tbuckley/cabot-search huggingface dataset:
Rituximab for IgG4-related disease: a prospective, open-label trial
Authors: Mollie N Carruthers, Mark D Topazian, Arezou Khosroshahi, Thomas E Witzig, Zachary S Wallace, Philip A Hart, Vikram Deshpande, Thomas C Smyrk, Suresh Chari, John H Stone
Journal: Annals of the Rheumatic Diseases (2015)

Objectives To evaluate the efficacy of rituximab (RTX) in IgG4-related disease (IgG4-RD) in an open-label pilot trial. Methods We treated 30 IgG4-RD patients with two doses of RTX (1000 mg each). The participants were either treated with RTX alone (n = 26; 87%) or required to discontinue baseline glucocorticoids (GC) within 2 months (n = 4; 13%). Disease activity was measured by the IgG4-RD Responder Index (IgG4-RD RI) and physician's global assessment (PGA). Disease response was defined as the improvement of the IgG4-RD RI by two points. The primary outcome, measured at 6 months, was defined as: (1) decline of the IgG4-RD RI ≥2 points compared with baseline; (2) no disease flares before month 6; and (3) no GC use between months 2 and 6. Complete remission was defined as an IgG4-RD RI score of 0 with no GC use. Results Disease responses occurred in 97% of participants. The baseline IgG4-RD RI and PGA values, 11±7 and 63±22 mm, respectively, declined to 1±2 and 11±16 mm at 6 months (both p&lt;0.00001). The primary outcome was achieved by 23 participants (77%). Fourteen (47%) were in complete remission at 6 months, and 12 (40%) remained in complete remission at 12 months. Among the 19 with elevated baseline serum IgG4, IgG4 concentrations declined from a mean of 911 mg/dL (range 138–4780 mg/dL) to 422 mg/dL (range 56–2410 mg/dL) at month 6 (p&lt;0.05). However, only 8 (42%) of the 19 achieved normal values. Conclusions RTX appears to be an effective treatment for IgG4-RD, even without concomitant GC therapy. Trial registration number ClinicalTrials.gov identifier: NCT01584388 .
Two-stage phase II study of imatinib mesylate in subjects with refractory or relapsing neuroblastoma
Authors: L. Calafiore, L. Amoroso, O. Della Casa Alberighi, R. Luksch, G. Zanazzo, A. Castellano, M. Podda, C. Dominici, R. Haupt, M.V. Corrias, A. Garaventa
Journal: Annals of Oncology (2013)
A Philosophical Obituary: Dr. Jack Kevorkian Dead at 83 Leaving End of Life Debate in the US Forever Changed
Authors: Timothy F. Murphy
Journal: The American Journal of Bioethics (2011)

Jack Kevorkian, died June 3, 2011, but not by his own hand or through physician-assisted suicide (Schneider 2011). Kevorkian is best known as the physician who helped dozens of people end their liv...
Nonselective Cation Currents Regulate Membrane Potential of Rabbit Coronary Arterial Cell
Authors: Kuniko Terasawa, Toshiaki Nakajima, Haruko Iida, Kuniaki Iwasawa, Hitoshi Oonuma, Taisuke Jo, Toshihiro Morita, Fumitaka Nakamura, Yoshiharu Fujimori, Teruhiko Toyo-oka, Ryozo Nagai
Journal: Circulation (2002)

The effects of lysophosphatidylcholine (LPC) on electrophysiological activities and intracellular Ca2+ concentration ([Ca2+]i) were investigated in coronary arterial smooth muscle cells (CASMCs).The patch clamp techniques and Ca2+ measurements were applied to cultured rabbit CASMCs. The membrane potential was -46.0+/-5.0 mV, and LPC depolarized it. Replacement of extracellular Na+ with NMDG+ hyperpolarized the membrane and antagonized the depolarizing effects of LPC. In Na+-, K+-, or Cs+-containing solution, the voltage-independent background current with reversal potential (E(r)) of approximately +0 mV was observed. Removal of Cl- failed to affect it. When extracellular cations were replaced by NMDG+, E(r) was shifted to negative potentials. La3+ and Gd3+ abolished the background current, but nicardipine and verapamil did not inhibit it. In Na+-containing solution, LPC induced a voltage-independent current with E(r) of approximately +0 mV concentration-dependently. Similar current was recorded in K+- and Cs+-containing solution. La3+ and Gd3+ inhibited LPC-induced current, but nicardipine and verapamil did not inhibit it. In cell-attached configurations, single-channel activities with single-channel conductance of approximately 32pS were observed when patch pipettes were filled with LPC. LPC increased [Ca2+]i as the result of Ca2+ influx, and La3+ completely antagonized it.These results suggest that (1) nonselective cation current (I(NSC)) contributes to form membrane potentials of CASMCs and (2) LPC activates I(NSC), resulting in an increase of [Ca2+]i. Thus, LPC may affect CASMC tone under various pathophysiological conditions such as ischemia.
Endothelium dysfunction in systemic lupus erythematosus patients with pulmonary hypertension
Authors: Olga Yakovleva, Aleksandra Klekot, Svyatoslav Semenenko
Journal: European Respiratory Journal (2011)

Endothelium dysfunction plays one of the most important parts in progress of cardio-vascular pathology in SLE.   Objective:  To determine the state of endothelium dependent and endotheliun independent regulation of vascular tone in patients with SLE-associated pulmonary arterial hypertension (SLE-PAH).   Methods:  80 patients with valid SLE diagnosis were examined with ultrasonographic scan of brachial artery to asses the endothelium dependent vasodilatation (EDVD) and endothelium independent vasodilatation (EIDVD) according to reactive hyperemia test and test with nitroglycerine. PAH was manifested on the Doppler-echocardiogram in 35 SLE patients. The average duration of SLE in these patients was 14±1.6 years. A control group consisted of 20 healthy persons.   Results:  There was not significant difference between the initial diameters of brachial artery in SLE (3.35±0.06 mm) and SLE-PAH groups (3.43±0.09 mm) compared with control group (3.46±0.07 mm). The significant reduction of EDVD on 34% in SLE patients compared to healthy persons was determined in the test with reactive hyperemia. Abnormalities of endothelium dependent vascular tone regulation in patients with PAH were more expressed (reduced on 48% compared with healthy persons) (p   Conclusion:  Abnormality of EDVD is dominated in SLE patients. The most evident disorder of EDVD occurs in SLE patients during the PAH progress. In patients with PAH also noted reduction of vasoregulation function of smooth-muscular cells, because they had impared EIDVD.
Different Genetic Features Associated with Colon and Rectal Carcinogenesis
Authors: Milo Frattini, Debora Balestra, Simona Suardi, Maria Oggionni, Paola Alberici, Paolo Radice, Aurora Costa, Maria Grazia Daidone, Ermanno Leo, Silvana Pilotti, Lucio Bertario, Marco A. Pierotti
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers. Experimental Design: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18. Results: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN− SCRCs. All MIN− SCRCs showed β-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN− SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q. Conclusions: The APC-β-catenin pathway is inactivated in MIN− SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN− SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.
A potential link between peroxisome proliferator-activated receptor signalling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
Authors: F. Djouadi, Y. Lecarpentier, J.-L. Hebert, P. Charron, J. Bastin, C. Coirault
Journal: Cardiovascular Research (2009)

AimsArrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by major fibro-fatty replacement of the right ventricle (RV). We hypothesized that changes in peroxisome proliferator-activated receptor (PPAR) signalling contributed to myocardium fatty accumulation and contractile dysfunction in ARVC.
Effects of intensive lipid-lowering therapy on the coronary arteries of asymptomatic subjects with elevated apolipoprotein B.
Authors: X Q Zhao, B G Brown, L Hillger, D Sacco, B Bisson, L Fisher, J J Albers
Journal: Circulation (1993)

Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms?Of 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B > or = 125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P < .001). Among the 91 symptomatic patients, those in the intensive group experienced definite (> or = 10%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P = .009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0% of conventional, regression (P = .04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P < .01); no asymptomatic patient had an event.Asymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.
Molecular Reconstruction of Extinct LINE-1 Elements and Their Interaction with Nonautonomous Elements
Authors: Bradley J. Wagstaff, Emily N. Kroutter, Rebecca S. Derbes, Victoria P. Belancio, Astrid M. Roy-Engel
Journal: Molecular Biology and Evolution (2012)

Non-long terminal repeat retroelements continue to impact the human genome through cis-activity of long interspersed element-1 (LINE-1 or L1) and trans-mobilization of Alu. Current activity is dominated by modern subfamilies of these elements, leaving behind an evolutionary graveyard of extinct Alu and L1 subfamilies. Because Alu is a nonautonomous element that relies on L1 to retrotranspose, there is the possibility that competition between these elements has driven selection and antagonistic coevolution between Alu and L1. Through analysis of synonymous versus nonsynonymous codon evolution across L1 subfamilies, we find that the C-terminal ORF2 cys domain experienced a dramatic increase in amino acid substitution rate in the transition from L1PA5 to L1PA4 subfamilies. This observation coincides with the previously reported rapid evolution of ORF1 during the same transition period. Ancestral Alu sequences have been previously reconstructed, as their short size and ubiquity have made it relatively easy to retrieve consensus sequences from the human genome. In contrast, creating constructs of extinct L1 copies is a more laborious task. Here, we report our efforts to recreate and evaluate the retrotransposition capabilities of two ancestral L1 elements, L1PA4 and L1PA8 that were active ∼18 and ∼40 Ma, respectively. Relative to the modern L1PA1 subfamily, we find that both elements are similarly active in a cell culture retrotransposition assay in HeLa, and both are able to efficiently trans-mobilize Alu elements from several subfamilies. Although we observe some variation in Alu subfamily retrotransposition efficiency, any coevolution that may have occurred between LINEs and SINEs is not evident from these data. Population dynamics and stochastic variation in the number of active source elements likely play an important role in individual LINE or SINE subfamily amplification. If coevolution also contributes to changing retrotransposition rates and the progression of subfamilies, cell factors are likely to play an important mediating role in changing LINE-SINE interactions over evolutionary time.
Multidisciplinary Approach to Diagnosis and Management of Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Dushyant V. Sahani, Dana J. Lin, Aradhana M. Venkatesan, Nisha Sainani, Mari Mino–Kenudson, William R. Brugge, Carlos Fernandez–Del–Castillo
Journal: Clinical Gastroenterology and Hepatology (2008)
Inhibition of Telomerase Activity Enhances Hyperthermia-Mediated Radiosensitization
Authors: Manjula Agarwal, Shruti Pandita, Clayton R. Hunt, Arun Gupta, Xuan Yue, Saira Khan, Raj K. Pandita, David Pratt, Jerry W. Shay, John-Stephen A. Taylor, Tej K. Pandita
Journal: Cancer Research (2008)

Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR); however, hyperthermia also induces heat shock protein 70 (HSP70) synthesis and HSP70 expression is associated with radioresistance. Because HSP70 interacts with the telomerase complex and expression of the telomerase catalytic unit (hTERT) extends the life span of the human cells, we determined if heat shock influences telomerase activity and whether telomerase inhibition enhances heat-mediated IR-induced cell killing. In the present study, we show that moderate hyperthermia (43 degrees C) enhances telomerase activity. Inhibition of telomerase activity with human telomerase RNA-targeted antisense agents, and in particular GRN163L, results in enhanced hyperthermia-mediated IR-induced cell killing, and ectopic expression of catalytic unit of telomerase (TERT) decreased hyperthermia-mediated IR-induced cell killing. The increased cell killing by heat and IR exposure in telomerase-inhibited cells correlates with delayed appearance and disappearance of gamma-H2AX foci as well as decreased chromosome repair. These results suggest that inactivation of telomerase before combined hyperthermia and radiotherapy could improve tumor killing.
BENOXAPROFEN AND THE SKIN
Authors: B.R. Allen
Journal: British Journal of Dermatology (1983)

Journal Article BENOXAPROFEN AND THE SKIN Get access B.R. Allen B.R. Allen Department of Dermatology, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 109, Issue 3, 1 September 1983, Pages 361–364, https://doi.org/10.1111/j.1365-2133.1983.tb03554.x Published: 01 September 1983
A Worldwide Perspective of Atypical Pathogens in Community-acquired Pneumonia
Authors: Forest W. Arnold, James T. Summersgill, Andrew S. LaJoie, Paula Peyrani, Thomas J. Marrie, Paolo Rossi, Francesco Blasi, Patricia Fernandez, Thomas M. File, Jordi Rello, Rosario Menendez, Lucia Marzoratti, Carlos M. Luna, Julio A. Ramirez
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Controversy still exists in the international literature regarding the need to use antimicrobials covering atypical pathogens when initially treating hospitalized patients with community-acquired pneumonia (CAP). In different regions of the world, monotherapy with a beta-lactam antimicrobial is common.We sought to correlate the incidence of CAP due to atypical pathogens in different regions of the world with the proportion of patients treated with an atypical regimen in those same regions. In addition, we sought to compare clinical outcomes of patients with CAP treated with and without atypical coverage.A secondary analysis was performed using two comprehensive international databases. World regions were defined as North America (I), Europe (II), Latin America (III), and Asia and Africa (IV). Time to reach clinical stability, length of hospital stay, and mortality were compared between patients treated with and without atypical coverage.The incidence of CAP due to atypical pathogens from 4,337 patients was 22, 28, 21, and 20% in regions I-IV, respectively. The proportion of patients treated with atypical coverage from 2,208 patients was 91, 74, 53, and 10% in regions I-IV, respectively. Patients treated with atypical coverage had decreased time to clinical stability (3.7 vs. 3.2 d, p < 0.001), decreased length of stay (7.1 vs. 6.1 d, p < 0.01), decreased total mortality (11.1 vs. 7%, p < 0.01), and decreased CAP-related mortality (6.4 vs. 3.8%, p = 0.05).The significant global presence of atypical pathogens and the better outcomes associated with antimicrobial regimens with atypical coverage support empiric therapy for all hospitalized patients with CAP with a regimen that covers atypical pathogens.
Effect of rate or rhythm control on quality of life in persistent atrial fibrillation
Authors: Vincent E. Hagens, Adelita V. Ranchor, Eric Van Sonderen, Hans A. Bosker, Otto Kamp, Jan G.P. Tijssen, J.Herre Kingma, Harry J.G.M. Crijns, Isabelle C. Van Gelder
Journal: Journal of the American College of Cardiology (2004)
2015 Clinical trials update in sickle cell anemia
Authors: Natasha Archer, Frédéric Galacteros, Carlo Brugnara
Journal: American Journal of Hematology (2015)

Polymerization of HbS and cell sickling are the prime pathophysiological events in sickle cell disease (SCD). Over the last 30 years, a substantial understanding at the molecular level has been acquired on how a single amino acid change in the structure of the beta chain of hemoglobin leads to the explosive growth of the HbS polymer and the associated changes in red cell morphology. O2 tension and intracellular HbS concentration are the primary molecular drivers of this process, and are obvious targets for developing new therapies. However, polymerization and sickling are driving a complex network of associated cellular changes inside and outside of the erythrocyte, which become essential components of the inflammatory vasculopathy and result in a large range of potential acute and chronic organ damages. In these areas, a multitude of new targets for therapeutic developments have emerged, with several ongoing or planned new therapeutic interventions. This review outlines the key points of SCD pathophysiology as they relate to the development of new therapies, both at the pre-clinical and clinical levels.
Prognostic Effect of Circulating Adiponectin in a Randomized 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women at Risk for Breast Cancer
Authors: Debora Macis, Sara Gandini, Aliana Guerrieri-Gonzaga, Harriet Johansson, Paolo Magni, Massimiliano Ruscica, Matteo Lazzeroni, Davide Serrano, Massimiliano Cazzaniga, Serena Mora, Irene Feroce, Maria Pizzamiglio, Maria Teresa Sandri, Marcella Gulisano, Bernardo Bonanni, Andrea DeCensi
Journal: Journal of Clinical Oncology (2011)

Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer. Patients and Methods We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period. Results At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels. Conclusion Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.
S-Adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: A randomized, double-blind, placebo-controlled study with negative results
Authors: Jose Ribalta, Humberto Reyes, Manuel C. Gonzalez, Joaquin Iglesias, Marco Arrese, Jaime Poniachik, Claudina Molina, Nelly Segovia
Journal: Hepatology (1991)

S-Adenosyl-L-methionine has been reported to induce beneficial effects in intrahepatic cholestasis of pregnancy. Because cholestasis of pregnancy has a high prevalence in Chile and a deleterious effect on fetal prognosis, we decided to verify the efficacy of S-adenosyl-L-methionine in this disease. Eighteen patients with pruritus that appeared during pregnancy and with elevated serum levels of bile salts (68.1 +/- 15.9 mumol/L; mean +/- S.E.M.) and ALT (226 +/- 50 KU/L) were enrolled in a prospective double-blind study comparing the effects of the drug with a placebo. S-Adenosyl-L-methionine, 900 mg, or placebo was administered in daily intravenous infusions for 20 days. Every 5 days liver function tests were done and pruritus was assessed using a preestablished score. No significant differences in pruritus or in serum levels of bile salts, ALT, bilirubin and alkaline phosphatases were seen during or after treatment between patients who received S-adenosyl-L-methionine (n = 9) or placebo (n = 9). No relevant adverse reactions were detected. Most patients had cesarean sections because of reasons unrelated to the therapeutic trial. All newborns had Apgar scores greater than 7 and normal postnatal development. Our patients had moderately severe to severe cholestasis of pregnancy as indicated by the onset of pruritus before wk 32 of pregnancy. Seven of nine multiparous patients had a past history of recurrent cholestasis of pregnancy. In this study, the administration of S-adenosyl-L-methionine during 20 days did not improve intrahepatic cholestasis of pregnancy.