it. Both the Fc receptors and the enhancing capacity of the antisera were strictly specific for the BN genotype. It is suggested that the anti-"Fc receptor" antibody could play an important role in the induction of enhancement by impairing host T-B collaboration as a result of its binding to graft allogeneic "Fc receptors" which appear to be analogous to the major histocompatibility complex (MHC)-coded Ia antigens of the mouse.
Identification and characterization of developmentally regulated genes in vascular smooth muscle cells.
Authors: D K Han, G Liau
Journal: Circulation Research (1992)

We wish to understand the process of smooth muscle cell (SMC) proliferation and maturation during late fetal development and have examined some of the molecular changes associated with blood vessel maturation in late gestational and early neonatal life. By differential screening of a fetal aortic smooth muscle cDNA library, we identified a gene (F-31) that was developmentally regulated in aortic smooth muscle. The F-31 gene encodes a 2.3-kb RNA that was highly expressed in fetal aortic smooth muscle (25-day gestation), was lower in newborns, and was undetectable in the aortic smooth muscle of 4-week-old animals. F-31 was also highly expressed in fetal muscle, esophagus, heart, liver, lung, and placenta; its expression was lower in skin, kidney, and brain. By contrast, the expression of F-31 was low or undetectable in the corresponding tissue of adult animals. DNA sequence analysis of cDNAs encoding F-31 and data base comparison revealed a 73% homology with a previously identified, developmentally regulated gene called H19. We also found that insulin-like growth factor II (IGF-II) expression was developmentally regulated in smooth muscle. However, unlike F-31, expression of IGF-II was undetectable in the aortic smooth muscle of newborn animals. Analysis of the mRNA level of several genes that encode cytoskeletal proteins in neonatal, newborn, and adult smooth muscle indicates that total actin mRNA level, alpha-smooth muscle actin, and alpha-tropomyosin mRNA levels were similar between the late gestational period and 4 weeks after birth.(ABSTRACT TRUNCATED AT 250 WORDS)
Kaposi's Sarcoma–Associated Herpesvirus Viral IFN Regulatory Factor 3 Stabilizes Hypoxia-Inducible Factor-1α to Induce Vascular Endothelial Growth Factor Expression
Authors: Young C. Shin, Chul-Hyun Joo, Michaela U. Gack, Hye-Ra Lee, Jae U. Jung
Journal: Cancer Research (2008)

Abstract Kaposi's sarcoma–associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of both developmental and pathologic angiogenesis, composed of an oxygen-sensitive α-subunit and a constitutively expressed β-subunit. HIF-1 activity in tumors depends on the availability of the HIF-1α subunit, the levels of which are increased under hypoxic conditions. Recent studies have shown that HIF-1 plays an important role in KSHV reactivation from latency and pathogenesis. Here, we report a novel mechanism by which KSHV activates HIF-1 activity. Specific interaction between KSHV viral IFN regulatory factor 3 (vIRF3) and the HIF-1α subunit led to the HIF-1α stabilization and transcriptional activation, which induced vascular endothelial growth factor expression and ultimately facilitated endothelial tube formation. Remarkably, the central domain of vIRF3, containing double α-helix motifs, was sufficient not only for binding to HIF-1α but also for blocking its degradation in normoxic conditions. This indicates that KSHV has developed a unique mechanism to enhance HIF-1α protein stability and transcriptional activity by incorporating a viral homologue of cellular IRF gene into its genome, which may contribute to viral pathogenesis. [Cancer Res 2008;68(6):1751–9]
Junk food advertising contributes to young Americans' obesity
Authors: Kristina Fister
Journal: BMJ (2005)

Junk food and the advertising that promotes it are a serious threat to the health of young Americans, says a new report from the US Institute of Medicine.

The report summarises current evidence on the effect that advertising campaigns have on the food and beverage consumption of young people in the United States. The report was commissioned by the Congress.

The diets of young Americans differ substantially from recommended diets: they are too rich in energy, fat, salt, …
Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia.
Authors: R A Fava, N J Olsen, A E Postlethwaite, K N Broadley, J M Davidson, L B Nanney, C Lucas, A S Townes
Journal: The Journal of Experimental Medicine (1991)

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.
BNCI Horizon 2020: towards a roadmap for the BCI community
Authors: Clemens Brunner, Niels Birbaumer, Benjamin Blankertz, Christoph Guger, Andrea Kübler, Donatella Mattia, José del R. Millán, Felip Miralles, Anton Nijholt, Eloy Opisso, Nick Ramsey, Patric Salomon, Gernot R. Müller-Putz
Journal: Brain-Computer Interfaces (2015)

The brain-computer interface (BCI) field has grown dramatically over the past few years, but there are still no coordinated efforts to ensure efficient communication and collaboration among key stakeholders. The European Commission (EC) has recently renewed their efforts to establish such a coordination effort by funding a coordination and support action for the BCI community called ‘BNCI Horizon 2020’ after the ‘Future BNCI’ project. Major goals of this new project include developing a roadmap for the next decade and beyond, encouraging discussion and collaboration within the BCI community, fostering communication with the general public, and the foundation of an international BCI Society. We present a short overview of current and past EU-funded BCI projects and provide evidence of a growing research and industrial community. Efficient communication also entails the establishment of clear terminology, which is a major goal of BNCI Horizon 2020. To this end, we give a brief overview of current BCI-related terms and definitions. A major networking activity in the project was the BNCI Horizon 2020 Retreat in Hallstatt, Austria. Over 60 experts participated in this event to discuss the future of the BCI field in a series of plenary talks, targeted discussions, and parallel focus sessions. A follow-up event was the EU BCI Day at the 6th International Brain-Computer Interface Conference in Graz, Austria. This networking event included plenary talks by eight companies and representatives from all seven ongoing EU research projects, poster presentations, demos, and discussions. Another goal of BNCI Horizon 2020 is the foundation of an official BCI Society. In this article, we summarize the current status of this process. Finally, we present visions for future BCI applications developed within BNCI Horizon 2020 using input from external BCI experts as well. We identify common themes and conclude with six exemplary use cases.