tbuckley/cabot-search huggingface dataset:
Evolution of class switching
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Antibody class switching emerged in evolutionary history when bony fish grew legs and became amphibians. On [page 733][1], Barreto and colleagues show that the switch-inducing enzyme AID (activation-induced cytidine deaminase) is in working order in bony fish, suggesting that the evolution of the
Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects
Authors: E Daviskas, SD Anderson, I Gonda, S Eberl, S Meikle, JP Seale, G Bautovich
Journal: European Respiratory Journal (1996)

Hyperosmolarity of the airway surface liquid (ASL) has been proposed as the stimulus for hyperpnoea-induced asthma. We found previously that mucociliary clearance (MCC) was increased after isocapnic hyperventilation (ISH) with dry air, and we proposed that the increase related to transient hyperosmolarity of the ASL. We investigated the effect of increasing the osmolarity of the ASL on MCC, by administering an aerosol of concentrated salt solution. MCC was measured using 99mTc-sulphur colloid, gamma camera and computer analysis in 12 asthmatic and 10 healthy subjects on three separate days, involving administration of each of the following: 1) ultrasonically nebulized 14.4% saline; 2) ultrasonically nebulized 0.9% saline; and 3) no aerosol intervention (control). The (mean +/- SD) volume of nebulized 14.4% saline was 2.2 +/- 1.2 mL for asthmatics and 3.2 +/- 0.7 mL for healthy subjects. This volume was delivered over a period of 5.4 +/- 1.3 and 6.4 +/- 0.7 min for asthmatic and healthy subjects, respectively. The airway response to 14.4% saline was assessed on a separate visit and the fall in forced expiratory volume in one second (FEV1) was 22 +/- 4% in the asthmatic and 3 +/- 2% in the healthy subjects. Compared to the MCC with the 0.9% saline and control, the hypertonic aerosol increased MCC in both groups. In asthmatic subjects, MCC of the whole right lung in 1 h was 68 +/- 10% with 14.4% saline vs 44 +/- 14% with 0.9% saline and 39 +/- 13% with control. In healthy subjects, MCC of the whole right lung in 1 h was 53 +/- 12% with 14.4% saline vs 41 +/- 15% with 0.9% saline and 36 +/- 13% with control. We conclude that an increase in osmolarity of the airway surface liquid increases mucociliary clearance both in asthmatic and healthy subjects. These findings are in keeping with our previous suggestion that the increase in mucociliary clearance after isotonic hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid.
Bone turnover in non-steroid treated rheumatoid arthritis.
Authors: J E Compston, S Vedi, P I Croucher, N J Garrahan, M M O'Sullivan
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVE--To examine whether changes in cancellous bone turnover and resorption cavity depth contribute to bone loss in patients with non-steroid treated rheumatoid arthritis. METHODS--Iliac crest biopsies were obtained from 37 patients with non-steroid treated rheumatoid arthritis, 13 male and 24 female, aged 37-71 years. Bone turnover and resorption cavity characteristics were quantitatively assessed using semiautomated computerised techniques. RESULTS--When compared with age- and sex-matched control values, there was a significant reduction in bone formation rate at tissue level and activation frequency (P &lt; 0.001) in the patient group. The eroded perimeter, mean and maximum eroded depth and cavity area were also significantly reduced (P &lt; 0.01, &lt; 0.005, &lt; 0.01 and &lt; 0.005 respectively). CONCLUSION--These results demonstrate low bone turnover in non-steroid treated rheumatoid arthritis and indicate that the reduced bone mass in these patients is due mainly to a negative remodelling balance.
Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia
Authors: Nirmala Mavila, David James, Pranavkumar Shivakumar, Marie V. Nguyen, Sarah Utley, Katrina Mak, Allison Wu, Shengmei Zhou, Larry Wang, Christopher Vendyres, Megan Groff, Kinji Asahina, Kasper S. Wang
Journal: Hepatology (2014)

Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. Whereas the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a rhesus rotavirus-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker, PROMININ-1 (PROM1), adjacent to ductular reactions within regions of periportal fibrosis. PROM1 positive (pos) cells express Collagen-1α1 . Subsets of PROM1 pos cells coexpress progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and alpha-SMOOTH MUSCLE ACTIN (αSMA). Expansion of the PROM1 pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGFβ) signaling. In vitro cotreatment of PROM1-expressing Mat1a−/− hepatic progenitor cells with recombinant human FGF10 and TGFβ1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1α1 , Fibronectin , and α-Sma . Infants with BA demonstrate similar expansion of periportal PROM1 pos cells with activated Mothers Against Decapentaplegic Homolog 3 (SMAD3) signaling in association with increased hepatic expression of FGF10 , FGFR1 , and FGFR2 as well as mesenchymal genes SLUG and SNAIL . Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype. Conclusion : Expansion of collagen-producing PROM1 pos cells within regions of periportal fibrosis is associated with activated FGF and TGFβ pathways in both experimental and human BA. PROM1 pos cells may therefore play an important role in the biliary fibrosis of BA. (Hepatology 2014;60:941–953)
The Influence of Statin Medications on Prostate-specific Antigen Levels
Authors: Robert J. Hamilton, Kenneth C. Goldberg, Elizabeth A. Platz, Stephen J. Freedland
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundRecent data suggest that statin use may be associated with a reduced risk of advanced prostate cancer. However, the influence of statins on prostate-specific antigen (PSA) levels and what effect this could potentially have on prostate cancer diagnosis are unknown.
Insulin Receptor Structure and Function in Normal and Pathological Conditions
Authors: Andrew B. Becker, Richard A. Roth
Journal: Annual Review of Medicine (1990)

The insulin receptor is a large cell surface glycoprotein that concentrates insulin at the site of action and also initiates responses to insulin. The receptor is a disulfide-linked oligomer comprised of two α and two β subunits. Signal transduction through the insulin receptor appears to require the activation of an intrinsic tyrosine-specific protein kinase activity. A variety of disorders, both acquired and genetic, are associated with the development of insulin resistance and are frequently the result of cellular defects in insulin receptor structure, function, and action. The recent cloning of several mutant receptors from patients with genetic forms of extreme insulin resistance has increased our understanding of insulin resistance on the molecular level.
Increased carotid artery intima-media thickness is associated with a novel mutation of low-density lipoprotein receptor independently of major cardiovascular risk factors
Authors: Paolo Pauciullo, Alessandro Giannino, Mario De Michele, Marco Gentile, Rosario Liguori, Anagnostis Argiriou, Alessandra Carlotto, Fulvio Faccenda, Mario Mancini, M.Gene Bond, Vincenzo De Simone, Paolo Rubba
Journal: Metabolism (2003)
Long-Term Efficacy of Intracoronary Irradiation in Inhibiting In-Stent Restenosis
Authors: David J. Brenner, Richard C. Miller
Journal: Circulation (2001)

Background —Intracoronary irradiation is a promising modality for inhibition of in-stent restenosis. Results of randomized clinical trials at 6 months after gamma ray irradiation are highly encouraging. The first results at 3 years after irradiation, while still showing benefit, have shown significant late loss. The probable mechanism of the radiation is to inactivate (prevent from dividing) most cells that otherwise could proliferate to produce neointimal formation. We measured the proportion of cells that survive with their clonogenic potential intact after the doses and dose rates used in the randomized trials, and we then modeled the subsequent repopulation of the surviving cells that might cause late restenosis. Methods and Results —Human aortic smooth muscle cells were irradiated with gamma rays, including the doses and dose rates used in current trials, and clonogenic surviving fractions were measured. The subsequent repopulation of the surviving cells was modeled with the assumption that the repopulation kinetics were similar to those in unirradiated cells. The radiation is expected to delay the time to restenosis by factors of ≈6 to 8, depending on the dose, shifting the delay from a median of 6 months (for no irradiation) to median values from 36 months (for a nominal 13 Gy) to 43 months (for a nominal 15 Gy). Conclusions —These results and predictions are quantitatively consistent with clinical results and suggest that clonogenic inactivation (prevention of cellular division) is the dominant mechanism of radiation action in the delay of restenosis. Intracoronary radiotherapy is a very promising modality for significantly delaying, although probably not preventing, in-stent restenosis.
Personalized—Not Omitted—Radiation Oncology for Breast Cancer
Authors: Alba Fiorentino, Rosario Mazzola, Francesco Ricchetti, Sergio Fersino, Niccolò Giaj Levra, Filippo Alongi
Journal: Journal of Clinical Oncology (2015)

TO THE EDITOR: The article by Bellon 1 reports that radiation therapy (RT) for breast cancer (BC) could be omitted for patients who are unlikely to benefit from locoregional therapy. In fact, an absolute improvement of local control less than 10% correlated with a BC mortality benefit of only 0.1%. Moreover, in the editorial, RT was described as being inconvenient because of toxicity. We appreciated that it was highlighted that no data supported the omission of RT after breast-conserving surgery (BCS) and that this possibility remains only speculative. In fact, the recent meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group 2 showed that, during the next 15 years, approximately one death from BC would be avoided for every four local recurrences avoided. It is well recognized that killing of locoregional microscopic tumor foci reduces the potential risk of local recurrences and distant metastasis. 2 Regarding the possibility of omitting RT in selected patients with BC without definitive data, several questions could emerge. First, can we omit a local treatment if it does not increase overall survival? In other cancer diseases, such as rectal cancer, the standard conservative treatment approach, including RT, reduces the risk of locoregional recurrences without increasing overall survival. To our knowledge, the omission of RT has never been discussed. Undoubtedly, the reduction of local recurrences improve quality of life for patients with BC. In European Organisation for Research and Treatment of Cancer (EORTC) trial 10801, BCS with RT was associated with a better body image compared with a mastectomy approach. 3 Second, considering the increased risk of local failure when RT is omitted, shall we consider more intensive follow-up? Two randomized trials did not show any effect of intensive diagnostic follow-up on 5- and 10-year mortality for patients with primary BC treated with BCS and RT. 4,5 Therefore, these data are no longer reliable if RT is not performed, and, probably, intensive follow-up should be proposed to patients to prevent local recurrence, increasing health care system costs.
Medical treatment of ulcerative colitis: scoring the advances.
Authors: C J Hawkey, A B Hawthorne
Journal: Gut (1988)

Recently, oenological prejudices were challenged by the use of a points scoring system (from 50 to 100) to evaluate wine in a book now widely regarded as one of the most authoritative. On this scale, a 1981 Chateau Citran described as 9emaciated9 scored 65, a 1983 Chateau Kirwan scored 85, and a 1982 Petrus 100. If the same approach were used for drugs used in ulcerative colitis to quantify an advance over conditions existing at the time of its introduction how would they score? Because they were the first available drugs in their class and clearly constituted major advances, corticosteroids and sulphasalazine both score 95, the score being limited by a high level of side effects. The new salicylates score 75, because they extend the benefits of sulphasalazine to a minority of patients but they have the potential to score 90 if increased dosing and greater effectiveness over sulphasalazine can be achieved. Salicylate enemas score 80, because they advance treatment over topical corticosteroids for patients with resistant distal disease, but the mode of delivery needs improvement. Steroid foams also score 80, particularly if the patient9s vote is taken into account. Azathioprine9s score cannot be calculated because there is doubt over its efficacy, but it is potentially 88 if it saves patients with difficult disease from colectomy. We can only guess what an oral non-absorbed steroid would score, but if response rates for relapse were substantially improved, or if corticosteroids could be used as effective maintenance treatment, it could be as high as 95. There are indications that we should 9watch this space9.
Medical management of nephropathy in type I diabetes mellitus
Authors: J A Breyer
Journal: Journal of the American Society of Nephrology (1995)

Diabetic nephropathy is the single most common cause of end-stage renal disease in the United States. Recently, several major therapeutic interventions have been developed and demonstrated to slow or halt the progression of renal failure in patients with diabetes and diabetic kidney disease. The Diabetes Control and Complications Trial demonstrated that microalbuminuria developed in fewer patients in the intensive blood sugar control group than in the conventional therapy group. Similarly, the risk of developing proteinuria was reduced by intensive blood sugar control. Multiple studies have demonstrated that in patients with insulin-dependent diabetes and proteinuria, lowering the systemic blood pressure slows the rate of decline in renal function and improves patients' survival. In the recently completed trial of ACE inhibition in diabetic nephropathy, ACE inhibitors were specifically shown to decrease dramatically the risk of doubling of serum creatinine or reaching a combined outcome of end-stage renal disease or death. In studies in small numbers of patients with insulin-dependent diabetes and established diabetic nephropathy, dietary protein restriction has also been demonstrated to slow the rate of decline of renal function. New potential interventions currently undergoing study include the use of aldose reductase inhibitors, the use of drugs that prevent the formation of advanced glycosylation end-products, and the use of angiotensin II receptor antagonists. Thus, several established benefits have recently been demonstrated to help prevent the development of or slow the progression of diabetic nephropathy, including blood pressure control, blood sugar control, and treatment with ACE inhibitors. Dietary protein restriction may also be of benefit. Multiple new interventions are undergoing clinical trials currently.
An extensive function evaluation in severe asthma with airflow limitation
Authors: Rodrigo Athanazio, Regina Carvalho-Pinto, Samia Rached, Frederico Fernandes, Klaus Rabe, Alberto Cukier, Rafael Stelmach
Journal: European Respiratory Journal (2014)

Asthma is classically characterized by full reversal of airway obstruction. However, a significant proportion of patients demonstrate partial obstruction reversibility despite best treatment. We aim to compare characteristics of non-controlled severe asthma patients with persistent (PO) and fixed (FO) airflow obstruction to those with non-persistent obstruction (NPO). Sixty-two non-controlled severe asthmatics received high inhaled corticosteroid dose plus LABA for 12 weeks. In the first two weeks they also received oral prednisone (OC=40mg.day-1). They were evaluated according to ACQ, spirometry, pletismography and Single Breath N2 washout test, at baseline (T-2), after OC trial (T2) and at the end of the study (T12). ACQ and functional data at T-2 and T2 are shown in table below. At T12, all subgroups presented a slight worsening in functional status although still better than baseline.

View this table:

Clinical and functional characteristics of severe asthmatic patients after standardized treatment





Our data confirm that a high proportion of severe asthmatic patients persists with airflow obstruction despite optimal theraphy. Small airway measurements are sensitive in identifying those most likely to respond to treatment and may help to understand the pathophysiology involved in remodeling and fixed obstruction in asthmatic patients.
Oxygen therapy in myocardial infarction: an historical perspective
Authors: Richard Beasley, Mark Weatherall, Sarah Aldington, David Mchaffie, Geoffrey Robinson
Journal: Journal of the Royal Society of Medicine (2007)

It is over 100 years since the use of oxygen to relieve angina pectoris was first described by Steele.1 More importantly, it is over 50 years since Russek and colleagues cautioned that the administration of 100% oxygen may actually be contraindicated in patients with myocardial infarction or angina pectoris in whom the arterial oxygen saturation is normal.2 Since this warning, there have been numerous reports of potentially harmful effects of high flow oxygen in the treatment of myocardial infarction, yet it is routine clinical practice to administer oxygen to virtually all patients in this situation. In this essay we have considered, from an historical perspective, the findings from the key studies of the effects of oxygen therapy in patients with myocardial infarction. We propose that randomized controlled trials are urgently required.
The active identification and management of chronic refractory breathlessness is a human right
Authors: David C Currow, Amy P Abernethy, Danielle N Ko
Journal: Thorax (2013)

Chronic refractory breathlessness is defined as breathlessness at rest or on minimal exertion that will persist chronically despite optimal treatment of the underlying cause(s). At any time, 1% of the population report a modified Medical Research Council dyspnoea score of ≥3 chronically. Despite the prevalence, severity and chronicity of this symptom and an evidence base of affordable and safe interventions, chronic refractory breathlessness remains grossly undertreated. Many patients and clinicians accept the presence of the chronic refractory breathlessness as an inevitable part of an illness, with no thought of treating the symptom despite an evidence base for its safe treatment. Consensus statements from major respiratory clinician organisations now endorse such a clinical course. Failure to enquire about, assess and properly treat chronic refractory breathlessness with opioids as outlined in specialist clinical guidelines is now an unacceptable level of care ethically and is, arguably, a breach of people9s human rights. Adequate pain control through access to pain relief is now accepted as a human right and, given its burden across the world, the symptomatic treatment of chronic refractory breathlessness should be seen in exactly the same way.
Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing
Authors: Francisca Ferrer-Marín, Beatriz Bellosillo, Luz Martínez-Avilés, Gloria Soler, Pablo Carbonell, Ginés Luengo-Gil, Eva Caparrós, José M Torregrosa, Carlos Besses, Vicente Vicente
Journal: Journal of Hematology & Oncology (2013)

We have characterized the molecular changes underlying the transformation of a JAK2V617F+-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F+-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.
A Randomized, Phase II, Biomarker-Selected Study Comparing Erlotinib to Erlotinib Intercalated With Chemotherapy in First-Line Therapy for Advanced Non–Small-Cell Lung Cancer
Authors: Fred R. Hirsch, Fairooz Kabbinavar, Tim Eisen, Renato Martins, Fredrick M. Schnell, Rafal Dziadziuszko, Katherine Richardson, Frank Richardson, Bret Wacker, David W. Sternberg, Jason Rusk, Wilbur A. Franklin, Marileila Varella-Garcia, Paul A. Bunn, D. Ross Camidge
Journal: Journal of Clinical Oncology (2011)

Erlotinib prolongs survival in patients with advanced non-small-cell lung cancer (NSCLC). We report the results of a randomized, phase II study of erlotinib alone or intercalated with chemotherapy (CT + erlotinib) in chemotherapy-naïve patients with advanced NSCLC who were positive for epidermal growth factor receptor (EGFR) protein expression and/or with high EGFR gene copy number.
The role of perlecan in arterial injury and angiogenesis
Authors: A SEGEV
Journal: Cardiovascular Research (2004)

Perlecan is a large heparan sulfate proteoglycan (HSPG), which is a major component of the vessel wall. In relation to vascular biology, perlecan has been shown to be a potent inhibitor of smooth muscle cell (SMC) activity. In vivo experiments in animal models of arterial injury have shown that perlecan may inhibit thrombosis and intimal hyperplasia. On the other hand, perlecan has been shown to have opposing effects on endothelial cells (ECs), where it promotes in vitro and in vivo angiogenesis and plays an important role in mediating tumor growth. These diverse biological effects, or "the perlecan paradox", are discussed in this review paper. The properties of perlecan including inhibition of SMC activity and thrombosis while enhancing EC proliferation are ideal for the prevention of in-stent restenosis. Perlecan's pro-angiogenic effects may be used for the treatment of various ischemic diseases such as intractable coronary artery disease and peripheral vascular disease.
Re: Improving the Cost-Effectiveness of Colorectal Cancer Screening
Authors: F. Loeve
Journal: JNCI Journal of the National Cancer Institute (2000)

point out, health planners tend not tobe so farsighted and the technologies fortreating and screening for colorectalcancer will most likely improve in fu-ture decades. Thus, the sigmoidoscopyprogram may be replaced by an alterna-tive screening program within 30 years.Fig. 1 shows what happens if the sig-moidoscopy screening program is aban-doned after 10 years or 20 years. A 10-year screening program will achieve netcost savings in the 19