tbuckley/cabot-search huggingface dataset:
Phase III Trial Comparing Adjuvant Treatment With Pegylated Interferon Alfa-2b Versus Observation: Prognostic Significance of Autoantibodies—EORTC 18991
Authors: Marna G. Bouwhuis, Stefan Suciu, Alessandro Testori, Wim H. Kruit, François Salès, Poulam Patel, Cornelis J. Punt, Mario Santinami, Alain Spatz, Timo L.M. ten Hagen, Alexander M.M. Eggermont
Journal: Journal of Clinical Oncology (2010)

Conflicting data have been reported concerning the prognostic value of autoimmune antibodies in patients with melanoma treated with adjuvant interferon alfa-2b (IFN). We evaluated the prognostic significance of autoantibodies in the European Organisation for Research and Treatment of Cancer 18991 trial, comparing long-term administration of pegylated IFN (PEG-IFN) with observation.Anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined by enzyme-linked immunosorbent assays in 296 patients before random assignment and every 6 months after random assignment for up to 5 years. Prognostic impact of autoantibodies on recurrence-free survival (RFS) was assessed using the following three Cox models: a model that considered autoantibody appearance as a time-independent variable (model 1); a model that considered a patient to be autoantibody positive from the first positive test (model 2); and a model in which the most recent autoantibody test was used to define the status of the patient (model 3).Patients who were autoantibody negative at baseline were analyzed (n = 220). Occurrence of autoantibodies during follow-up was higher in the PEG-IFN-treated patients (18% in the observation arm v 52% in the PEG-IFN arm). Autoantibody appearance was of prognostic importance by using model 1 (hazard ratio [HR] = 0.56; 95% CI, 0.36 to 0.87; P = .01). However, when guarantee-time bias was taken into account using model 2 (HR = 1.19; 95% CI, 0.75 to 1.88; P = .46) or method 3 (HR = 1.14; 95% CI, 0.71 to 1.83; P = .59), significance was lost. Results were similar when treatment groups were analyzed separately.Appearance of autoimmune antibodies is neither a prognostic nor a predictive factor for improved outcome in patients with melanoma treated with PEG-IFN.
Increased collagen-linked pentosidine levels and advanced glycosylation end products in early diabetic nephropathy.
Authors: P J Beisswenger, L L Moore, T Brinck-Johnsen, T J Curphey
Journal: Journal of Clinical Investigation (1993)

Advanced glycosylation end products (AGEs) may play an important role in the development of diabetic vascular sequelae. An AGE cross-link, pentosidine, is a sensitive and specific marker for tissue levels of AGEs.To evaluate the role of AGEs in the development of diabetic nephropathy and retinopathy, we studied pentosidine levels and the clinical characteristics of 48 subjects with insulin-dependent diabetes mellitus. Diabetic nephropathy was classified as normal, microalbuminuria, or gross proteinuria, and retinopathy was graded as none, background, or proliferative. NEWLY OBSERVED FINDINGS: Significant elevation of pentosidine (P = 0.025) was found in subjects with microalbuminuria or gross proteinuria (73.03 +/- 9.47 vs 76.46 +/- 6.37 pmol/mg col) when compared with normal (56.96 +/- 3.26 pmol/mg col). Multivariate analysis to correct for age, duration of diabetes, and gender did not modify the results. Elevated pentosidine levels were also found in those with proliferative when compared with those with background retinopathy (75.86 +/- 5.66 vs 60.42 +/- 5.98 pmol/mg col) (P < 0.05).Microalbuminuria is associated with elevated levels of pentosidine similar to those found in overt diabetic nephropathy suggesting that elevated AGE levels are already present during the earliest detectable phase of diabetic nephropathy.
Host Responses in Tissue Repair and Fibrosis
Authors: Jeremy S. Duffield, Mark Lupher, Victor J. Thannickal, Thomas A. Wynn
Journal: Annual Review of Pathology Mechanisms of Disease (2012)

Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary "effector" cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis.
Mechanisms of Integrin–Vascular Endothelial Growth Factor Receptor Cross-Activation in Angiogenesis
Authors: Ganapati H. Mahabeleshwar, Weiyi Feng, Kumar Reddy, Edward F. Plow, Tatiana V. Byzova
Journal: Circulation Research (2007)

The functional responses of endothelial cells are dependent on signaling from peptide growth factors and the cellular adhesion receptors, integrins. These include cell adhesion, migration, and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. This study identifies the molecular requirements for the cross-activation between beta3 integrin and tyrosine kinase receptor 2 for vascular endothelial growth factor (VEGF) receptor (VEGFR-2) on endothelium. The relationship between VEGFR-2 and beta3 integrin appears to be synergistic, because VEGFR-2 activation induces beta3 integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF-induced tyrosine phosphorylation of VEGFR-2. We demonstrate here that adhesion- and growth factor-induced beta3 integrin tyrosine phosphorylation are directly mediated by c-Src. VEGF-stimulated recruitment and activation of c-Src and subsequent beta3 integrin tyrosine phosphorylation are critical for interaction between VEGFR-2 and beta3 integrin. Moreover, c-Src mediates growth factor-induced beta3 integrin activation, ligand binding, beta3 integrin-dependent cell adhesion, directional migration of endothelial cells, and initiation of angiogenic programming in endothelial cells. Thus, the present study determines the molecular mechanisms and consequences of the synergism between 2 cell surface receptor systems, growth factor receptor and integrins, and opens new avenues for the development of pro- and antiangiogenic strategies.
Expression of type 1 angiotensin II receptor subtypes and angiotensin II-induced calcium mobilization along the rat nephron.
Authors: N Bouby, A Hus-Citharel, J Marchetti, L Bankir, P Corvol, C Llorens-Cortes
Journal: Journal of the American Society of Nephrology (1997)

The localization of two type 1 angiotensin II receptor subtype mRNA, AT1A and AT1B, was determined by reverse transcription-PCR on microdissected glomeruli and nephron segments. The coupling sensitivity of these two receptor subtypes was evaluated by measuring variations in intracellular calcium ([Ca2+]i) elicited by angiotensin II (Ang II) in structures expressing either AT1A or AT1B mRNA, using Fura-2 fluorescence. The highest expression of AT1 mRNA was found in glomerulus, proximal tubule, and thick ascending limb. In glomerulus, AT1A and AT1B mRNA were similarly expressed, whereas in all nephron segments AT1A mRNA expression was dominant (approximately 84%). The increase in [Ca2+]i elicited by 10(-7) mol/L Ang II was highest in proximal segments (delta [Ca2+]i is approximately equivalent to 300 to 400 nmol/L) and thick ascending limb (delta [Ca2+]i is approximately equivalent to 200 nmol/L). In glomerulus and collecting duct, the response was lower (delta < 100 nmol/L). The median effective concentrations for Ang II were of the same order of magnitude in glomerulus (12.2 nmol/L), in which both AT1A and AT1B are expressed, and in cortical thick ascending limb (10.3 nmol/ L), in which AT1A is almost exclusively expressed. The Ang II-induced calcium responses were totally abolished by the AT1 receptor antagonist losartan (1 mumol/L) but not by the AT2 antagonist PD 123319 (1 mumol/L). In the absence of external Ca2+, the peak phase of the response induced by 10(-7) mol/L Ang II was reduced and shortened, suggesting that a part of the [Ca2+]i increase originated from the mobilization of the intracellular Ca2+ pool. In conclusion, these results demonstrate that in the rat kidney: (1) AT1A is the predominant AT1 receptor subtype expressed in the nephron segments, (2) glomerulus is the only structure with a relatively high AT1B mRNA content, and (3) AT1A and AT1B receptor subtypes do not differ in their efficiency for the activation of calcium second-messenger system.
Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans
Authors: F Lanzarotto, B Panarotto, R Sorbara, M Panteghini, F Pagani, S Sosta, A Lanzini
Journal: Gut (1999)

BACKGROUND Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the posssiblity that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. AIMS To investigate the effect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. METHODS Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. RESULTS Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic effect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p&lt;0.04). CONCLUSIONS Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no effect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted effect of enhancing the proportion of UDCA in the pool. This effect may be of benefit in the treatment of cholestatic liver diseases.
Analysis of HIV-1– and CMV-specific memory CD4 T-cell responses during primary and chronic infection
Authors: Alexandre Harari, G. Paolo Rizzardi, Kim Ellefsen, Donatella Ciuffreda, Patrick Champagne, Pierre-Alexandre Bart, Daniel Kaufmann, Amalio Telenti, Roland Sahli, Giuseppe Tambussi, Laurent Kaiser, Adriano Lazzarin, Luc Perrin, Giuseppe Pantaleo
Journal: Blood (2002)
Sonography and subclinical synovitis
Authors: B Bresnihan
Journal: Annals of the Rheumatic Diseases (2004)

Evaluating the sound of silence

The approach to the treatment of rheumatoid arthritis (RA) has changed substantially in recent years.1 Firstly, it is now common practice to introduce conventional disease modifying antirheumatic drugs (DMARDs) such as methotrexate, and even targeted biological therapies, within months of the onset of symptoms.2 One reason for this change is the growing appreciation that irreversible structural damage can occur very early in the course of inflammatory arthritis.3 Secondly, the establishment of dedicated early arthritis clinics facilitates early referral of patients with recent onset inflammatory arthritis for specialist evaluation and management.4 Thirdly, rheumatologists now have access to targeted therapies that greatly reduce the rate of progressive joint damage.5–7 Finally, it has been established that DMARDs reduces the rate of progressive joint damage most effectively when introduced within 6 months of symptom onset.8 In this context, the achievement of a sustained clinical remission in RA, the complete and permanent resolution of synovial inflammation, could become a realistic therapeutic goal. The same should be true of other inflammatory arthropathies.

### Ultrasonography demonstrates subclinical synovitis

The advances in rheumatology practice have depended on carefully validated measures of the clinical course and outcome. Rheumatologists employ clinical criteria that include quantifying the number of inflamed joints to define diagnostic categories,9 disease activity,10 response to treatment,11 and remission.12 In addition, it has …
Novel Mutations in Thiazide-Sensitive Na-Cl Cotransporter Gene of Patients with Gitelman's Syndrome
Authors: TOSHIAKI MONKAWA, ISAO KURIHARA, KAZUO KOBAYASHI, MATSUHIKO HAYASHI, TAKAO SARUTA
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Gitelman's syndrome (GS) is an autosomal recessive disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria that has recently been reported to be linked to thiazide-sensitive Na-Cl cotransporter (TSC) gene mutations. In this study, possible mutations in the TSC gene of six Japanese patients clinically diagnosed with GS were investigated. Twenty-six exons encoding TSC were amplified by PCR and then completely sequenced by the direct sequencing method. Patient A showed a missense mutation of Arg 642 to Cys on the paternal allele and a missense mutation of Val 578 to Met and a 2-bp deletion (nucleotide 2543-2544) on the maternal allele. This deletion results in a frameshift that alters codon 837 to encode a stop signal rather than phenylalanine, and it is predicted to lead to loss of the latter half of the intracellular carboxy terminus. In the second family, two affected sisters, patients B and C, had a homozygous missense mutation of Thr 180 to Lys. Both of their parents, who are consanguineously married, have a heterozygous Thr180Lys mutation. Patient D has a homozygous mutation Thr180Lys, which is the same as the second family. Haplotype analysis indicates that patients B and C are not related to patient D. In patients E and F, we could identify only one mutant allele; Ala569Glu and Leu849His, respectively. All of the mutations identified are novel except for the Arg642Cys mutation, which has been found in a Japanese GS patient. Although further in vitro study is required to prove that the mutations are responsible for GS, it is possible that Thr180Lys and Arg642Cys mutations might be common mutations in Japanese GS.
The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response
Authors: Kislay Parvatiyar, Zhiqiang Zhang, Rosane M. Teles, Songying Ouyang, Yan Jiang, Shankar S. Iyer, Shivam A. Zaver, Mirjam Schenk, Shang Zeng, Wenwan Zhong, Zhi Jie Liu, Robert L. Modlin, Yong Jun Liu, Genhong Cheng
Journal: Nature Immunology (2012)
Leg Symptoms in Peripheral Arterial Disease
Authors: Mary McGrae McDermott, Philip Greenland, Kiang Liu, Jack M. Guralnik, Michael H. Criqui, Nancy C. Dolan, Cheeling Chan, Lillian Celic, William H. Pearce, Joseph R. Schneider, Leena Sharma, Elizabeth Clark, Daniel Gibson, Gary J. Martin
Journal: JAMA (2001)

Persons with lower-extremity peripheral arterial disease (PAD) are often asymptomatic or have leg symptoms other than intermittent claudication (IC).To identify clinical characteristics and functional limitations associated with a broad range of leg symptoms identified among patients with PAD.Cross-sectional study of 460 men and women with PAD and 130 without PAD, who were identified consecutively, conducted between October 1998 and January 2000 at 3 Chicago-area medical centers.Ankle-brachial index score of less than 0.90; scores from 6-minute walk, accelerometer-measured physical activity over 7 days, repeated chair raises, standing balance (full tandem stand), 4-m walking velocity, San Diego claudication questionnaire, Geriatric Depression Score Short-Form, and the Walking Impairment Questionnaire.All groups with PAD had poorer functioning than participants without PAD. The following values are for patients without IC vs those with IC. Participants in the group with leg pain on exertion and rest (n = 88) had a higher (poorer) score for neuropathy (5.6 vs 3.5; P<.001), prevalence of diabetes mellitus (48.9% vs 26.7%; P<.001), and spinal stenosis (20.8% vs 7.2%; P =.002). The atypical exertional leg pain/carry on group (exertional leg pain other than IC associated with walking through leg pain [n = 41]) and the atypical exertional leg pain/stop group (exertional leg pain other than IC that causes one to stop walking [n = 90]) had better functioning than the IC group. The group without exertional leg pain/inactive (no exertional leg pain in individual who walks </=6 blocks per week [n = 28]) and the leg pain on exertion and rest group had poorer functioning than those with IC. Adjusting for age, sex, race, and comorbidities and compared with IC, participants with atypical exertional leg pain/carry on achieved a greater distance on the 6-minute walk (404.3 vs 328.5 m; P<.001) and were less likely to stop during the 6-minute walk (6.8% vs 36%; P =.002). The group with pain on exertion and rest had a slower time for completing 5 chair raises (13.5 vs 11.9 seconds; P =.009), completed the tandem stand less frequently (37.5% vs 60.0%; P =.004), and had a slower 4-m walking velocity (0.80 vs 0.90 m/s; P<.001).There is a wide range of leg symptoms in persons with PAD beyond that of classic IC. Comorbid disease may contribute to these symptoms in PAD. Functional impairments are found in every PAD symptom group, and the degree of functional limitation varies depending on the type of leg symptom.
Radioactivity: Effects of Whole Body Irradiation
Authors: E. P. Cronkite, George Brecher
Journal: Annual Review of Medicine (1952)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Herbal Composition PC-SPES for Management of Prostate Cancer: Identification of Active Principles
Authors: M. Sovak
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: The herbal mixture PC-SPES, used to manage advanced prostate cancer, has proven thrombogenic and highly estrogenic in clinical trials. However, attempts to identify the active compounds in PC-SPES have yielded incongruous results. Moreover, warfarin was identified in the serum of a patient taking PC-SPES who experienced a bleeding disorder. To determine the active components in PC-SPES potentially responsible for these effects, we analyzed PC-SPES lots manufactured from l996 through mid-2001. Methods: Antineoplastic activity of PC-SPES and its individual component extracts was determined by colony-forming assays with several prostate cancer cell lines, and estrogenicity was determined by analyzing expression of an estrogen-responsive reporter gene in breast cancer cells. High-pressure liquid chromatography was used to isolate, identify, and quantify components of PC-SPES. Components were also identified by proton nuclear magnetic resonance, gas chromatography/mass spectrometry, and mass spectra analysis. Results: PC-SPES lots manufactured from 1996 through mid-1999 contained the synthetic compounds indomethacin (range = 1.07–13.19 mg/g) and diethylstilbestrol (range = 107.28–159.27 μg/g) and were two to six times more antineoplastic and up to 50 times more estrogenic than lots manufactured after the spring of 1999. In lots manufactured after mid-1999, gradual declines in the concentrations of indomethacin (from 1.56 to 0.70 mg/g), diethylstilbestrol (from 46.36 to 0.00 μg/g), and total phytosterols (from 0.586 to 0.085 mg/g) were observed. Warfarin was identified for the first time in lots manufactured after July 1998 (range = 341–560 μg/g). In the August 2001 lot, increases were found in concentrations of the natural products licochalcone A (from 27.6 to 289.2 μg/g) and baicalin (from 12.5 to 38.8 mg/g). Conclusions: The phytochemical composition of PC-SPES varied by lot, and chemical analyses detected various amounts of the synthetic drugs diethylstilbestrol, indomethacin, and warfarin and several natural products. To qualify for clinical pharmacologic exploration, nutritional supplements including herbal mixtures should meet standards of quality control under the Good Manufacturing Practice system, and the manufacturers of such supplements should provide reliable analytical quality assurance.
A rat model of human T lymphocyte virus type I (HTLV-I) infection. 1. Humoral antibody response, provirus integration, and HTLV-I-associated myelopathy/tropical spastic paraparesis-like myelopathy in seronegative HTLV-I carrier rats.
Authors: N Ishiguro, M Abe, K Seto, H Sakurai, H Ikeda, A Wakisaka, T Togashi, M Tateno, T Yoshiki
Journal: The Journal of Experimental Medicine (1992)

Human T lymphocyte virus type I (HTLV-I) can be transmitted into several inbred strains of newborn and adult rats by inoculating newly established HTLV-I-immortalized rat T cell lines or the human T cell line MT-2. The transmission efficiency exceeds 80%, regardless of strain differences or the age at transmission. The production of anti-HTLV-I antibodies significantly differs among the strains and depends on the age at the time of transmission. Rats neonatally inoculated with HTLV-I-positive rat or human cells generally become seronegative HTLV-I carriers throughout their lives, whereas adult rats inoculated with HTLV-I-positive cells at 16 wk of age become seropositive HTLV-I carriers. The HTLV-I provirus genome is present in almost all organs, regardless of whether the carriers are seronegative or seropositive. According to antibody titers to HTLV-I, there are three groups of inbred rat strains: ACI, F344, and SDJ (high responders); WKA, BUF, and LEJ (intermediate responders); and LEW (low responder). Three of three 16-mo-old seronegative HTLV-I carrier rats of the WKA strain developed spastic paraparesis of the hind legs. Neuropathological examinations revealed that the lesions were confined primarily to the lateral and anterior funiculi of the spinal cord. Both myelin and axons were extensively damaged in a symmetrical fashion, and infiltration with massive foamy macrophages was evident. The most severe lesions were at levels of the thoracic cord and continued from the cervical to the lumbar area. These histopathological features as well as clinical symptoms largely parallel findings in humans with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). These HTLV-I carrier rats, in particular the WKA rats described above, can serve as a useful animal model for investigating virus-host interactions in the etiopathogenesis of HTLV-I-related immunological diseases, particularly HAM/TSP.