tbuckley/cabot-search huggingface dataset:
Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.
Authors: D E Hughes, B R MacDonald, R G Russell, M Gowen
Journal: Journal of Clinical Investigation (1989)

Bisphosphonates inhibit bone resorption in vivo and in vitro by unknown mechanisms. The effect of bisphosphonates on the formation of osteoclasts from their mononuclear hematopoietic precursors was investigated using human long-term marrow cultures in which multinucleated cells form that express most of the known features of the osteoclast phenotype (e.g., bone resorption, tartrate-resistant acid phosphatase, calcitonin responsiveness, and reactivity with specific MAbs). The five bisphosphonates that were tested strongly inhibited 1,25-dihydroxyvitamin D3-stimulated formation of these cells with the same relative potencies as they inhibit bone resorption in vivo. Two representative compounds (3-amino-1-hydroxypropylidene-1,1-bisphosphonate and dichloromethylene bisphosphonate) failed to inhibit the proliferation of precursors of the osteoclast-like cells. However, these compounds decreased the proportion of mononuclear and multinucleated cells expressing an osteoclast antigen, thus suggesting a degree of specificity for cells of the osteoclast lineage. We conclude that bisphosphonates are potent inhibitors of osteoclast-like cell formation in long-term human marrow cultures, and that this may be related to their ability to inhibit bone resorption in vivo.
Functional Polymorphisms of <i>UCP2</i> and <i>UCP3</i> Are Associated With a Reduced Prevalence of Diabetic Neuropathy in Patients With Type 1 Diabetes
Authors: Gottfried Rudofsky, Antonia Schroedter, Andreas Schlotterer, Olga E. Voron’ko, Martin Schlimme, Joerg Tafel, Berend H. Isermann, Per M. Humpert, Michael Morcos, Angelika Bierhaus, Peter P. Nawroth, Andreas Hamann
Journal: Diabetes Care (2006)

We studied the association between polymorphisms in the UCP genes and diabetes complications in patients with type 1 diabetes.We analyzed 227 patients with type 1 diabetes using PCR and subsequent cleavage by restriction endonucleases for the promoter variants A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene.No effect of the A-3826G polymorphism in the UCP1 gene on diabetes complications was found. Patients who were heterozygous or homozygous for the G-866A polymorphism in the UCP2 gene or the C-55T polymorphism in the UCP3 gene had a significantly reduced prevalence of diabetic neuropathy (UCP2: odds ratio 0.44 [95% CI 0.24-0.79], P = 0.007; UCP3: 0.48 [0.25-0.92], P = 0.031), whereas there was no association with other diabetes complications. This effect was stronger when G-866A and C-55T occurred in a cosegregatory manner (UCP2 and UCP3: 0.28 [0.12-0.65], P = 0.002). Furthermore, a multiple logistic regression model showed an age- and diabetes duration-independent effect of the cosegregated polymorphisms on the prevalence of diabetic neuropathy (P = 0.013).Our data indicate that both the G-866A polymorphism in the UCP2 gene and the C-55T polymorphism in the UCP3 gene are associated with a reduced risk of diabetic neuropathy in type 1 diabetes. Thus, the results presented here support the hypothesis that higher expression of uncoupling protein might prevent mitochondria-mediated neuronal injury and, ultimately, diabetic neuropathy.
Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help
Authors: Laura Mandik-Nayak, Jennifer Racz, Barry P. Sleckman, Paul M. Allen
Journal: The Journal of Experimental Medicine (2006)

In K/BxN mice, arthritis is induced by autoantibodies against glucose-6-phosphate-isomerase (GPI). To investigate B cell tolerance to GPI in nonautoimmune mice, we increased the GPI-reactive B cell frequency using a low affinity anti-GPI H chain transgene. Surprisingly, anti-GPI B cells were not tolerant to this ubiquitously expressed and circulating autoantigen. Instead, they were found in two functionally distinct compartments: an activated population in the splenic marginal zone (MZ) and an antigenically ignorant one in the recirculating follicular/lymph node (LN) pool. This difference in activation was due to increased autoantigen availability in the MZ. Importantly, the LN anti-GPI B cells remained functionally competent and could be induced to secrete autoantibodies in response to cognate T cell help in vitro and in vivo. Therefore, our study of low affinity autoreactive B cells reveals two distinct but potentially concurrent mechanisms for their activation, of which one is T cell dependent and the other is T cell independent.
The effect of dry heat on mite, cat, and dog allergens
Authors: G. Cain, A. J. Elderfield, R. Green, F. I. Smillie, M. D. Chapman, A. Custovic, A. Woodcock
Journal: Allergy (1998)

Background Various techniques have been tried in an attempt to reduce allergen levels in homes. This study investigated the effect of dry heat on mite, cat, and dog allergens. Methods Samples (50 mg) of Dermatophagoides pteronyssinus and D. farinae cultures, and of house dust rich in the major cat and dog allergens Fel d 1 and Can f 1 were heated for 5, 10, 15, 30, and 60 min at 60°, 80°, 100M20°, and 140°C. Control samples remained at room temperature. Extracts were assayed with the appropriate two‐site mono‐ or mono/polyclonal sandwich ELISA, Results For Der p 1, the breakdown was proportional to temperature and heating time; after 30 min at 120°C, allergen levels were reduced to &lt; 1 % of control. Der p 2 was more heat stable, requiring 140°C for 30‐60 min to achieve &gt;99% reduction. D. farinae groups 1 and 2 allergens showed results similar to those obtained with D. pteronyssinus. In contrast. Can f 1 and Fel d 1 were considerably more thermostable, with 50% and 70%, respectively, of allergen remaining after 60 min at 140°C. Conciusions The effect of dry heat on allergens increased with increasing time and temperature, cat and dog allergens demonstrating greater heat resistance than mite allergens. Dry heating methods may represent an alternative technique for removal of mite allergens: however, the greater stability of Fel d 1 and Can f 1 suggests that this procedure may not be appropriate for pet allergens.
Serum Lactate Dehydrogenase Predicts for Overall Survival Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Inhibition of Mammalian Target of Rapamycin
Authors: Andrew J. Armstrong, Daniel J. George, Susan Halabi
Journal: Journal of Clinical Oncology (2012)

Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor.We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS).Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514).Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.
Impaired muscle mitochondrial density and/or function: a COPD-specific mitochondropathy or simply deconditioning?
Authors: Aili L. Lazaar, Paul L. Greenhaff
Journal: European Respiratory Journal (2012)

Chronic obstructive pulmonary disease (COPD) is a pulmonary disease with some systemic consequences. Skeletal muscle dysfunction is one of the earliest systemic manifestations of COPD in some patients, and contributes to limited exercise capacity and poor health outcomes. The aetiology of skeletal muscle abnormalities in COPD is not fully understood, but probably represents a combination of deconditioning, muscle atrophy and nutritional deficiencies. Studies have shown that skeletal muscle from patients with COPD displays other abnormalities including increased oxidative stress, muscle fibre apoptosis and mitochondrial dysfunction. Indeed, reduced mitochondrial density and function are recognised as important components of skeletal muscle dysfunction in COPD, and reduced oxidative capacity at a skeletal muscle level is likely to contribute to exercise limitation in this population. Mitochondrial density and function are potential therapeutic targets in COPD, but it remains uncertain whether impaired mitochondrial density and/or function are attributable to ageing, inactivity and deconditioning, a COPD-specific “mitochondropathy”, or a combination of these factors. However, endurance exercise training is known to increase mitochondrial density and function in healthy volunteers, whether determined by, for example, measurements of maximal activities of mitochondrial enzymes or oxygen consumption and adenosine triphosphate production rates in …
Factors affecting sunscreen use and sun avoidance in a U.S. national sample of organ transplant recipients
Authors: E.L. Mihalis, A. Wysong, W.J. Boscardin, J.Y. Tang, M.M. Chren, S.T. Arron
Journal: British Journal of Dermatology (2012)

Organ transplant recipients have an increased risk of nonmelanoma skin cancers due to immunosuppressive therapy following transplantation. Use of sunscreen has been shown to reduce this risk.To identify patient and healthcare factors associated with sun-protective behaviours in organ transplant recipients after transplantation with the goal of increasing overall sunscreen use.This study utilized a cross-sectional, retrospective survey from a national sample of 198 organ transplant recipients in the U.S.A. from 2004 to 2008 with no prior diagnosis of skin cancer. The main outcome measures were sunscreen use and sun avoidance before and after transplantation. Frequency of sunscreen use and sun exposure was obtained by self-report on Likert scales ranging from never to always, and these responses were converted to a numerical scale from 0 to 4.Overall sunscreen use increased after transplantation (from a score of 1·4 to 2·1, P < 0·001). Sex, Fitzpatrick skin type, receiving advice to avoid sun from a healthcare provider, and pretransplantation sunscreen use were significantly associated with frequency of post-transplantation sunscreen use in multivariate models. Pretransplantation sun exposure, advice to avoid sun and pretransplantation sunscreen use were significantly associated with sun avoidance post-transplantation.Both patient features and clinician advice are associated with sun-protective behaviours after organ transplantation. These results will help physicians target expanded sun-protection counselling to those patients most in need of such intervention.
Bayesian Fundamentalism or Enlightenment? On the explanatory status and theoretical contributions of Bayesian models of cognition
Authors: Matt Jones, Bradley C. Love
Journal: Behavioral and Brain Sciences (2011)

Abstract The prominence of Bayesian modeling of cognition has increased recently largely because of mathematical advances in specifying and deriving predictions from complex probabilistic models. Much of this research aims to demonstrate that cognitive behavior can be explained from rational principles alone, without recourse to psychological or neurological processes and representations. We note commonalities between this rational approach and other movements in psychology – namely, Behaviorism and evolutionary psychology – that set aside mechanistic explanations or make use of optimality assumptions. Through these comparisons, we identify a number of challenges that limit the rational program's potential contribution to psychological theory. Specifically, rational Bayesian models are significantly unconstrained, both because they are uninformed by a wide range of process-level data and because their assumptions about the environment are generally not grounded in empirical measurement. The psychological implications of most Bayesian models are also unclear. Bayesian inference itself is conceptually trivial, but strong assumptions are often embedded in the hypothesis sets and the approximation algorithms used to derive model predictions, without a clear delineation between psychological commitments and implementational details. Comparing multiple Bayesian models of the same task is rare, as is the realization that many Bayesian models recapitulate existing (mechanistic level) theories. Despite the expressive power of current Bayesian models, we argue they must be developed in conjunction with mechanistic considerations to offer substantive explanations of cognition. We lay out several means for such an integration, which take into account the representations on which Bayesian inference operates, as well as the algorithms and heuristics that carry it out. We argue this unification will better facilitate lasting contributions to psychological theory, avoiding the pitfalls that have plagued previous theoretical movements.
Epithelium-Intrinsic NAIP/NLRC4 Inflammasome Drives Infected Enterocyte Expulsion to Restrict Salmonella Replication in the Intestinal Mucosa
Authors: Mikael E. Sellin, Anna A. Müller, Boas Felmy, Tamas Dolowschiak, Médéric Diard, Aubry Tardivel, Kendle M. Maslowski, Wolf-Dietrich Hardt
Journal: Cell Host & Microbe (2014)
Long-Term Renoprotective Effects of Losartan in Diabetic Nephropathy
Authors: Steen Andersen, Lise Tarnow, Francois Cambien, Peter Rossing, Tina R. Juhl, Jaap Deinum, Hans-Henrik Parving
Journal: Diabetes Care (2003)

OBJECTIVE—Several observational follow-up studies have found that the D allele of the insertion (I)/deletion (D) polymorphism of the ACE gene (ACE/ID) is associated with an increased risk of renal function loss, even during ACE inhibition. Therefore, we investigated the long-term effect of the angiotensin II subtype-1 (AT1) receptor antagonist losartan (100 mg o.d.) on kidney function in II and DD type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS—A total of 54 hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (n = 26) or the deletion (n = 28) allele were included in the study. After a 4-week washout, the patients received losartan (tablet, 100 mg o.d.) and were followed prospectively with a mean follow-up period of 36 months. Patients and investigators were blinded to ACE genotypes. At baseline, after 2 and 4 months and every 6 months thereafter, glomerular filtration rate (GFR), albuminuria, and 24-h blood pressure were determined. RESULTS—At baseline, GFR, albuminuria, and blood pressure were similar in the two genotype groups, II versus DD: mean (SD), 86 (22) vs. 88 (24) ml · min–1 · 1.73 m–2; median (interquartile range), 1,134 (598–2,023) vs. 1,451 (893–1,766) mg/24 h; and mean (SD), 156/82 (17/9) vs. 153/80 (17/11) mmHg, respectively. GFR decreased similarly in both genotype groups, versus DD, respectively (P = 0.4): geometric mean (95% CI), 2.9 (2.0–4.2) vs. 3.4 (2.3–5.1) ml · min–1 · year–1. Albuminuria and arterial blood pressure were significantly reduced during the study; no differences were noted between groups. During follow-up, albuminuria was decreased by 75% (95% CI 59–85) and 73% (56–83) in the II and DD groups, respectively (P &amp;lt; 0.01 vs. baseline). Mean systolic and diastolic blood pressures were 139/74 mmHg (14/8) in both genotype groups during the study (P &amp;lt; 0.01 vs. baseline). CONCLUSIONS—In contrast to previous observational studies with ACE inhibitors, long-term treatment with losartan has similar beneficial renoprotective effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients with ACE II and DD genotypes.
Different Roles for Caveolin-1 in the Development of Non-Small Cell Lung Cancer <b> <i>versus</i> </b> Small Cell Lung Cancer
Authors: Noriaki Sunaga, Kuniharu Miyajima, Makoto Suzuki, Mitsuo Sato, Michael A. White, Ruben D. Ramirez, Jerry W. Shay, Adi F. Gazdar, John D. Minna
Journal: Cancer Research (2004)

Abstract Caveolin-1 (CAV1), an essential structural constituent of caveolae that plays an important role in cellular processes such as transport and signaling, has been implicated in the development of human cancers. However, it is unclear whether CAV1 is acting like an oncogene or tumor suppressor gene. We found that CAV1 expression was reduced or absent in 95% of small cell lung cancers (SCLCs; n = 21 lines), whereas it was retained in 76% of non-small cell lung cancers (NSCLCs; n = 25 lines) compared with normal human lung epithelial cultures, where it was abundantly expressed. CAV1 expression was tightly linked to the ability to grow attached to the plastic cell culture surface, whereas CAV1-nonexpressing lung cancers of both SCLC and NSCLC type grew as suspension cultures. In addition, attached lung cancer cultures expressed phosphorylated focal adhesion kinase, whereas suspension cultures did not. Lack of CAV1 expression was tightly associated with CAV1 promoter methylation (P &amp;lt; 0.0001) such that CAV1 methylation was found in 93% of SCLCs (n = 15) and 9% of NSCLCs (n = 11), whereas 5-aza-2′deoxycytidine treatment restored CAV1 expression in SCLCs. Exogenous CAV1 expression in SCLCs significantly inhibited soft-agar colony formation but did not lead to attachment. By contrast, CAV1 knockdown in NSCLCs mediated by small interfering RNA against CAV1 led to inhibition of cellular proliferation and soft-agar and liquid colony formation. Importantly, CAV1 knockdown led to reduced phospho-focal adhesion kinase and RalA, but not RalB, levels in NSCLC cells. These results suggest different roles for CAV1 in SCLC, where CAV1 acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth.
Transforming Growth Factor β Receptor Endoglin Is Expressed in Cardiac Fibroblasts and Modulates Profibrogenic Actions of Angiotensin II
Authors: Kui Chen, Jawahar L. Mehta, Dayuan Li, Lija Joseph, Jacob Joseph
Journal: Circulation Research (2004)

Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of Ang II-induced myocardial fibrosis remain to be clarified. We postulated that Ang II alters transforming growth factor beta (TGF-beta) receptor expression, specifically that of endoglin, and thereby modulates cardiac fibroblast (CF) collagen metabolism. Experiments were conducted using CF from adult Sprague Dawley rats to determine the expression of TGF-beta1 receptors including endoglin, and the role of Ang II type 1 (AT1) and type 2 (AT2) receptors, and MAPK p42/44 in this process. The functional role of endoglin in modulating Ang II effects on matrix metalloproteinase-1 (MMP-1) and type I collagen expression was also analyzed. Endoglin gene and protein expression were consistently identified in quiescent CFs. Ang II increased the expression of endoglin mRNA and protein in a concentration and time-dependent manner, with no effect on TGF-beta receptors I and II expression. This effect was AT1 receptor mediated, because AT1 receptor antagonists valsartan, candesartan, and losartan inhibited Ang II-induced endoglin expression, whereas the AT2 receptor antagonist PD123319 had no effect. MAPKp42/44 inhibition attenuated Ang II-induced endoglin expression. Ang II-induced decrease in MMP-1 protein expression and increase in type I collagen protein expression were both blocked by a specific endoglin antibody. Hence, our results indicate that endoglin is upregulated in CFs by Ang II via the AT1 receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II-induced cardiac remodeling.
Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles
Authors: Xinguo Jiang, Andrey V. Malkovskiy, Wen Tian, Yon K. Sung, Wenchao Sun, Joe L. Hsu, Sathish Manickam, Dhananjay Wagh, Lydia-Marie Joubert, Gregg L. Semenza, Jayakumar Rajadas, Mark R. Nicolls
Journal: Biomaterials (2013)
Microbial Epitopes Act as Altered Peptide Ligands to Prevent Experimental Autoimmune Encephalomyelitis
Authors: Pedro J. Ruiz, Hideki Garren, David L. Hirschberg, Annette M. Langer-Gould, Mia Levite, Marcela V. Karpuj, Scott Southwood, Alessandro Sette, Paul Conlon, Lawrence Steinman
Journal: The Journal of Experimental Medicine (1999)

Molecular mimicry refers to structural homologies between a self-protein and a microbial protein. A major epitope of myelin basic protein (MBP), p87–99 (VHFFKNIVTPRTP), induces experimental autoimmune encephalomyelitis (EAE). VHFFK contains the major residues for binding of this self-molecule to T cell receptor (TCR) and to the major histocompatibility complex. Peptides from papilloma virus strains containing the motif VHFFK induce EAE. A peptide from human papilloma virus type 40 (HPV 40) containing VHFFR, and one from HPV 32 containing VHFFH, prevented EAE. A sequence from Bacillus subtilis (RKVVTDFFKNIPQRI) also prevented EAE. T cell lines, producing IL-4 and specific for these microbial peptides, suppressed EAE. Thus, microbial peptides, differing from the core motif of the self-antigen, MBPp87–99, function as altered peptide ligands, and behave as TCR antagonists, in the modulation of autoimmune disease.
Phosphorylation Regulates Id3 Function in Vascular Smooth Muscle Cells
Authors: Scott T. Forrest, Angela M. Taylor, Ian J. Sarembock, Demetra Perlegas, Coleen A. McNamara
Journal: Circulation Research (2004)

Understanding the mechanisms that regulate cell cycle progression in vascular smooth muscle cells (VSMCs) is key to understanding and modulating vascular lesion formation. Results of the present study provide the first evidence that phosphorylation of the helix-loop-helix factor Id3 in VSMCs occurs in vitro and in vivo and provides a regulatory switch controlling Id3-induced regulation of p21 Cip1 and VSMC growth.
Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma
Authors: Yasushi Yatabe, Ritsuro Suzuki, Kensei Tobinai, Yoshihiro Matsuno, Ryo Ichinohasama, Masataka Okamoto, Motoko Yamaguchi, Jun Ichi Tamaru, Naokuni Uike, Yuko Hashimoto, Yasuo Morishima, Taizan Suchi, Masao Seto, Shigeo Nakamura
Journal: Blood (2000)