tbuckley/cabot-search huggingface dataset:
Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein.
Authors: M F van den Broek, E J Hogervorst, M C Van Bruggen, W Van Eden, R van der Zee, W B van den Berg
Journal: The Journal of Experimental Medicine (1989)

We report that streptococcal cell wall (SCW)-induced arthritis in rats, a T cell-dependent chronic, erosive polyarthritis, can be prevented by pretreatment of the rats with the mycobacterial 65-kD heat shock protein. This 65-kD protein shows extensive amino acid homology with prokaryotic and eukaryotic 65-kD heat shock proteins and is a ubiquitous bacterial common antigen. Both the clinical and histopathologic manifestations of the arthritis were prevented completely when rats were pretreated with 50 micrograms of 65-kD protein intraperitoneally at 35, 25, 15, or 5 d before administration of SCW. In such protected rats, SCW-specific T cell responses were suppressed, as compared with responses in arthritic rats. Pretreatment with 65-kD protein had no effect on the production of antibodies against SCW, on a nonspecific inflammatory reaction (zymosan-induced arthritis), or on general cellular immunity in vivo (delayed type hypersensitivity reaction to a nonrelated protein antigen). Furthermore, the protection against SCW arthritis was transferable by splenic T cells to naive recipients. Our data show that pretreatment with the 65-kD mycobacterial heat shock protein protects rats against a subsequent bacterium-induced arthritis. This protection is immunologically specific and resides in the lymphoid cell population.
Impact of Telmisartan Versus Ramipril on Renal Endothelial Function in Patients With Hypertension and Type 2 Diabetes
Authors: Roland E. Schmieder, Christian Delles, Albert Mimran, Jean P. Fauvel, Luis M. Ruilope
Journal: Diabetes Care (2007)

One of the earliest signs of vascular change is endothelial dysfunction, which is also known to provoke albuminuria and to predict cardiovascular prognosis. The aim of this study was to analyze the effects of renin-angiotensin system (RAS) blockade on renal endothelial function.In a multicenter, prospective, double-blind, forced-titration, randomized study, 96 patients with type 2 diabetes, hypertension, glomerular filtration rate >80 ml/min, and normo- or microalbuminuria were treated once daily with 40/80 mg telmisartan or 5/10 mg ramipril for 9 weeks.The mean +/- SE fall in renal plasma flow (RPF) in response to intravenous N(G)-monomethyl-L-arginine (L-NMMA), reflecting the magnitude of nitric oxide (NO) activity, increased with telmisartan from 71.9 +/- 9.0 ml/min before therapy to 105.2 +/- 9.7 ml/min at the end of treatment (P < 0.001). With ramipril, RPF response to L-NMMA increased from 60.1 +/- 12.2 to 87.8 +/- 9.2 ml/min (P = 0.018). The adjusted difference between treatments was -17.1 +/- 13.7 ml/min (P = 0.214). In accordance, telmisartan increased RPF at rest (i.e., without L-NMMA) from 652.0 +/- 27.0 to 696.1 +/- 31.0 ml/min (P = 0.047), whereas ramipril produced no significant changes in RPF. The more the basal NO activity improved, the greater was the vasodilatory effect on renal vasculature (r = 0.47, P < 0.001).In patients with type 2 diabetes, telmisartan and ramipril both increased NO activity of the renal endothelium significantly, which in turn may support the preservation of cardiovascular and renal function.
Ca2+/Calmodulin-Dependent Protein Kinase II Stimulates c-fos Transcription and DNA Synthesis by a Src-Based Mechanism in Glomerular Mesangial Cells
Authors: Yuan Wang, Rangnath Mishra, Michael S. Simonson
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Mesangial cell growth factors elevate intracellular free [Ca2+]i, but mechanisms linking [Ca2+]i to gene expression and DNA synthesis are unclear. This study investigated the hypothesis that Ca2+/calmodulin-dependent protein kinase II (CaMK II), which is activated by elevated [Ca2+]i, increases c-fos transcription and DNA synthesis via a Src-based mechanism. In cultured rat mesangial cells, dominant negative Src (SrcK−) blocked activation of the c-fos gene promoter by CaMK II 290, a constitutively active form of CaMK IIα. Activation of the c-fos promoter by CaMK II 290 was also blocked by COOH-terminal Src kinase, which phosphorylates and inactivates c-Src. A pharmacologic CaMK inhibitor, KN-93, did not block activation of the c-fos promoter by ectopically expressed v-Src. Stimulation of c-Src by endothelin-1 required CaMK II activity, further supporting the notion that CaMK II acts upstream of Src in a signaling cassette. Activation of the c-fos promoter by CaMKII290 and Src required the c-fos serum response element. Dominant negative SrcK− also blocked induction of DNA synthesis in mesangial cells by CaMK II 290. Collectively, these results suggest that in mesangial cells Src protein tyrosine kinases act downstream of CaMKII in a signaling pathway in which [Ca2+]i induces the c-fos promoter and increases DNA synthesis. E-Mail: [email protected]
Axis II Comorbidity of Substance Use Disorders Among Patients Referred for Treatment of Personality Disorders
Authors: Andrew E. Skodol, John M. Oldham, Peggy E. Gallaher
Journal: American Journal of Psychiatry (1999)

The purpose of this study was to determine the extent of comorbid substance use disorders in patients referred for treatment of personality disorders.Two hundred inpatients and outpatients were assessed by semistructured interviews for substance use and personality disorders. Univariate odds ratios were calculated for groups of substance use disorders and each DSM-III-R axis II disorder; comorbidity among axis II disorders was controlled in multivariate models predicting current or lifetime substance use disorder groups. The impact of personality disorder on chronicity and overall impairment associated with substance use disorders was evaluated.Close to 60% of subjects with substance use disorders had personality disorders. Borderline personality disorder was significantly associated with current substance use disorders, excluding alcohol and cannabis, and with lifetime alcohol, stimulant, and other substance use disorders, excluding cannabis. Antisocial personality disorder was associated with lifetime substance use disorders other than alcohol, cannabis, and stimulants. These relationships remained significant after controlling for the presence of all other personality disorders. There was no evidence that personality disorders increased the chronicity of substance use disorders, but comorbid personality disorders were associated with greater global impairment.Borderline personality disorder may be associated with a wide variety of substance use disorders, especially among patients seeking treatment for personality problems.
Identification of Renal Progenitor-Like Tubular Cells that Participate in the Regeneration Processes of the Kidney
Authors: Akito Maeshima, Shin Yamashita, Yoshihisa Nojima
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The present study was conducted to explore renal progenitor-like cells that are actively engaged in tubular regeneration after injury. For addressing this issue, the existence of label-retaining cells (LRC; slow-cycling cells) in normal rat kidneys by in vivo bromodeoxyuridine (BrdU) labeling was examined. LRC were scattering among renal epithelial tubular cells of normal rat kidneys. During the recovery after renal ischemia, LRC underwent cell division and most of them became positive for proliferating cell nuclear antigen. In contrast, proliferating cell nuclear antigen–positive but BrdU-negative tubular cells were rarely observed, suggesting that cells proliferating during tubular regeneration are essentially derived from LRC. At an early phase of tubular regeneration, descendants of LRC expressed a mesenchymal marker, vimentin, and eventually became positive for an epithelial marker, E-cadherin, after multiple cell divisions. These findings suggested that LRC function as a source of regenerating cells to replace injured cells. Collectively, it was concluded that LRC are renal progenitor-like tubular cells that provide regenerating cells, which actively proliferate and eventually differentiate into epithelial cell, during tubular regeneration. It may be possible to regenerate renal tubules in vivo through the activation of LRC.
Unshackling caspase-7 for cancer therapy
Authors: Maria Eugenia Guicciardi, Gregory J. Gores
Journal: Journal of Clinical Investigation (2013)

Numerous solid tumors and hematologic malignancies acquire resistance to apoptosis-inducing chemotherapeutic drugs by downregulating the key effector caspase-3. These cells rely on caspase-7 to execute the apoptotic program, yet binding with XIAP constitutively inhibits active caspase-7 (p19/p12-CASP7). In this issue, Lin et al. describe how a newly synthesized drug is able to disrupt the XIAP:p19/p12-CASP7 complex and induce apoptosis in caspase-3–deficient cancer cells in vitro and in vivo. As this compound appears to exhibit minimal toxicity on normal tissues, it may represent a promising therapeutic agent to help treat caspase-3–deficient tumors.
MRI of Breast Tumor Initiating Cells Using the Extra Domain-B of Fibronectin Targeting Nanoparticles
Authors: Yujin Sun, Hoe Suk Kim, Jinho Park, Mulan Li, Lianji Tian, YoonSeok Choi, Byung Ihn Choi, Sangyong Jon, Woo Kyung Moon
Journal: Theranostics (2014)

The identification of breast tumor initiating cells (BTICs) is important for the diagnosis and therapy of breast cancers.This study was undertaken to evaluate whether the extra domain-B of fibronectin (EDB-FN) could be used as a new biomarker for BTICs and whether EDB-FN targeting superparamagnetic iron oxide nanoparticles (SPIONs) could be used as a magnetic resonance imaging (MRI) contrast agent for BTIC imaging in vitro and in vivo.BTICs (NDY-1) exhibited high EDB-FN expression, whereas non-BTICs (MCF-7, BT-474, SUM-225, MDA-MB-231) did not exhibit EDB-FN expression.Furthermore, Cy3.3-labeled EDB-FN specific peptides (APT EDB ) showed preferential binding to the targeted NDY-1 cells.To construct an EDB-FN targeted imaging probe, APT EDB was covalently attached to a thermally cross-linked SPION (TCL-SPION) to yield APT EDB -TCL-SPION.In the in vitro MRI of cell phantoms, selective binding of APT EDB -TCL-SPION to NDY-1 cells was evident, but little binding was observed in MCF-7 cells.After the intravenous injection of APT EDB -TCL-SPION into the NDY-1 mouse tumor xenograft model, a significant decrease in the signal within the tumor was observed in the T 2 *-weighted images; however, there was only a marginal change in the signal of non-targeting SPIONs such as APT scramble -TCL-SPION or TCL-SPION.Taken together, we report for the first time that EDB-FN was abundantly expressed in BTICs and may therefore be useful as a new biomarker for identifying BTICs.Our study also suggests that APT EDB -TCL-SPION could be used as an MRI contrast agent for BTIC imaging.
Aromatase and other steroidogenic genes in endometriosis: translational aspects
Authors: E. Attar, S.E. Bulun
Journal: Human Reproduction Update (2005)

Endometriosis is a common, chronic and estrogen-dependent gynaecological disorder associated with pelvic pain and infertility. In addition to, or perhaps as a consequence of, immune, environmental and genetic factors, endometriotic lesions show high estradiol (E2) biosynthesis and low E2 inactivation compared with normal endometrium. Current medical therapies of pain, which aim to lower circulating E2 concentrations, are not effective in at least half of these patients. We and others recently demonstrated the expression of a few steroidogenic genes in endometriosis. The most important genes in this group are steroidogenic acute regulatory protein (StAR) and aromatase. Both are essential for E2 production. Prostaglandin E2 (PGE2) is the most potent known stimulator of both StAR and aromatase. PGE2 production in endometriosis is up-regulated by increased levels of the enzyme cyclo-oxygenase-2 (COX-2) in this tissue. COX-2 in turn is stimulated by E2, interleukin-1β (IL-1β) and PGE2 itself in endometrial and endometriotic cells. Thus, there is a positive feedback loop that favours continuous formation of E2 and PGE2 in endometriosis. These basic findings led to recent phase-II studies employing aromatase inhibitors in the treatment of endometriosis. Aromatase inhibitors treat both postmenopausal and premenopausal endometriosis at least as effectively as the existing medical treatments. In premenopausal women, we and others administered aromatase inhibitors in combination with an ovarian-suppressant treatment. In this review, we emphasize the most recent basic studies in detail and provide a short summary of recent clinical trials.
Spiroindolone KAE609 for Falciparum and Vivax Malaria
Authors: Nicholas J. White, Sasithon Pukrittayakamee, Aung Pyae Phyo, Ronnatrai Rueangweerayut, François Nosten, Podjanee Jittamala, Atthanee Jeeyapant, Jay Prakash Jain, Gilbert Lefèvre, Ruobing Li, Baldur Magnusson, Thierry T. Diagana, F. Joel Leong
Journal: New England Journal of Medicine (2014)

KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum.
Normative Values for Corneal Nerve Morphology Assessed Using Corneal Confocal Microscopy: A Multinational Normative Data Set
Authors: Mitra Tavakoli, Maryam Ferdousi, Ioannis N. Petropoulos, Julie Morris, Nicola Pritchard, Andrey Zhivov, Dan Ziegler, Danièle Pacaud, Kenneth Romanchuk, Bruce A. Perkins, Leif E. Lovblom, Vera Bril, J. Robinson Singleton, Gordon Smith, Andrew J.M. Boulton, Nathan Efron, Rayaz A. Malik
Journal: Diabetes Care (2015)

OBJECTIVE Corneal confocal microscopy is a novel diagnostic technique for the detection of nerve damage and repair in a range of peripheral neuropathies, in particular diabetic neuropathy. Normative reference values are required to enable clinical translation and wider use of this technique. We have therefore undertaken a multicenter collaboration to provide worldwide age-adjusted normative values of corneal nerve fiber parameters. RESEARCH DESIGN AND METHODS A total of 1,965 corneal nerve images from 343 healthy volunteers were pooled from six clinical academic centers. All subjects underwent examination with the Heidelberg Retina Tomograph corneal confocal microscope. Images of the central corneal subbasal nerve plexus were acquired by each center using a standard protocol and analyzed by three trained examiners using manual tracing and semiautomated software (CCMetrics). Age trends were established using simple linear regression, and normative corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) reference values were calculated using quantile regression analysis. RESULTS There was a significant linear age-dependent decrease in CNFD (−0.164 no./mm2 per year for men, P &amp;lt; 0.01, and −0.161 no./mm2 per year for women, P &amp;lt; 0.01). There was no change with age in CNBD (0.192 no./mm2 per year for men, P = 0.26, and −0.050 no./mm2 per year for women, P = 0.78). CNFL decreased in men (−0.045 mm/mm2 per year, P = 0.07) and women (−0.060 mm/mm2 per year, P = 0.02). CNFT increased with age in men (0.044 per year, P &amp;lt; 0.01) and women (0.046 per year, P &amp;lt; 0.01). Height, weight, and BMI did not influence the 5th percentile normative values for any corneal nerve parameter. CONCLUSIONS This study provides robust worldwide normative reference values for corneal nerve parameters to be used in research and clinical practice in the study of diabetic and other peripheral neuropathies.
Lymphoid and myeloid differentiation of fetal liver CD34+lineage- cells in human thymic organ culture.
Authors: A Bárcena, A H Galy, J Punnonen, M O Muench, D Schols, M G Roncarolo, J E de Vries, H Spits
Journal: The Journal of Experimental Medicine (1994)

In this article, we report that the human fetal thymus contains CD34bright cells (&amp;lt; 0.01% of total thymocytes) with a phenotype that resembles that of multipotent hematopoietic progenitors in the fetal bone marrow. CD34bright thymocytes were CD33-/dull and were negative for CD38, CD2, and CD5 as well as for the lineage markers CD3, CD4, and CD8 (T cells), CD19 and CD20 (B cells), CD56 (NK cells), glycophorin (erythrocytes), and CD14 (monocytes). In addition, total CD34+ lineage negative (lin-) thymocytes contained a low number of primitive myeloid progenitor cells, thus suggesting that the different hematopoietic lineages present in the thymus may be derived from primitive hematopoietic progenitor cells seeding the thymus. To investigate whether the thymus is permissive for the development of non-T cells, human fetal organ culture (FTOC) assays were performed by microinjecting sorted CD34+lin- fetal liver cells into fragments of HLA-mismatched fetal thymus. Sequential phenotypic analysis of the FTOC-derived progeny of CD34+lin- cells indicated that the differentiation into T cells was preceded by a wave of myeloid differentiation into CD14+CD11b+CD4dull cells. Donor-derived B cells (CD19+CD20+) were also generated, which produced immunoglobulins (IgG and IgM) when cultured under appropriate conditions, as well as functional CD56+CD3- NK cells, which efficiently killed K562 target cells in cytotoxicity assays. These results demonstrate that the microinjection of fetal liver hematopoietic progenitors into fetal thymic organ fragments results in multilineage differentiation in vitro.
Behavioral and Psychiatric Symptoms in Prion Disease
Authors: Andrew Thompson, Angus MacKay, Peter Rudge, Ana Lukic, Marie-Claire Porter, Jessica Lowe, John Collinge, Simon Mead
Journal: American Journal of Psychiatry (2014)

The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression. Prominent behavioral and psychiatric symptoms have been recognized since these diseases were first described. While research on such symptoms in common dementias has led to major changes in the way these symptoms are managed, evidence to guide the care of patients with prion disease is scarce. The authors review the published research and draw on more than 10 years' experience at the U.K. National Prion Clinic, including two large prospective clinical research studies in which more than 300 patients with prion disease have been followed up from diagnosis to death, with detailed observational data gathered on symptomatology and symptomatic treatments. The authors group behavioral and psychiatric symptoms into psychotic features, agitated features, and mood disorder and describe their natural history, showing that they spontaneously improve or resolve in many patients and are short-lived in many others because of rapid progression of global neurological disability. Diagnostic category, disease severity, age, gender, and genetic variation are or may be predictive factors. The authors review the observational data on pharmacological treatment of these symptoms in the U.K. clinical studies and make cautious recommendations for clinical practice. While nonpharmacological measures should be the first-line interventions for these symptoms, the authors conclude that there is a role for judicious use of pharmacological agents in some patients: antipsychotics for severe psychosis or agitation; benzodiazepines, particularly in the late stages of disease; and antidepressants for mood disorder.
Inducible nitric oxide synthase activity contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites
Authors: James Walter Ferguson, Anna Dover, Stanley Chia, Nick Cruden, Peter Clive Hayes, Dave Newby
Journal: Gut (2005)

<b>Background:</b> Overexpression of inducible nitric oxide synthase (iNOS) and increased nitric oxide generation may be associated with the hyperdynamic circulation of patients with cirrhosis. We have, for the first time, used the highly selective iNOS inhibitor, 1400W, to determine whether iNOS activity contributes to the regulation of vascular tone in patients with cirrhosis and ascites. <b>Methods:</b> Bilateral forearm blood flow was measured using strain gauge plethysmography in eight patients with cirrhosis and ascites, and eight matched healthy volunteers during intrabrachial infusion of 1400W (0.1–1 μmol/min), N<sup>G</sup>-monomethyl-L-arginine (L-NMMA, a non-selective NOS inhibitor; 2–8 μmol), and norepinephrine (a control vasoconstrictor; 60–480 pmol/min). <b>Results:</b> In patients with cirrhosis, 1400W, L-NMMA, and norepinephrine caused dose dependent reductions in forearm blood flow: peak reductions of 11 (5)%, 37 (4)%, and 48 (5)%, respectively (p&lt;0.05 for all). In contrast, 1400W had no effect on blood flow (+4 (8)%; NS) in healthy controls despite similar reductions in blood flow with L-NMMA and norepinephrine (39 (5)% and 49 (5)%, respectively; p&lt;0.05 for both). <b>Conclusions:</b> We have, for the first time, demonstrated that 1400W causes peripheral vasoconstriction in patients with cirrhosis but not healthy matched controls. This suggests that iNOS contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites, and may contribute towards the hyperdynamic circulation associated with this condition.
DNA Double-Strand Breaks
Authors: Linda Bross, Masamichi Muramatsu, Kazuo Kinoshita, Tasuku Honjo, Heinz Jacobs
Journal: The Journal of Experimental Medicine (2002)

The activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin (Ig) genes, both of which are associated with DNA double-strand breaks (DSBs). As AID is capable of deaminating deoxy-cytidine (dC) to deoxy-uracil (dU), it might induce nicks (single strand DNA breaks) and also DNA DSBs via a U-DNA glycosylase-mediated base excision repair pathway (‘DNA-substrate model’). Alternatively, AID functions like its closest homologue Apobec1 as a catalytic subunit of a RNA editing holoenzyme (‘RNA-substrate model’). Although rearranged Vλ genes are preferred targets of SHM we found that germinal center (GC) B cells of AID-proficient and -deficient Vλ1-expressing GC B cells display a similar frequency, distribution, and sequence preference of DSBs in rearranged and also in germline Vλ1 genes. The possible roles of DSBs in relation to AID function and SHM are discussed.
Novel methylation targets in de novo acute myeloid leukemia with prevalence of chromosome 11 loci
Authors: Laura J. Rush, Zunyan Dai, Dominic J. Smiraglia, Xin Gao, Fred A. Wright, Michael Frühwald, Joseph F. Costello, William A. Held, Li Yu, Ralf Krahe, Jonathan E. Kolitz, Clara D. Bloomfield, Michael A. Caligiuri, Christoph Plass
Journal: Blood (2001)