tbuckley/cabot-search huggingface dataset:
Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN
Authors: Pamela J. Garl, Janet M. Wenzlau, Heather A. Walker, John M. Whitelock, Mercedes Costell, Mary C.M. Weiser-Evans
Journal: Circulation Research (2003)

We were interested in the elucidation of the interaction between the heparan sulfate proteoglycan, perlecan, and PTEN in the regulation of vascular smooth muscle cell (SMC) growth. We verified serum-stimulated DNA synthesis, and Akt and FAK phosphorylation were significantly reduced in SMCs overexpressing wild-type PTEN. Our previous studies showed perlecan is a potent inhibitor of serum-stimulated SMC growth. We report in the present study, compared with SMCs plated on fibronectin, serum-stimulated SMCs plated on perlecan exhibited increased PTEN activity, decreased FAK and Akt activities, and high levels of p27, consistent with SMC growth arrest. Adenoviral-mediated overexpression of constitutively active Akt reversed perlecan-induced SMC growth arrest while morpholino antisense-mediated loss of endogenous PTEN resulted in increased growth and phosphorylation of FAK and Akt of SMCs on perlecan. Immunohistochemical and Western analyses of balloon-injured rat carotid artery tissues showed a transient increase in phosphoPTEN (inactive) after injury, correlating to high rates of neointimal cell replication; phosphoPTEN was largely limited to actively replicating SMCs. Similarly, in the developing rat aorta, we found increased PTEN activity associated with increased perlecan deposition and decreased SMC replication rates. However, significantly decreased PTEN activity was detected in aortas of perlecan-deficient mouse embryos, consistent with SMC hyperplasia observed in these animals, compared with E17.5 heterozygous controls that produce abundant amounts of perlecan at this developmental time point. Our data show PTEN is a potent endogenously produced inhibitor of SMC growth and increased PTEN activity mediates perlecan-induced suppression of SMC proliferation.
Disseminated tumor cells from the bone marrow of patients with nonmetastatic primary breast cancer are predictive of locoregional relapse
Authors: A.D. Hartkopf, M. Wallwiener, T.N. Fehm, M. Hahn, C.B. Walter, I. Gruber, S.Y. Brucker, F.-A. Taran
Journal: Annals of Oncology (2015)
Genetic polymorphisms of the matrix metalloproteinase-3 (MMP-3) and tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) modulate the development of ankylosing spondylitis
Authors: J C-C Wei, H-S Lee, W-C Chen, L-J Shiu, S-F Yang, R-H Wong
Journal: Annals of the Rheumatic Diseases (2008)

The aetiology of ankylosing spondylitis (AS) remains unclear. Inflammation progresses to fibrosis and calcification of the spine and sacroiliac joints in AS development. Fibrosis results from excessive accumulations of the extracellular matrix (ECM). ECM turnover depends on the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs).To evaluate the effects of the MMP-3 -1171 and TIMP-1 372 T>C polymorphisms on the modified risk of AS.Genotypes of 241 patients with AS and 241 controls were identified by PCR. Disease activity and functional status were assessed by the Bath Ankylosing Spondylitis Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Global (BAS-G) Score.MMP-3 6A/6A carriers had a 2.41-fold (95% confidence interval (CI) 1.55 to 3.74) increased risk of AS compared with 6A/5A and 5A/5A carriers. TIMP-1 C alleles had a greater risk of AS, but this was not significant (odds ratio (OR) = 1.28, 95% CI 0.92 to 1.77). Pairwise analysis of the MMP-3/TIMP-1 alleles showed that 6A/C (OR = 3.23, 95% CI 1.50 to 6.95) and 6A/T (OR = 2.55, 95% CI 1.17 to 5.54) had a significantly greater risk of AS than the 5A/T alleles. After adjustment for the effects of age, gender and disease duration, the MMP-3/TIMP-1 5A/T alleles had the lowest BASDAI (p = 0.02), BASFI (p = 0.05) and BAS-G (p = 0.02) among all MMP-3/TIMP-1 alleles.The findings highlight the importance of the MMP-3 and TIMP-1 genes as crucial elements in AS development.
Differential major histocompatibility complex-related activation of idiotypic suppressor T cells. Suppressor T cells cross-reactive to two distantly related lysozymes are not induced by one of them.
Authors: L Adorini, M A Harvey, D Rozycka-Jackson, A Miller, E E Sercarz
Journal: The Journal of Experimental Medicine (1980)

B10 (H-2b) mice are genetic nonresponders to hen egg-white lysozyme (HEL) and the distantly related human lysozyme (HUL). However, anti-HEL or anti-HUL primary antibody responses in vivo or in vitro can be obtained in B10 mice by immunization with the appropriate lysozyme coupled to erythrocytes. T cells able to suppress either anti-lysozyme plaque-forming cells (PFC) response are induced in B10 mice after immunization with HEL-complete Freund's adjuvant (CFA) or HUL-CFA. This cross-reactivity of HEL and HUL in the induction and the expression of suppressive activity is in marked contrast to their very low cross-reactivity at the PFC level. These results suggest that either HEL or HUL can stimulate a suppressor T cell which recognizes a particular epitope present on both lysozymes. Suppressor cells induced by HEL or HUL bear the same predominant idiotype found on the majority of anti-HEL antibodies, and on the small proportion of anti-HUL antibodies cross-reactive with HEL. B10.Q (H-2q) mice are responders in vivo to HEL-CFA, but not to HUL-CFA. In contrast to B10, HEL-CFA priming in B10.Q micr induces helper cells whereas HUL-CFA priming induces suppressor cells. These suppressor cells are cross-reactive with HEL and are fully able to suppress HEL-specific helper cells. The presence of HEL-specific suppressor cell precursors in B10.Q mice which are not activated by HEL, seems to implicate differential choice by the antigen presenting system as a basis for Ir gene control, rather than the absence of a regulatory cell type from the T cell repertoire.
Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor
Authors: Yasuaki Hata, Allen Clermont, Teruaki Yamauchi, Eric A. Pierce, Izumi Suzuma, Hiroyuki Kagokawa, Hiroshi Yoshikawa, Gregory S. Robinson, Tatsuro Ishibashi, Toshihiko Hashimoto, Fumio Umeda, Sven E. Bursell, Lloyd Paul Aiello
Journal: Journal of Clinical Investigation (2000)

Prostacyclin-stimulating factor (PSF) acts on vascular endothelial cells to stimulate the synthesis of the vasodilatory molecule prostacyclin (PGI2). We have examined the expression, regulation, and hemodynamic bioactivity of PSF both in whole retina and in cultured cells derived from this tissue. PSF was expressed in all retinal cell types examined in vitro, but immunohistochemical analysis revealed PSF mainly associated with retinal vessels. PSF expression was constitutive in retinal pericytes (RPCs) but could be modulated in bovine retinal capillary endothelial cells (RECs) by cell confluency, hypoxia, serum starvation, high glucose concentrations, or inversely by soluble factors present in early vs. late retinopathy, such as TGF-β, VEGF, or bFGF. In addition, RPC-conditioned media dramatically increased REC PGI2 production, a response inhibited by blocking PSF with a specific antisense oligodeoxynucleotide (ODN). In vivo, PGI2 increased retinal blood flow (RBF) in control and diabetic animals. Furthermore, the early drop in RBF during the initial weeks after inducing diabetes in rats, as well as the later increase in RBF, both correlated with levels of retinal PSF. RBF also responded to treatment with RPC-conditioned media, and this effect could be partially blocked using the antisense PSF ODN. We conclude that PSF expressed by ocular cells can induce PGI2, retinal vascular dilation, and increased retinal blood flow, and that alterations in retinal PSF expression may explain the biphasic changes in RBF observed in diabetes.
Pemetrexed (ALIMTA), A Novel Multitargeted Antineoplastic Agent
Authors: Alex A. Adjei
Journal: Clinical Cancer Research (2004)

Abstract Pemetrexed (ALIMTA, LY231514, MTA) is a novel antimetabolite that inhibits at least three enzymes involved in the folate pathway. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small cell lung cancer as well as in a broad array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Promising activity has also been demonstrated when pemetrexed is combined with platinum compounds (cisplatin, carboplatin, and oxaliplatin), vinorelbine, and gemcitabine. Low level dietary supplement of folic acid and vitamin B12 has significantly decreased the mucosal and bone marrow toxicity of pemetrexed without compromising its antitumor effect.
An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium
Authors: Louise A. Johnson, Steven Clasper, Andrew P. Holt, Patricia F. Lalor, Dilair Baban, David G. Jackson
Journal: The Journal of Experimental Medicine (2006)

The exit of antigen-presenting cells and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such an exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels are unknown. We show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LECs), leading to expression of the key leukocyte adhesion receptors intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of dendritic cells (DCs) via afferent lymphatics. Lastly, we show that tumor necrosis factor alpha stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking monoclonal antibodies. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for antiinflammatory therapy.
Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis.
Authors: M Marx, R A Perlmutter, J A Madri
Journal: Journal of Clinical Investigation (1994)

Microvascular endothelial cells in vivo exhibit a plastic phenotype, forming a nonproliferative, differentiated capillary network, while retaining their ability to respond to injury by proliferation, migration and neovascularization. The presence of PDGF receptors and PDGF responsiveness in microvascular endothelial cells and the significance of PDGF isoforms in the control of endothelial cell growth and differentiation remain controversial. Since culture of microvascular endothelial cells in a three-dimensional (3D) system induced cell differentiation and angiogenesis and inhibited proliferation, the present study investigates the role of different extracellular matrix environments in inducing different microvascular endothelial cell phenotypes on microvascular endothelial cell PDGF receptor expression and PDGF responsiveness. In conventional two-dimensional (2D) culture, microvascular endothelial cells expressed both PDGF receptor alpha and beta chains. Suramin treatment demonstrated continuous downregulation of the alpha receptor surface expression. PDGF BB and, to a lesser extent, PDGF AB were mitogenic in 2D-culture, PDGF AA failed to induce any proliferative response despite inducing receptor autophosphorylation. During in vitro angiogenesis induced by 3D-culture, both PDGF receptors were rapidly downregulated. Assessment of cell proliferation showed quiescent cells and PDGF unresponsiveness. We conclude that the induction of a differentiated phenotype during in vitro angiogenesis (tube formation) driven in part by the spatial organization of the surrounding matrix is associated with a downregulation of PDGF receptors. Identification of the molecular cell-matrix interactions involved in this receptor regulation may allow for targeted manipulation of cell growth in vivo and lead to novel therapeutic applications for PDGF.
Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial
Authors: Ivo N van Schaik, Filip Eftimov, Pieter A van Doorn, Esther Brusse, Leonard H van den Berg, W Ludo van der Pol, Catharina G Faber, Joost CH van Oostrom, Oscar JM Vogels, Rob DM Hadden, Bert U Kleine, Anouk GW van Norden, Jan JGM Verschuuren, Marcel GW Dijkgraaf, Marinus Vermeulen
Journal: The Lancet Neurology (2010)
Early renal damage in patients with sickle cell disease in sub-Saharan Africa: a multinational, prospective, cross-sectional study
Authors: Brigitte Ranque, Aymeric Menet, Ibrahima Bara Diop, Marie Michèle Thiam, Dapa Diallo, Saliou Diop, Ibrahima Diagne, Ibrahima Sanogo, Samuel Kingue, David Chelo, Guillaume Wamba, Mamadou Diarra, Jean Baptiste Anzouan, Roland N'Guetta, Cheick Oumar Diakite, Youssouf Traore, Gaëlle Legueun, Indou Deme-Ly, Suzanne Belinga, Kouakou Boidy, Ismael Kamara, Pierre-Louis Tharaux, Xavier Jouven
Journal: The Lancet Haematology (2014)
Diagnosis and Management of Congenital Adrenal Hyperplasia
Authors: Maria I. New
Journal: Annual Review of Medicine (1998)

Congenital adrenal hyperplasia is a family of inborn errors of steroidogenesis, each characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex, and can lead to sexual ambiguity in both genetic males and females. The enzymes most often affected are 21-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase, and less often, 17α-hydroxylase/17, 20-lyase and cholesterol desmolase. Decreased production of cortisol results in increased pituitary secretion of adrenocorticotropic hormone. The elevated adrenocorticotropic hormone stimulates both the accumulation of precursor steroids in the impeded pathways and excessive steroid synthesis in other adrenal biosynthetic pathways unaffected by the enzyme deficiency. Correct identification of the enzyme affected is achieved by the observation of clinical syndromes reflecting distinct hormonal patterns, and it is measured quantitatively as low levels of cortisol and other adrenal steroids, as well as increased levels of steroids proximal to the blocked step. Many of the corresponding genes for the described enzymes have been isolated and characterized, and specific mutations causing many cases of congenital adrenal hyperplasia have been identified. These advances have important implications for early prenatal diagnosis and prenatal treatment.
Prophylaxis of Radiation-Associated Mucositis in Conventionally Treated Patients With Head and Neck Cancer: A Double-Blind, Phase III, Randomized, Controlled Trial Evaluating the Clinical Efficacy of an Antimicrobial Lozenge Using a Validated Mucositis Scoring System
Authors: S. El-Sayed, A. Nabid, W. Shelley, J. Hay, J. Balogh, M. Gelinas, R. MacKenzie, N. Read, E. Berthelet, H. Lau, J. Epstein, P. Delvecchio, P. K. Ganguly, F. Wong, P. Burns, D. Tu, J. Pater
Journal: Journal of Clinical Oncology (2002)

Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer.One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system.Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P =.61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays.This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.
Attitudes to Adhesion
Authors: Guy Nash
Journal: Journal of the Royal Society of Medicine (2001)

Professor Ellis's review of the legal consequences of intra-abdominal adhesions (July 2001, JRSM pp. 331-332) was timely. We have been investigating surgeons' attitudes to this common problem. Though there is little clinical evidence, barrier agents such as Seprafilm have been shown experimentally to lessen adhesions without importantly reducing anastomotic strength1. Perhaps recent adverse events2 have caused some surgeons to abstain from using such agents.

Three points mentioned by Professor Ellis's article were included in a questionnaire sent online to our Forum for Registrars In Surgical Training (www.frist.org/temp/guynash.html ). General surgeons were asked whether they routinely warn patients, before laparotomy, of the risk of adhesions; whether they believe that covering a bowel anastomosis with omentum decreases the risk of future adhesions; and whether they use an agent, if available, in the hope of avoiding further adhesions in a patient with multiple previous laparotomies.

Of the 50 who replied initially, 7 routinely warn about adhesions, 12 favour omental covering and 25 would not currently use an agent such as Seprafilm. On the evidence of this small survey, the lack of consensus on aetiology and epidemiology extends to practical management.
Stimulation by thyroid-stimulating hormone and Grave's immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo.
Authors: K Sato, K Yamazaki, K Shizume, Y Kanaji, T Obara, K Ohsumi, H Demura, S Yamaguchi, M Shibuya
Journal: Journal of Clinical Investigation (1995)

To elucidate the pathogenesis of thyroid gland hypervascularity in patients with Graves' disease, we studied the expression of mRNAs for vascular endothelial growth factor (VEGF) and its receptor, Flt family, using human thyroid follicles in vitro and thiouracil-fed rats in vivo. Human thyroid follicles, cultured in the absence of endothelial cells, secreted de novo-synthesized thyroid hormone in response to thyroid-stimulating hormone (TSH) and Graves' IgG. The thyroid follicles produced VEGF mRNA but not flt-1 mRNA. The expression of VEGF mRNA was enhanced by insulin, tumor-promoting phorbol ester, calcium ionophore, dibutyryl cAMP, TSH, and Graves' IgG. When rats were fed thiouracil for 4 wk, their serum levels of TSH were increased at day 3. VEGF mRNA was also increased on day 3, accompanied by an increase in flt family (flt-1 and KDR/ flk-1) mRNA expression. These in vitro and in vivo findings suggest that VEGF is produced by thyroid follicles in response to stimulators of TSH receptors, via the protein kinase A and C pathways. VEGF, a secretable angiogenesis factor, subsequently stimulates Flt receptors on endothelial cells in a paracrine manner, leading to their proliferation and producing hypervascularity of the thyroid gland, as seen in patients with Graves' disease.
Absence of Kaposi's Sarcoma–associated Herpesvirus in Patients with Pulmonary Arterial Hypertension
Authors: Cornelia Henke-Gendo, Michael Mengel, Marius M. Hoeper, Khaled Alkharsah, Thomas F. Schulz
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

In addition to Kaposi's sarcoma, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) has been associated with two other diseases: primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. Recently, evidence of KSHV infection was reported in plexiform lesions of idiopathic pulmonary arterial hypertension (IPAH) as well as in adjacent parenchyma and bronchial epithelial cells.To further investigate a possible association of KSHV and pulmonary arterial hypertension.Twenty-six lungs explanted from German patients suffering from IPAH were tested for the presence of KSHV antigen and genomes by immunohistochemistry (IHC) and polymerase chain reaction (PCR).When stained with a commercial monoclonal antibody directed against the latency-associated nuclear antigen of KSHV, LANA-1, a positive signal reminiscent of the "speckled" nuclear pattern typical of latently KSHV-infected cells was found in 16 (61.5%) cases. Alveolar and bronchial epithelial cells in areas of unremarkable lung tissue, but not cells within the plexiform lesions, were the predominantly stained cell types. Different KSHV-PCR assays (based on orf26, orfK6, and orf72) performed on samples that had tested positively in IHC, however, could not confirm KSHV infection, indicating that the IHC signal was not due to KSHV infection. One IHC-negative patient tested positive by PCR. A PCR based on consensus degenerate hybrid oligonucleotide primers (CODEHOP) to detect yet unknown gamma-herpesviruses did not reveal any specific sequences.KSHV is unlikely to play a role in the pathogenesis of IPAH.