tbuckley/cabot-search huggingface dataset:
Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits
Authors: Nicole Heise, Nilushi S. De Silva, Kathryn Silva, Amanda Carette, Giorgia Simonetti, Manolis Pasparakis, Ulf Klein
Journal: The Journal of Experimental Medicine (2014)

Germinal centers (GCs) are the sites where memory B cells and plasma cells producing high-affinity antibodies are generated during T cell–dependent immune responses. The molecular control of GC B cell maintenance and differentiation remains incompletely understood. Activation of the NF-κB signaling pathway has been implicated; however, the distinct roles of the individual NF-κB transcription factor subunits are unknown. We report that GC B cell–specific deletion of the NF-κB subunits c-REL or RELA, which are both activated by the canonical NF-κB pathway, abolished the generation of high-affinity B cells via different mechanisms acting at distinct stages during the GC reaction. c-REL deficiency led to the collapse of established GCs immediately after the formation of dark and light zones at day 7 of the GC reaction and was associated with the failure to activate a metabolic program that promotes cell growth. Conversely, RELA was dispensable for GC maintenance but essential for the development of GC-derived plasma cells due to impaired up-regulation of BLIMP1. These results indicate that activation of the canonical NF-κB pathway in GC B cells controls GC maintenance and differentiation through distinct transcription factor subunits. Our findings have implications for the role of NF-κB in GC lymphomagenesis.
Nephrotic syndrome in adults
Authors: Richard P Hull, David J A Goldsmith
Journal: BMJ (2008)

The nephrotic syndrome is one of the best known presentations of adult or paediatric kidney disease. The term describes the association of (heavy) proteinuria with peripheral oedema, hypoalbuminaemia, and hypercholesterolaemia (box 1). Protein in the urine (“coagulable urine”) was first described in 1821, 15 years before Richard Bright’s celebrated series of descriptions of “albuminous urine.”1

#### Box 1 Diagnostic criteria for nephrotic syndrome

Nephrotic syndrome has an incidence of three new cases per 100 000 each year in adults.2 It is a relatively rare way for kidney disease to manifest compared with reduced kidney function or microalbuminuria as a complication of systemic diseases, such as diabetes and raised blood pressure.3

#### Summary points

Patients with nephrotic syndrome can present to primary or secondary care with diverse symptoms that reflect the primary process or with one of the many systemic complications of the syndrome.4 Although nephrotic syndrome is relatively common in renal practice, it is seen only rarely in primary or secondary care. This can result in a delayed or overlooked diagnosis, especially as many other conditions have similar symptoms. For example, severe peripheral (leg) oedema is seen in congestive cardiac failure, hypoalbuminaemia can be caused …
Mapping of Chromosome 1p Deletions in Myeloma Identifies <i>FAM46C</i> at 1p12 and <i>CDKN2C</i> at 1p32.3 as Being Genes in Regions Associated with Adverse Survival
Authors: Kevin D. Boyd, Fiona M. Ross, Brian A. Walker, Christopher P. Wardell, William J. Tapper, Laura Chiecchio, GianPaolo Dagrada, Zoe J. Konn, Walter M. Gregory, Graham H. Jackson, J. Anthony Child, Faith E. Davies, Gareth J. Morgan
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact. Experimental Design: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data. Results: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting. Conclusion: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations. Clin Cancer Res; 17(24); 7776–84. ©2011 AACR.
High Familial Risk in Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Authors: Silva Saarinen, Eero Pukkala, Pia Vahteristo, Markus J. Mäkinen, Kaarle Franssila, Lauri A. Aaltonen
Journal: Journal of Clinical Oncology (2013)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is one of the two established Hodgkin lymphoma (HL) subtypes. The risk factors of NLPHL are largely unknown. In general, genetic factors are known to have a modest effect on the risk of HL; however, familial risk in NLPHL has not been previously examined. We conducted a population-based study by using the Finnish registries and evaluated the familial risk in NLPHL.We launched a population-based search to identify patients with NLPHL and their relatives by examining the records of the Finnish Cancer Registry, established in 1953, and the official Finnish population registries. We collected a data set of 692 patients with NLPHL, identified their 4,280 first-degree relatives, and calculated the registry-based standardized incidence ratios (SIRs) for different cancers in the first-degree relatives. In addition, the primary tumor biopsies of HL-affected relatives were collected when possible, the HL diagnoses were re-reviewed by a hematopathologist, and the SIR for NLPHL was calculated on the basis of confirmed NLPHL diagnoses.On the basis of confirmed NLPHL diagnoses, the SIR for NLPHL was 19 (95% CI, 8.8 to 36) in the first-degree relatives. The risk was most prominent in female relatives of young patients. The registry-based SIR for classical HL was 5.3 (95% CI, 3.0 to 8.8), and for non-Hodgkin lymphoma, it was 1.9 (95% CI, 1.3 to 2.6).Our results implicate an unexpectedly high familial component in the development of NLPHL. Research is warranted to identify the putative genetic and environmental factors underlying this finding and to develop strategies for better management of patients with NLPHL and their relatives.
Development of Proximal Coronary Arteries in Quail Embryonic Heart
Authors: Katsumi Ando, Yuji Nakajima, Toshiyuki Yamagishi, Sadamu Yamamoto, Hiroaki Nakamura
Journal: Circulation Research (2003)

Studies have shown that the proximal coronary artery (PCA) develops via endothelial ingrowth from the peritruncal ring (PR) of the coronary vasculature. However, the details of PCA formation remain unclear. We examined the development of PCAs in quail embryonic hearts from 5 to 9 days of incubation (embryonic day [ED]) using double-immunostaining for QH1 (quail endothelial marker) and smooth muscle alpha-actin. At 6 to 7 ED, several QH1-positive endothelial strands from the PR penetrated the facing sinuses, and in some embryos, several endothelial strands penetrated the posterior (noncoronary) sinus. At 7 to 8 ED, the endothelial strands penetrating the facing sinuses seemed to fuse, forming a proximal coronary stem that was demarcated from the aortic wall by the nascent smooth muscle layer of the coronary artery. By 9 ED, two coronary stems were completely formed, and the endothelial strands previously penetrating the noncoronary sinus had disappeared. Confocal microscopy at 6 ED revealed discontinuous QH1-positive endothelial progenitors in the aortic wall at sites where the endothelial strands would later develop. Observations demonstrate that during the formation of the PCA, endothelial strands from the PR penetrate the facing sinuses and then fuse, whereas those strands penetrating the noncoronary sinus disappear. Thereafter, the coronary artery tunica media demarcates the definitive PCA from the aortic media.
Treatment of Hepatitis C
Authors: Anita Kohli, Ashton Shaffer, Amy Sherman, Shyam Kottilil
Journal: JAMA (2014)

Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon.To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration-approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence.A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19,063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine.Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks' duration: 82%-93%; SVR for genotype 3, 24 weeks' duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients.New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapies may lead to the treatment of many more people with chronic HCV infection.
Increased soluble CD14 in bronchoalveolar lavage fluid of stable lung transplant recipients
Authors: C. Ward, E.H. Walters, L. Zheng, H. Whitford, T.J. Williams, G.I. Snell
Journal: European Respiratory Journal (2002)

Macrophages, neutrophils and infection have been implicated in the genesis of the bronchiolitis obliterans syndrome (BOS) post lung transplantation. sCD14 is a soluble form of a shed-cell surface protein. It is capable of promoting cytokine-induced inflammation and it's presence in clinically stable lung transplant recipients (LTR) might be important as an early marker of BOS. Bronchalveolar lavage (BAL) and blood samples were taken from 26 stable LTR, at or near their best forced expiratory volume in one second who were free from infection. sCD14 levels were measured via enzyme-linked immunosorbent assay. Cell counts were performed on unfiltered BAL. LTR neutrophil count, BAL sCD14 and serum sCD14 levels were higher than controls (median 3.8% versus 1.3%, p&lt;0.05; 11.5 ng·mL −1 versus 6 ng·mL −1 , p&lt;0.001; 6.2 µg·mL −1 versus 2.4 µg·mL −1 , p&lt;0.05, respectively). BAL albumin and sCD14 correlated (regression coefficient: 0.77, p&lt;0.001). In this hypothesis-generating, cross-sectional study, the authors have described for the first time soluble CD14 levels in the bronchoalveolar lavage and serum of stable lung transplant recipients, and show that these are elevated compared to controls. This is a practicable candidate marker system, which can be tested for a predictive role in bronchiolitis obliterans syndrome following lung transplantation. The origin of this cellular protein and its temporal relationship to the development of the bronchiolitis obliterans syndrome remains to be elucidated in more definitive longitudinal studies, which should include other measurements potentially relevant to the innate immune system, such as bronchoalveolar lavage endotoxin levels.
Association of Meat and Fat Intake With Liver Disease and Hepatocellular Carcinoma in the NIH-AARP Cohort
Authors: N. D. Freedman, A. J. Cross, K. A. McGlynn, C. C. Abnet, Y. Park, A. R. Hollenbeck, A. Schatzkin, J. E. Everhart, R. Sinha
Journal: JNCI Journal of the National Cancer Institute (2010)

Background Several plausible mechanisms, including fat, iron, heterocyclic amines, and N -nitroso compounds, link meat intake with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Few studies have investigated these associations.
Rheumatoid arthritis near remission: clinical rather than laboratory inflammation is associated with radiographic progression
Authors: D. Aletaha, F. Alasti, J. S. Smolen
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Disease activity in rheumatoid arthritis (RA) can be measured clinically (eg, swollen joint count (SJC)) or systemically (eg, C reactive protein (CRP)). In general, both contribute to the progression of joint damage, but the relevance of residual inflammation in patients near remission is unclear. <h3>Objective</h3> To determine the independent contribution of SJC and CRP to progression of joint damage in patients near remission. <h3>Methods</h3> Data from methotrexate monotherapy arms of the ASPIRE, ERA, Leflunomide, PREMIER and TEMPO trials (n=1184) were pooled and the average SJC and CRP values from visits at 6, 9 and 12 months were determined. The two variables were then dichotomised into active and inactive, where inactive was defined as a mean. Radiographic outcomes were assessed according to these definitions. <h3>Results</h3> The greatest progression was seen in patients in whom both SJC and CRP were active and the smallest in those in whom both were inactive. If SJC was inactive, radiographic progression was not different between those with inactive or active CRP (0.7±4.3/year and 0.8±5.4/year, respectively, p=0.19). However, if CRP was inactive (&lt;1 mg/dl), SJC status still determined radiographic progression (0.7±4.3/year and 1.8±5.6/year, for inactive and active SJC, respectively, p=0.004). The importance of SJC in patients with inactive CRP was also shown in a linear model (p=0.019), while CRP was not significantly different in patients with inactive SJC (p=0.40). <h3>Conclusion</h3> In patients with RA who are near remission, the amount of joint swelling appears to be more predictive of radiographic progression than the amount of CRP.
Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency.
Authors: B J Burri, L Sweetman, W L Nyhan
Journal: Journal of Clinical Investigation (1981)

Biotin-responsive multiple carboxylase deficiency is an inherited disorder of organic acid metabolism in man in which there are deficiencies of propionyl-coenzyme A (CoA), 3-methylcrotonyl-CoA, and pyruvate carboxylases that can be corrected with large doses of biotin. It has been proposed that the basic defect in patients with the early infantile form of the disease is in holocarboxylase synthetase, the enzyme that covalently attaches biotin to the inactive apocarboxylases to form active holocarboxylases. We have developed an assay for holocarboxylase synthetase in extracts of human fibroblasts using as substrate apopropionyl-CoA carboxylase partially purified from livers of biotin-deficient rats. Fibroblasts from the initial patient with the infantile form of biotin-responsive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 30-40% of normal, a Km for ATP of 0.3 mM similar to the normal Km of 0.2 mM, and a highly elevated Km for biotin of 126 ng/ml, about 60 times the normal Km of 2 ng/ml. These results show that the primary defect in this patient is a mutation affecting holocarboxylase synthetase activity, and thus a genetic defect of the metabolism of biotin.
Alcohol and Aldehyde Dehydrogenase Polymorphisms in Men With Type I and Type II Alcoholism
Authors: Young-Gyu Chai, Dong-Yul Oh, Eun Kee Chung, Gil Sook Kim, Leen Kim, Yu-Sang Lee, Ihn-Geun Choi
Journal: American Journal of Psychiatry (2005)

The authors examined the genetic polymorphisms of alcohol dehydrogenase 2 and 3 (ADH2 and ADH3) and aldehyde dehydrogenase (ALDH2) in patients diagnosed as having Cloninger's type I or type II alcoholism.Seventy-two alcoholic men and 38 nonalcoholic, healthy men were tested for the distribution of genotypes and alleles of ADH2, ADH3, and ALDH2. Forty-eight of the alcoholic men had type I alcoholism, and 24 had type II alcoholism.The frequencies of ADH2*1 and ADH3*2 alleles were significantly higher in men with type II alcoholism than in men with type I alcoholism and healthy men. The frequency of the ALDH2*1 allele was significantly higher in men with alcohol dependence than in healthy men.The genetic characteristics of alcohol dehydrogenases in men with type I alcoholism were similar to those of healthy men, and the genetic characteristics of aldehyde dehydrogenase in men with type I alcoholism were similar to those of men with type II alcoholism. These findings suggest that the genetic characteristics of alcohol metabolism in type I alcoholism fall between nonalcoholism and type II alcoholism.
Insulinlike Growth Factor-1 in Lung Transplants with Obliterative Bronchiolitis
Authors: JEAN-MARIE CHARPIN, MARC STERN, DOMINIQUE GRENET, DOMINIQUE ISRAËL-BIET
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Bronchiolitis obliterans syndrome (BOS) is the major complication limiting survival of lung transplant recipients (Tx patients). The mechanisms underlying this fibrotic process are not known. We assessed IGF-1 and IGFBP-3 expression, critical mediators in different models of pulmonary fibrosis, in nine Tx patients. Three of them developed a BOS at 8, 14, and 17 mo postgraft, respectively. Two of the remaining six displayed a recurrent cytomegalovirus (CMV) infection, and four are in stable condition. IGF-1 mRNA expression was quantitated by RT-PCR in cells from four to six BAL per patient performed during the first 6 mo postgraft. Contrasting with a constantly low expression of IGF-1 mRNA in BAL cells from the six patients without BOS, the three patients with BOS presented marked peaks of IGF-1 on two to five occasions during the study period. These peaks, 3- to 13-fold increased compared with values from the former patients, preceded the diagnosis of BOS by 7, 13, and 17 mo, respectively. On the other hand, IGFBP-3 was highly and exclusively expressed in the three patients with BOS, the mRNA as well as the gene product as demonstrated by Western blotting. Our data strongly argue for a role of IGF-1 and IGFBP-3 in the fibrotic process underlying BOS, and for their possible value as an early marker of this complication.
Endobronchial ultrasonography with guide-sheath for peripheral pulmonary lesions
Authors: E. Kikuchi, K. Yamazaki, N. Sukoh, J. Kikuchi, H. Asahina, M. Imura, Y. Onodera, N. Kurimoto, I. Kinoshita, M. Nishimura
Journal: European Respiratory Journal (2004)

The usefulness of endobronchial ultrasonography (EBUS) with guide-sheath (GS) as a guide for transbronchial biopsy (TBB) for diagnosing peripheral pulmonary lesions (PPL)s and for improving diagnostic accuracy was evaluated in this study. EBUS-GS-guided TBB was performed in 24 patients with 24 PPLs of < or =30 mm in diameter (average diameter=18.4 mm). A 20-MHz radial-type ultrasound probe, covered with GS was inserted via a working bronchoscope channel and advanced to the PPL in order to produce an EBUS image. The probe with the GS was confirmed to reach the lesion by EBUS imaging and X-ray fluoroscopy. When the lesion was not identified on the EBUS image, the probe was removed and a curette was used to lead the GS to the lesion. After localising the lesion, the probe was removed, and TBB and bronchial brushing were performed via the GS. Nineteen peripheral lesions (79.2%) were visualised by EBUS. All patients whose PPLs were visible on EBUS images subsequently underwent an EBUS-GS-guided diagnostic procedure. A total of 14 lesions (58.3%) were diagnosed. Even when restricted to PPLs <20 mm in diameter, the diagnostic sensitivity was 53%. In conclusion, endobronchial ultrasonography with guide sheath-guided transbronchial biopsy was feasible and effective for diagnosing peripheral pulmonary lesions.
Intralesional and intravenous treatment of cutaneous B-cell lymphomas with the monoclonal anti-CD20 antibody rituximab: report and follow-up of eight cases
Authors: K. Kerl, C. Prins, J.H. Saurat, L.E. French
Journal: British Journal of Dermatology (2006)

Background Rituximab (MabThera®; Roche, Basel, Switzerland; an anti‐CD20 chimeric monoclonal antibody) has been shown to have significant activity in nodal B‐cell lymphomas, with few associated adverse effects. Its efficacy and safety were first demonstrated in the treatment of systemic B‐cell lymphomas. Intravenous and subsequently intralesional administration of rituximab have also been reported to be effective and well tolerated in cutaneous B‐cell lymphoma (CBCL). The comparative efficacy of intravenous vs. intralesional rituximab in CBCL is not known. Objectives To evaluate the objective response rate, relapse rate, time to progression, and tolerance in patients with CBCL treated with intravenous or intralesional rituximab. Methods Eight patients with multiple primary CBCL (four follicle centre lymphoma and four marginal zone lymphoma) were treated with intralesional rituximab (six patients; 10–30 mg per lesion, three times weekly for one or two cycles at a 4‐week interval) or intravenous rituximab (two patients; 375 mg m−2 once weekly for four consecutive weeks). Results Complete clinical remission was obtained in all cases. The two patients treated intravenously did not relapse during a follow‐up period of 18–24 months. Four of six patients treated intralesionally presented a relapse of new lesions at another site within a mean of 6 months after treatment. The injected lesions did not, however, recur. New lesions also responded to another cycle of intralesional rituximab. Tolerance to treatment was very good in both treatment groups. Conclusions Rituximab therapy of CBCL appears to have a potential advantage in cases where lesions are localized in sites that are difficult to treat with radiotherapy or surgery and in which secondary scarring or alopecia is likely. Intralesional injections of rituximab allow the use of considerably smaller doses compared with intravenous treatment, with similar response rates and tolerance. However, within a 12‐month follow‐up period, relapse of CBCL with new lesions at distinct sites was frequently observed after intralesional treatment.