tbuckley/cabot-search huggingface dataset:
Autophagy is activated in systemic lupus erythematosus and required for plasmablast development
Authors: Alexander J Clarke, Ursula Ellinghaus, Andrea Cortini, Amanda Stranks, Anna Katharina Simon, Marina Botto, Timothy J Vyse
Journal: Annals of the Rheumatic Diseases (2014)

Autophagy has emerged as a critical homeostatic mechanism in T lymphocytes, influencing proliferation and differentiation. Autophagy in B cells has been less studied, but genetic deficiency causes impairment of early and late developmental stagesTo explore the role of autophagy in the pathogenesis of human and murine lupus, a disease in which B cells are critical effectors of pathology.Autophagy was assessed using multiple techniques in NZB/W and control mice, and in patients with systemic lupus erythematosus (SLE) compared to healthy controls. We evaluated the phenotype of the B cell compartment in Vav-Atg7(-/-) mice in vivo, and examined human and murine plasmablast formation following inhibition of autophagy.We found activation of autophagy in early developmental and transitional stages of B cell development in a lupus mouse model even before disease onset, and which progressively increased with age. In human disease, again autophagy was activated compared with healthy controls, principally in naïve B cells. B cells isolated from Vav-Atg7(F/F) mice failed to effectively differentiate into plasma cells following stimulation in vitro. Similarly, human B cells stimulated in the presence of autophagy inhibition did not differentiate into plasmablasts.Our data suggest activation of autophagy is a mechanism for survival of autoreactive B cells, and also demonstrate that it is required for plasmablast differentiation, processes that induce significant cellular stress. The implication of autophagy in two major pathogenic pathways in SLE suggests the potential to use inhibition of autophagy as a novel treatment target in this frequently severe autoimmune disease.
INTERACTION OF THE RHEUMATOID FACTOR WITH ANTIGEN-ANTIBODY COMPLEXES AND AGGREGATED GAMMA GLOBULIN
Authors: G. M. Edelman, H. G. Kunkel, E. C. Franklin
Journal: The Journal of Experimental Medicine (1958)

The effect of highly purified rheumatoid factor on the precipitin reactions of various antigen-antibody systems was determined. The amount of nitrogen precipitated was increased over a broad range when the factor was added to ovalbumin, human albumin, or human gamma globulin, and the corresponding rabbit antibodies. In the zone of antigen excess, soluble antigen-antibody complexes were precipitated by rheumatoid factor. Soluble aggregates of human and rabbit gamma globulin, produced by heating at 63 degrees C., treatment with urea plus mercaptoethanol or treatment with guanidine, also precipitated with rheumatoid factor. Ultracentrifugal analysis of dissolved specific precipitates showed the presence of aggregated gamma globulin. The sedimentation rate of reactive aggregates was greater than 20 S, and concentrated preparations free of the non-reactive 7 S gamma globulin could be prepared by various procedures of zone centrifugation. These aggregates showed a high inhibitory capacity in the sensitized sheep cell agglutination reaction. Solid gamma globulin, prepared by heat denaturation, also selectively adsorbed the rheumatoid factor, and removed or decreased the activity in the various precipitation and agglutination reactions. Elution of highly purified active preparations from the solid gamma globulin could be carried out with urea or acid buffers. Evidence for interaction between rheumatoid factor and low molecular weight gamma globulin without precipitation, was also obtained. This interaction appears to occur in the circulation of patients with rheumatoid arthritis. The question of whether the rheumatoid factor represents an antibody to gamma globulin was discussed. Points of similarity to the behavior of complement also were cited.
Body Mass Index and Risk of Colorectal Cancer According to Fatty Acid Synthase Expression in the Nurses’ Health Study
Authors: Aya Kuchiba, Teppei Morikawa, Mai Yamauchi, Yu Imamura, Xiaoyun Liao, Andrew T. Chan, Jeffrey A. Meyerhardt, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino
Journal: JNCI Journal of the National Cancer Institute (2012)

Fatty acid synthase (FASN) plays an important role in energy metabolism of fatty acids and is overexpressed in some colon cancers. We investigated whether associations between body mass index (BMI) and risk of colorectal cancer varied according to FASN expression. During follow-up of 109 051 women in the ongoing prospective Nurses' Health Study, a total of 1351 incident colon and rectal cancers were diagnosed between 1986 and 2004. We constructed tissue microarrays of the available resected tumor samples (n = 536), and FASN expression was analyzed by immunohistochemistry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. All statistical tests were two-sided. High BMI was associated with an increased risk of FASN-negative (no or weak expression) colorectal cancer compared with normal BMI (high BMI [≥30 kg/m 2 ], ie, obese vs normal BMI [18.5–22.9 kg/m 2 ], HR = 2.25, 95% CI = 1.49 to 3.40, Ptrend < .001) but not with FASN-positive (moderate to strong expression) colorectal cancer. A statistically significant heterogeneity in colorectal cancer risks was observed between FASN-negative and FASN-positive tumors ( Pheterogeneity = .033). The age-adjusted incidence rates for FASN-positive and FASN-negative colorectal cancers were 10.9 and 7.1, respectively, per 100 000 person-years. This molecular pathological epidemiology study supports a role of energy metabolism in colorectal cancer pathogenesis.
Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia
Authors: Marthe S. Paats, Ingrid M. Bergen, Wessel E.J.J. Hanselaar, E. Christine Groeninx van Zoelen, Henk C. Hoogsteden, Rudi W. Hendriks, Menno M. van der Eerden
Journal: European Respiratory Journal (2012)

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters. Levels of interleukin (IL)-6, IL-8, IL-10, IL-1β, tumour necrosis factor-α, interferon (IFN)-γ, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals. Systemic cytokine levels were also measured on days 7 and 30. In bronchoalveolar lavage fluid of CAP patients, levels of IL-6, IL-8 and IFN-γ were significantly increased compared with healthy individuals, but no correlations with disease severity were found. Systemic levels of IL-6, IL-10 and IFN-γ were significantly higher in severe CAP patients than in nonsevere CAP patients and healthy individuals. Moreover, these cytokines showed a significant correlation with the pneumonia severity index. In the total group of CAP patients, systemic IL-8 and IL-22 levels were also increased compared with healthy individuals. We therefore conclude that IL-6, IL-10 and IFN-γ are important cytokines in CAP, although differences in disease severity upon admission are only reflected by systemic levels of these cytokines.
Musculoskeletal Complications in Type 1 Diabetes
Authors: Mary E. Larkin, Annette Barnie, Barbara H. Braffett, Patricia A. Cleary, Lisa Diminick, Judy Harth, Patricia Gatcomb, Ellen Golden, Janie Lipps, Gayle Lorenzi, Carol Mahony, David M. Nathan
Journal: Diabetes Care (2014)

The development of periarticular thickening of skin on the hands and limited joint mobility (cheiroarthropathy) is associated with diabetes and can lead to significant disability. The objective of this study was to describe the prevalence of cheiroarthropathy in the well-characterized Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort and examine associated risk factors, microvascular complications, and the effect of former DCCT therapy (intensive [INT] vs. conventional [CONV]) on its development.This cross-sectional analysis was performed in 1,217 participants (95% of the active cohort) in EDIC years 18/19 after an average of 24 years of follow-up. Cheiroarthropathy-defined as the presence of any one of the following: adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, Dupuytren's contracture, or a positive prayer sign-was assessed using a targeted medical history and standardized physical examination. A self-administered questionnaire (Disabilities of the Arm, Shoulder and Hand [DASH]) assessed functional disability.Cheiroarthropathy was present in 66% of subjects (64% of the INT group and 68% of the CONV group; P = 0.1640) and was associated with age, sex, diabetes duration, skin intrinsic fluorescence, HbA1c, neuropathy, and retinopathy (P < 0.005 for each). DASH functional disability scores were worse among subjects with cheiroarthropathy (P < 0.0001).Cheiroarthropathy is common in people with type 1 diabetes of long duration (∼30 years) and is related to longer duration and higher levels of glycemia. Clinicians should include cheiroarthropathy in their routine history and physical examination of patients with type 1 diabetes because it causes clinically significant functional disability.
MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer
Authors: Maria Teresa Landi, Yingdong Zhao, Melissa Rotunno, Jill Koshiol, Hui Liu, Andrew W. Bergen, Maurizia Rubagotti, Alisa M. Goldstein, Ilona Linnoila, Francesco M. Marincola, Margaret A. Tucker, Pier Alberto Bertazzi, Angela C. Pesatori, Neil E. Caporaso, Lisa M. McShane, Ena Wang
Journal: Clinical Cancer Research (2010)

The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non-small cell lung cancer.We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics.MiR expression profiles strongly differed between adenocarcinoma and SQ (P(global) < 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2- to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ.We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches.
DJ-1/park7 modulates vasorelaxation and blood pressure via epigenetic modification of endothelial nitric oxide synthase
Authors: Kyung Jong Won, Seung Hyo Jung, Soo Hyun Jung, Kang Pa Lee, Hwan Myung Lee, Dong-Youb Lee, Eun-Seok Park, Junghwan Kim, Bokyung Kim
Journal: Cardiovascular Research (2013)

AimsDJ-1/park7, a multifunctional protein, may play essential roles in the vascular system. However, the function of DJ-1/park7 in vascular contractility has remained unclear. The present study was designed to investigate whether the DJ-1/park7 is involved in the regulation of vascular contractility and systolic blood pressure (SBP).
Explaining the Racial Difference in AKI Incidence
Authors: Morgan E. Grams, Kunihiro Matsushita, Yingying Sang, Michelle M. Estrella, Meredith C. Foster, Adrienne Tin, W.H. Linda Kao, Josef Coresh
Journal: Journal of the American Society of Nephrology (2014)

African Americans face higher risk of AKI than Caucasians. The extent to which this increased risk is because of differences in clinical, socioeconomic, or genetic risk factors is unknown. We evaluated 10,588 African-American and Caucasian participants in the Atherosclerosis Risk in Communities study, a community-based prospective cohort of middle-aged individuals. Participants were followed from baseline study visit (1996-1999) to first hospitalization for AKI (defined by billing code), ESRD, death, or December 31, 2010. African-American participants were slightly younger (61.7 versus 63.1 years, P<0.001), were more often women (64.5% versus 53.2%, P<0.001), and had higher baseline eGFR compared with Caucasians. Annual family income, education level, and prevalence of health insurance were lower among African Americans than Caucasians. The unadjusted incidence of hospitalized AKI was 7.4 cases per 1000 person-years among African Americans and 5.8 cases per 1000 person-years among Caucasians (P=0.002). The elevated risk of AKI among African Americans persisted after adjustment for demographics, cardiovascular risk factors, kidney markers, and time-varying number of hospitalizations (adjusted hazard ratio, 1.20; 95% confidence interval [95% CI], 1.01 to 1.43; P=0.04); however, accounting for differences in income and/or insurance by race attenuated the association (P>0.05). High-risk APOL1 variants did not associate with AKI among African Americans (demographic-adjusted hazard ratio, 1.07; 95% CI, 0.69 to 1.65; P=0.77). In summary, the higher risk of AKI among African Americans may be related to disparities in socioeconomic status.
Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage
Authors: Marco Ladetto, Federica De Marco, Fabio Benedetti, Umberto Vitolo, Caterina Patti, Alessandro Rambaldi, Alessandro Pulsoni, Maurizio Musso, Anna M. Liberati, Attilio Olivieri, Andrea Gallamini, Enrico Pogliani, Delia Rota Scalabrini, Vincenzo Callea, Francesco Di Raimondo, Vincenzo Pavone, Alessandra Tucci, Sergio Cortelazzo, Alessandro Levis, Mario Boccadoro, Ignazio Majolino, Alessandro Pileri, Alessandro M. Gianni, Roberto Passera, Paolo Corradini, Corrado Tarella
Journal: Blood (2008)
Application of phage display to high throughput antibody generation and characterization
Authors: Darren J Schofield, Anthony R Pope, Veronica Clementel, Jenny Buckell, Susan DJ Chapple, Kay F Clarke, Jennie S Conquer, Anna M Crofts, Sandra RE Crowther, Michael R Dyson, Gillian Flack, Gareth J Griffin, Yvette Hooks, William J Howat, Anja Kolb-Kokocinski, Susan Kunze, Cecile D Martin, Gareth L Maslen, Joanne N Mitchell, Maureen O'Sullivan, Rajika L Perera, Wendy Roake, S Paul Shadbolt, Karen J Vincent, Anthony Warford, Wendy E Wilson, Jane Xie, Joyce L Young, John McCafferty
Journal: Genome biology (2007)

Abstract We have created a high quality phage display library containing over 10 10 human antibodies and describe its use in the generation of antibodies on an unprecedented scale. We have selected, screened and sequenced over 38,000 recombinant antibodies to 292 antigens, yielding over 7,200 unique clones. 4,400 antibodies were characterized by specificity testing and detailed sequence analysis and the data/clones are available online. Sensitive detection was demonstrated in a bead based flow cytometry assay. Furthermore, positive staining by immunohistochemistry on tissue microarrays was found for 37% (143/381) of antibodies. Thus, we have demonstrated the potential of and illuminated the issues associated with genome-wide monoclonal antibody generation.
Stepwise radical endoscopic resection for eradication of Barrett's oesophagus with early neoplasia in a cohort of 169 patients
Authors: R. E. Pouw, S. Seewald, J. J. Gondrie, P. H. Deprez, H. Piessevaux, H. Pohl, T. Rosch, N. Soehendra, J. J. Bergman
Journal: Gut (2010)

<h3>Background and Aims</h3> Endoscopic resection is safe and effective to remove early neoplasia (ie,high-grade intra-epithelial neoplasia/early cancer) in Barrett9s oesophagus. To prevent metachronous lesions during follow-up, the remaining Barrett9s oesophagus can be removed by stepwise radical endoscopic resection (SRER). The aim was to evaluate the combined experience in four tertiary referral centres with SRER to eradicate Barrett9s oesophagus with early neoplasia. <h3>Methods</h3> <i>Design</i>: Retrospective cohort study. <i>Setting</i>: Four tertiary referral centres. <i>Participants</i>: 169 patients (151 males, age 64 years (IQR 57–71), Barrett9s oesophagus 3 cm (IQR 2–5)) with early neoplasia in Barrett9s oesophagus ≤5 cm, without deep submucosal infiltration or lymph node metastases, treated by SRER between January 2000 and September 2006. <i>Intervention</i>: Endoscopic resection every 4–8 weeks, until complete endoscopic and histological eradication of Barrett9s oesophagus and neoplasia. <h3>Results</h3> According to intention-to-treat analysis complete eradication of all neoplasia and all intestinal metaplasia by the end of the treatment phase was reached in 97.6% (165/169) and 85.2% (144/169) of patients, respectively. One patient had progression of neoplasia during treatment and died of metastasised adenocarcinoma (0.6%). After median follow-up of 32 months (IQR 19–49), complete eradication of neoplasia and intestinal metaplasia was sustained in 95.3% (161/169) and 80.5% (136/169) of patients, respectively. Acute, severe complications occurred in 1.2% of patients, and 49.7% of patients developed symptomatic stenosis. <h3>Conclusions</h3> SRER of Barrett9s oesophagus ≤5 cm containing early neoplasia appears to be an effective treatment modality with a low rate of recurrent lesions during follow-up. The procedure, however, is technically demanding and is associated with oesophageal stenosis in half of the patients.
Periodontal management of HIV‐infected patients
Authors: M I Ryder
Journal: Periodontology 2000 (2000)

Recognition and diagnosis of the general oral manifestations and specific periodontal manifestations of HIV infection will continue to be a major responsibility of the dental practitioner. The dental team needs to understand the underlying principles of care for the necrotizing and inflammatory periodontal changes associated with HIV. In addition, the practitioner must take into consideration how the presence of opportunistic infections in the periodontium such as Candida as well as the patient's level of immunosuppression may affect conventional approaches to the common forms of periodontal diseases. By combining local and systemic therapy aimed at both preventing and treating oral lesions and periodontal diseases, combined with new systemic antiviral and vaccine therapies, dental and medical practitioners may together help reduce both the dental morbidity and the overall patient morbidity in the HIV infected patient.
Severe disorders of keratinization: effects of treatment with Tigason (etretinate)
Authors: RONALD MARKS, ANDREW Y. FINLAY, PETER J.A. HOLT
Journal: British Journal of Dermatology (1981)

Twenty patients with disabling disorders of keratinization were treated with Tigason (etretinate, Ro 10-9359), an oral aromatic retinoid, and the clinical responses and the effects on the skin were monitored. Most patients showed a considerable clinical improvement within 4 weeks. Side effects, such as cheilitis, were common but mostly transient or minor. In the skin there was a decrease in glucose-6-phosphate dehydrogenase activity within the granular cell layer of the epidermis, and an increase in mean epidermal thickness and mean corneocyte area. However, there was little apparent effect on epidermal proliferation or on histological and ultrastructural appearances. These findings suggest that the drug acts at a late stage of epidermal differentiation.
Octreotide Treatment of Acromegaly
Authors: S Ezzat, P J Snyder, W F Young, L D Boyajy, C Newman, A Klibanski, M E Molitch, A E Boyd, L Sheeler, D M Cook
Journal: Annals of Internal Medicine (1992)

Objective: To determine the effects of the somatostatin analog, octreotide acetate, in patients with acromegaly. Design: Double-blind, randomized trial. Setting: Fourteen university-affiliated medical centers. Patients: One hundred fifteen acromegalic patients, 70% of whom had persistent disease after pituitary surgery or radiotherapy. Intervention: Subcutaneous octreotide, 100 µg, or placebo every 8 hours for 4 weeks. Four weeks after the end of treatment, patients were randomized to receive 100 or 250 µg octreotide subcutaneously every 8 hours for 6 months. Results: After 2 weeks of treatment, a single 100-µg injection reduced mean serum growth hormone (GH) to 30% of the pretreatment concentration within 2 hours. The integrated mean GH level was reduced over 8 hours from 39 ± 11 µg/L to 9 ± 2 µg/L (P < 0.001). Mean plasma insulin-like growth factor-1 (IGF-1) was reduced from 5100 µ 400 U/L to 2400 ± 400 U/L (P < 0.001). After 6 months, the mean GH was reduced from 39 ± 13 to 15 ± 4 µg/L by 300 µg of octreotide and from 29 ± 5 µg/L to 9 ± 2 µg/L by 750 µg of octreotide daily. The mean IGF-1 concentration was suppressed to 2100 ± 300 and 2500 ± 400 U/L after 300 and 750 µg octreotide, respectively. Integrated mean GH levels were reduced to less than 5 µg/L in 53% (95% Cl, 39% to 67%) and 49% (Cl, 35% to 63%), and IGF-1 levels were normal in 68% (Cl, 54% to 82%) and 55% (Cl, 40% to 70%) of patients receiving low- and high-dose octreotide, respectively. A substantial decrease in headache, amount of perspiration, joint pain, and finger circumference occurred in two thirds of the patients. The pituitary size was reduced in 19% (Cl, 5% to 33%) and 37% (Cl, 22% to 52%) of patients receiving 6 months of low- and high-dose octreotide, respectively. Ten percent and 13% of patients in each treatment group developed transient diarrhea; 10% and 14%, biliary sludge; and 6% and 18%, cholelithiasis, respectively. Conclusion: Octreotide effectively decreased GH and IGF-1 concentrations in 53% and 68% of patients, respectively. The higher dose resulted in increased frequency of tumor shrinkage but added no biochemical or clinical benefit.