tbuckley/cabot-search huggingface dataset:
Characterization of a Novel Prostate-Specific Antigen–Activated Peptide-Doxorubicin Conjugate in Patients With Prostate Cancer
Authors: Robert S. DiPaola, John Rinehart, John Nemunaitis, Scott Ebbinghaus, Eric Rubin, Terry Capanna, Marie Ciardella, Susan Doyle-Lindrud, Susan Goodwin, Michelle Fontaine, Ned Adams, Adrienne Williams, Michael Schwartz, Greg Winchell, Karen Wickersham, Paul Deutsch, Siu-Long Yao
Journal: Journal of Clinical Oncology (2002)

To evaluate safety and pharmacokinetics (PK), and determine the recommended dose for efficacy studies, of L-377202, a novel peptide conjugate of doxorubicin (Dox) that releases the active metabolites leucine-doxorubicin (Leu-Dox) and Dox on cleavage by membrane-bound prostate-specific antigen (PSA).Nineteen patients with advanced hormone-refractory prostate cancer were treated intravenously with 71 cycles of L-377202 at escalating dose levels of 20 (n = 1), 40 (n = 3), 80 (n = 4), 160 (n = 3), 225 (n = 6), and 315 mg/m(2) (n = 2) once every 3 weeks. Toxicity, response, and PK of L-377202 were assessed.L-377202 was well tolerated. Dose-limiting grade 4 neutropenia was noted in two of two patients administered 315 mg/m(2) (both patients were able to resume therapy at 225 mg/m(2)). The recommended dose for efficacy studies was 225 mg/m(2), which induced grade 4 neutropenia in one of six patients. PK studies demonstrated that L-377202 was metabolized to Leu-Dox and Dox. PK were linear; after administration of single doses of 225 mg/m(2), the mean area under the concentration-time profiles of L-377202, Leu-Dox, and Dox were 6 micromol x L/h, 4 micromol x L/h, and 1 micromol x L/h, and peak concentrations were 14 micromol/L, 5 micromol/L, and 120 nmol/L, respectively. At 225 and 315 mg/m(2), five patients completed at least three cycles of therapy; two patients had a greater than 75% decrease in PSA, and one patient had a stabilized PSA. No response was noted at dose levels less than 225 mg/m(2).This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.
The Use of Epigenetic Biomarkers for Preclinical Detection of Hepatocellular Carcinoma: Potential for Noninvasive Screening of High-Risk Populations
Authors: Ashley G. Rivenbark, William B. Coleman
Journal: Clinical Cancer Research (2007)

In this issue of Clinical Cancer Research , Zhang et al. ([1][1]) examined the potential for the use of epigenetic biomarkers in a noninvasive approach to early detection of hepatocellular carcinoma in a population of high-risk patients from Taiwan. Using DNA prepared from serum samples
Quality of life and work in patients with rheumatoid arthritis and ankylosing spondylitis of working age
Authors: A M J Chorus
Journal: Annals of the Rheumatic Diseases (2003)

To investigate the relationship between work and quality of life (QOL) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) aged 16-59.1056 patients with RA and 658 with AS were included in the study. Data were obtained by postal questionnaire, which included several generic and disease related QOL instruments. Separate dimensions and physical and mental summary scores from the SF-36 were compared. Stepwise multiple regression was performed to study the relationship between work and physical and mental health related QOL, including disease related factors, coping, and fatigue.Physical health related QOL was reported to be worse, and mental health related QOL better, in RA than in AS in people of working age. No differences between RA and AS were found in somatic pain, physical role functioning, social functioning, emotional role functioning, vitality, or general health perception; nor were there any significant differences in fatigue and behavioural coping styles. Work was positively associated with physical health related QOL in both groups and, after disease characteristics, was the most important determinant. No association was found with mental health related QOL.Although physical health related QOL was worse in patients with RA, the impact on several dimensions of health related QOL in patients with RA and AS of working age under rheumatological care was comparable. Patients with RA and AS experienced similar limitations in physical role functioning, including work. Work is an important independent external determinant of physical health related QOL, but not of mental health related QOL.
Characterization of the kinetics of the passive and active transport mechanisms for bile acid absorption in the small intestine and colon of the rat
Authors: Eugene R. Schiff, Neal C. Small, John M. Dietschy
Journal: Journal of Clinical Investigation (1972)

Bile acid uptake occurs via passive diffusion in all regions of the intestine and via active absorption in the ileum. Determination of the passive permeability coefficient for ionized monomers ((*)P(-)) demonstrated that permeability decreased by a factor of 3.4, 6.8, and 8.1 for the addition of a hydroxyl, glycine, or taurine group, respectively, to the steroid nucleus. Removal of the negative charge increased permeation by a factor of 4.4; however, permeability coefficients for the protonated monomers showed the same relative decrease with addition of a hydroxyl group. The calculated incremental free energies of solution (deltaDeltaF(W-->1)) associated with these additions equaled + 757 (hydroxyl), + 1178 (glycine), and + 1291 (taurine) cal/mole. Passive permeability coefficients for the transverse colon showed the same relative relationships among the various bile acids. After making appropriate corrections for passive permeability across the ileum, apparent values for the maximal transport velocity ((*)V(max)) and Michaelis constant ((*)K(m)) of the active transport system were measured. (*)V(max) depended upon the number of hydroxyl groups on the steroid nucleus; values for the trihydroxy bile acids were high (1543-1906 pmoles/min per cm) while those for the dihydroxy (114-512 pmoles/min per cm) and monohydroxy (45-57 pmoles/min per cm) acids were lower. In contrast, (*)K(m) values were related to whether the bile acid was conjugated; unconjugated bile acids had values ranging from 0.37 to 0.49 mM, while values for the conjugated bile acids were approximately half as high (0.12-0.23 mM).
A selective peroxisome proliferator-activated receptor δ agonist PYPEP suppresses atherosclerosis in association with improvement of the serum lipoprotein profiles in human apolipoprotein B100 and cholesteryl ester transfer protein double transgenic mice
Authors: Noriyuki Naya, Keita Fukao, Akemi Nakamura, Tadateru Hamada, Masayuki Sugimoto, Midori Kojima, Norito Yoshimura, Ken-Ichiro Uwabe, Keiichi Imagawa, Kohji Nomura, Seijiro Hara, Toru Nakano, Takanori Iwasaki, Toshihiro Shinosaki, Kohji Hanasaki
Journal: Metabolism (2015)
Transport of dibasic amino acids, cystine, and tryptophan by cultured human fibroblasts: absence of a defect in cystinuria and Hartnup disease
Authors: Ulrich Groth, Leon E. Rosenberg
Journal: Journal of Clinical Investigation (1972)

Transport of lysine, arginine, cystine, and tryptophan was studied in cultured skin fibroblasts from normal controls and from patients with cystinuria and Hartnup disease. Each of these amino acids was accumulated against concentration gradients by energy-dependent, saturable mechanisms. Lysine and arginine were each transported by two distinct processes which they shared with each other and with ornithine. In contrast, cystine was taken up by a different transport system with no demonstrable affinity for the dibasic amino acids. The time course and Michaelis-Menten kinetics of lysine and cystine uptake by cells from three cystinuric patients differed in no way from those found in control cells. Similarly, the characteristics of tryptophan uptake by cells from a child with Hartnup disease were identical to those noted in control cells. These findings indicate that the specific transport defects observed in gut and kidney in cystinuria and Hartnup disease are not expressed in cultured human fibroblasts, thus providing additional evidence of the important role that cellular differentiation plays in the regulation of expression of the human genome.
Dominant-Negative Suppression of HCN1- and HCN2-Encoded Pacemaker Currents by an Engineered HCN1 Construct
Authors: Tian Xue, Eduardo Marbán, Ronald A. Li
Journal: Circulation Research (2002)

I f , a diastolic depolarizing current activated by hyperpolarization, is a key player in cardiac pacing. Despite the fact that I f has been known for over 20 years, the encoding genes, namely HCN1 to 4, have only recently been identified. Functional data imply that different HCN isoforms may coassemble to form heteromeric channel complexes, but little direct evidence is available. Subunit stoichiometry is also unknown. Although the pore region of HCN channels contains the g lycine-t y rosine- g lycine (GYG) signature motif found in K + -selective channels, they permeate both Na + and K + . In the present study, we probed the functional importance of the GYG selectivity motif in pacemaker channels by replacing this triplet in HCN1 with alanines (GYG 349–351 AAA or HCN1-AAA). HCN1-AAA did not yield functional currents; coexpression of HCN1-AAA with wild-type (WT) HCN1 suppressed normal channel activity in a dominant-negative manner (55.2±3.2%, 68.3±4.3%, 78.7±1.6%, 91.7±0.8%, and 97.9±0.2% current reduction at −140 mV for WT:AAA cRNA ratios of 4:1, 3:1, 2:1, 1:1, and 1:2, respectively) without affecting gating (steady-state activation, activation and deactivation kinetics) or permeation (reversal potential) properties. HCN1-AAA coexpression, however, did not alter the expressed current amplitudes of Kv1.4 and Kv2.1 channels, indicating that its suppressive effect was channel-specific. Statistical analysis reveals that a single HCN channel is composed of 4 monomeric subunits. Interestingly, HCN1-AAA also inhibited HCN2 in a dominant-negative manner with the same efficacy. We conclude that the GYG motif is a critical determinant of ion permeation for HCN channels, and that HCN1 and HCN2 readily coassemble to form heterotetrameric complexes.
Response of type B atrial vagal receptors to changes in wall tension during atrial filling.
Authors: G Recordati, F Lombardi, V S Bishop, A Malliani
Journal: Circulation Research (1975)

In anesthetized curarized cats with their chests open, we recorded the activity of type B right atrial vagal stretch receptors, right atrial pressure, and instantaneous dimensional changes of the right atrium. The nervous activity was analyzed during alterations in atrial dynamics produced by acute volume loading of the right atrium under control conditions and during sympathetic and vagal stimulations. Our results demonstrated that the mean frequency of discharge in the burst was dependent on the absolute tension and the rate of change in tension developed in atrial muscles during filling. The responses of different receptors to changes in atrial dynamics were qualitatively similar but characteristic for each receptor studied. In some experiments nervous activity was recorded after the cats had been killed: static and dynamic changes in atrial tension were then produced by injecting blood into the right atrium. Under these conditions dynamic stimuli always activated the receptors at tensions below the threshold for static stimuli. During dynamic stimuli the instantaneous firing rate was always higher than it was during static stimuli applied at the same level of tension. This study indicates that the nervous activity of type B atrial vagal receptors is closely dependent on static and dynamic changes in atrial wall tension.
Role of Ca2+- and swelling-activated Cl− channels in α1-adrenoceptor-mediated tone in pressurized rabbit mesenteric arterioles
Authors: C Remillard
Journal: Cardiovascular Research (2000)

Background: Ca2+-activated (ICl(Ca)) and swelling-induced (ICl(swell)) Cl− channels have, respectively, been postulated to participate in the membrane depolarization and contraction mediated by activation of α1-adrenoceptors and vascular wall distension during pressurization. Their respective function in generating active force in pressurized arterioles during α1-adrenoceptor stimulation remains unsettled. Objectives: Experimental protocols were designed to: (1) assess the relative contribution of ICl(Ca) to the pressure-dependence of lumen diameter of mesenteric arterioles at different states of activation of the α1-adrenoceptor, and (2) investigate the potential role of ICl(swell) in spontaneous and agonist-mediated myogenic reactivity. Methods: Segments of endothelium-denuded rabbit mesenteric arterioles with a lumen diameter of ∼70 μm were cannulated at both ends and studied under isobaric conditions at 36°C. Steady-state lumen diameter at each pressure step investigated (0–100 mmHg, in 20-mmHg increments) was measured by a video-microscopy edge-detection technique. Results: Under control conditions, 23% of the arterioles developed nifedipine-sensitive spontaneous myogenic tone. In the presence of 1 mM tetraethylammonium chloride (TEA) to inhibit Ca2+-dependent K+ channels, the α1-agonist phenylephrine (PE) contracted the vessels in a concentration-dependent manner (0.1–10 μM) and potentiated myogenic reactivity. The contraction mediated by 1 μM PE/TEA was abolished by 1 μM nifedipine, indicating that Ca2+ entry through voltage-gated Ca2+ channels was a necessary step in the cascade leading to contraction. Niflumic acid (NfA, 100 μM), a relatively selective inhibitor of ICl(Ca), had no effect on myogenic tone but reversed the PE-induced contraction, varying with the concentration of PE and transmural pressure. For PE concentrations between 0.1 and 1 μM, but not for 10 μM PE, the relaxing efficacy of NfA decreased as applied pressure was raised from 0 to 100 mmHg. At all pressure steps, the NfA-induced relaxation was inversely related to the concentration of PE. DIDS (200 μM), another Cl− channel blocker, inhibited spontaneous myogenic tone, and partially suppressed a component of contraction at elevated transmural pressures in arterioles incubated in 1 μM PE/1 mM TEA/100 μM NfA. Conclusions: Our data indicate that under low to moderate stimulation of the α1-adrenoceptor signaling pathway, ICl(Ca) channels play an important role in the sustained contraction produced. Their declining contribution to contraction with increasing transmural pressure may be explained, at least in part, by a progressive enhancement of stretch-induced ionic conductances, possibly volume-sensitive Cl− channels.
Preparation of a Designed Poly(trimethylene carbonate) Microvascular Network by Stereolithography
Authors: Sigrid Schüller‐Ravoo, Erwin Zant, Jan Feijen, Dirk W. Grijpma
Journal: Advanced Healthcare Materials (2014)

Designed flexible and elastic network structures are prepared by stereolitho­graphy using a photo‐crosslinkable resin based on a poly(trimethylene carbonate) (PTMC) macromer with a molecular weight of 3150 g/mol. Physical properties and the compatibility with human umbilical vein endothelial cells (HUVECs) are evaluated. The hydrophobic networks are found to be flexible and elastic, with an E modulus of 7.9 ± 0.1 MPa, a tensile strength of 3.5 ± 0.1 MPa and an elongation at break of 76.7 ± 0.7%. HUVECs attach and proliferate well on the surfaces of the built structures. A three‐dimensional microvascular network is designed to serve as a perfusable scaffold for tissue engineering. In the design, 5 generations of open channels each branch into 4 smaller channels yielding a microvascular region with a high density of capillaries. The overall cross‐­sectional area through which medium or blood can be perfused remains constant. These structures would ensure efficient nourishment of cells in a large volume of tissue. Built by stereolithography using the PTMC resin, the smallest channels of these structures have square cross‐sectional areas, with inner widths of approximately 224 μm and wall thicknesses of approximately 152 μm. The channels are open, allowing water to perfuse the scaffold at 0.279 ± 0.006 mL/s at 80 mmHg and 0.335 ± 0.009 mL/s at 120 mmHg.
Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line
Authors: Bonny L. Dickinson, Kamran Badizadegan, Zhen Wu, Jeremy C. Ahouse, Xiaoping Zhu, Neil E. Simister, Richard S. Blumberg, Wayne I. Lencer
Journal: Journal of Clinical Investigation (1999)

The MHC class I–related Fc receptor, FcRn, mediates the intestinal absorption of maternal IgG in neonatal rodents and the transplacental transport of maternal IgG in humans by receptor-mediated transcytosis. In mice and rats, expression of FcRn in intestinal epithelial cells is limited to the suckling period. We have recently observed, however, clear expression of FcRn in the adult human intestine, suggesting a function for FcRn in intestinal IgG transport beyond neonatal life in humans. We tested this hypothesis using the polarized human intestinal T84 cell line as a model epithelium. Immunocytochemical data show that FcRn is present in T84 cells in a punctate apical pattern similar to that found in human small intestinal enterocytes. Solute flux studies show that FcRn transports IgG across T84 monolayers by receptor-mediated transcytosis. Transport is bidirectional, specific for FcRn, and dependent upon endosomal acidification. These data define a novel bidirectional mechanism of IgG transport across epithelial barriers that predicts an important effect of FcRn on IgG function in immune surveillance and host defense at mucosal surfaces.
Advances in Analysis of Longitudinal Data
Authors: Robert D. Gibbons, Donald Hedeker, Stephen DuToit
Journal: Annual Review of Clinical Psychology (2010)

In this review, we explore recent developments in the area of linear and nonlinear generalized mixed-effects regression models and various alternatives, including generalized estimating equations for analysis of longitudinal data. Methods are described for continuous and normally distributed as well as categorical (binary, ordinal, nominal) and count (Poisson) variables. Extensions of the model to three and four levels of clustering, multivariate outcomes, and incorporation of design weights are also described. Linear and nonlinear models are illustrated using an example involving a study of the relationship between mood and smoking.
Targeting PI3Kγ activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response
Authors: Natalia F. Smirnova, Stéphanie Gayral, Christophe Pedros, Gervaise Loirand, Nathalie Vaillant, Nicole Malet, Sahar Kassem, Denis Calise, Dominique Goudounèche, Matthias P. Wymann, Emilio Hirsch, Alain-Pierre Gadeau, Laurent O. Martinez, Abdelhadi Saoudi, Muriel Laffargue
Journal: The Journal of Experimental Medicine (2014)

Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kγ-deficient mice and mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kγ KD CD4(+) T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kγ in CD4(+) T cells during IH formation. In addition we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3Kγ activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kγ inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kγ inhibition. Altogether, these findings demonstrate a new role for PI3Kγ activity in Th1-controlled IH development.
Screening for colorectal cancer: randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy
Authors: L Hol, M E van Leerdam, M van Ballegooijen, A J van Vuuren, H van Dekken, J C I Y Reijerink, A C M van der Togt, J D F Habbema, E J Kuipers
Journal: Gut (2009)

<h3>Background:</h3> Screening for colorectal cancer (CRC) is widely accepted, but there is no consensus on the preferred strategy. We conducted a randomised trial comparing participation and detection rates (DR) per screenee of guaiac-based faecal occult blood test (gFOBT), immunochemical FOBT (FIT), and flexible sigmoidoscopy (FS) for CRC screening. <h3>Methods:</h3> A representative sample of the Dutch population (n = 15 011), aged 50–74 years, was 1:1:1 randomised prior to invitation to one of the three screening strategies. Colonoscopy was indicated for screenees with a positive gFOBT or FIT, and for those in whom FS revealed a polyp with a diameter ⩾10 mm; adenoma with ⩾25% villous component or high grade dysplasia; serrated adenoma; ⩾3 adenomas; ⩾20 hyperplastic polyps; or CRC. <h3>Results:</h3> The participation rate was 49.5% (95% confidence interval (CI) 48.1 to 50.9%) for gFOBT, 61.5% (CI, 60.1 to 62.9%) for FIT and 32.4% (CI, 31.1 to 33.7%) for FS screening. gFOBT was positive in 2.8%, FIT in 4.8% and FS in 10.2%. The DR of advanced neoplasia was significantly higher in the FIT (2.4%; OR, 2.0; CI, 1.3 to 3.1) and the FS arm (8.0%; OR, 7.0; CI, 4.6 to 10.7) than the gFOBT arm (1.1%). FS demonstrated a higher diagnostic yield of advanced neoplasia per 100 invitees (2.4; CI, 2.0 to 2.8) than gFOBT (0.6; CI, 0.4 to 0.8) or FIT (1.5; CI, 1.2 to 1.9) screening. <h3>Conclusion:</h3> This randomised population-based CRC-screening trial demonstrated superior participation and detection rates for FIT compared to gFOBT screening. FIT screening should therefore be strongly preferred over gFOBT screening. FS screening demonstrated a higher diagnostic yield per 100 invitees than both FOBTs.
Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies
Authors: Jong J Joo, Jae Sul, Buhm Han, Chun Ye, Eleazar Eskin
Journal: Genome biology (2014)

Expression quantitative trait loci (eQTL) mapping is a tool that can systematically identify genetic variation affecting gene expression. eQTL mapping studies have shown that certain genomic locations, referred to as regulatory hotspots, may affect the expression levels of many genes. Recently, studies have shown that various confounding factors may induce spurious regulatory hotspots. Here, we introduce a novel statistical method that effectively eliminates spurious hotspots while retaining genuine hotspots. Applied to simulated and real datasets, we validate that our method achieves greater sensitivity while retaining low false discovery rates compared to previous methods.