tbuckley/cabot-search huggingface dataset:
Fibrocytes Contribute to Inflammation and Fibrosis in Chronic Hypersensitivity Pneumonitis through Paracrine Effects
Authors: Carolina García de Alba, Ivette Buendia-Roldán, Alfonso Salgado, Carina Becerril, Remedios Ramírez, Yolanda González, Marco Checa, Carmen Navarro, Victor Ruiz, Annie Pardo, Moisés Selman
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Hypersensitivity pneumonitis (HP) represents a lung inflammation provoked by exposure to a variety of antigens. Chronic HP may evolve to lung fibrosis. Bone marrow-derived fibrocytes migrate to injured tissues and contribute to fibrogenesis, but their role in HP is unknown.To assess the possible participation of fibrocytes in chronic HP.CD45(+)/CXCR4(+)/Col-I(+) circulating fibrocytes were evaluated by flow cytometry, and the presence of fibrocytes in HP and normal lungs by confocal microscopy. The concentration of CXCL12 in plasma and bronchoalveolar lavage fluids was quantified by ELISA. The effect of fibrocytes on lung fibroblasts and T lymphocytes was examined in co-cultures.The percentage of circulating fibrocytes was significantly increased in patients with HP compared with healthy individuals (5.3 ± 3.4% vs. 0.8 ± 0.7%; P = 0.00004). Numerous fibrocytes were found infiltrating the HP lungs near fibroblasts and lymphocytes. Plasma CXCL12 concentration was significantly increased in patients with HP (2,303.3 ± 813.7 vs. 1,385.6 ± 318.5 pg/ml; P = 0.00003), and similar results were found in bronchoalveolar lavage fluids. The chemokine was primarily expressed by epithelial cells. In co-cultures, fibrocytes induced on lung fibroblasts a significant increase in the expression of α1 type I collagen, matrix metalloprotease-1, and platelet-derived growth factor-β. Likewise, fibrocytes induced the up-regulation of CCL2 in HP lymphocytes and fibroblasts.These findings demonstrate that high levels of fibrocytes are present in the peripheral blood of patients with chronic HP and that these cells infiltrate the HP lungs. Fibrocytes may participate in the pathogenesis of HP, amplifying the inflammatory and fibrotic response by paracrine signaling inducing the secretion of a variety of proinflammatory and profibrotic molecules.
Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy
Authors: Wei Gao, Heungnam Kim, Mingqian Feng, Yen Phung, Charles P. Xavier, Jeffrey S. Rubin, Mitchell Ho
Journal: Hepatology (2014)

Wnt signaling is important for cancer pathogenesis and is often up-regulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as coreceptors or modulators of Wnt activation. Glypican-3 (GPC3) is an HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors, and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/β-catenin signaling in these cells. Then we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and nonsulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/β-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/β-catenin signaling in HCC cells and had potent antitumor activity in vivo . Conclusion : An antibody directed against the heparan sulfate of a proteoglycan shows efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy. (Hepatology 2014;60:576–587)
Serum 25-hydroxyvitamin D levels and lung function in adults with asthma: the HUNT Study
Authors: Tricia L. Larose, Arnulf Langhammer, Yue Chen, Carlos A. Camargo, Pål Romundstad, Xiao-Mei Mai
Journal: European Respiratory Journal (2014)

The association between vitamin D status and lung function in adults with asthma remains unclear. We studied this cross-sectional association and possible modification by sex and allergic rhinitis in 760 adults (aged 19–55 years) with self-reported asthma in the Nord-Trøndelag Health Study. Serum 25-hydroxyvitamin D (25(OH)D) level &lt;50 nmol·L −1 was considered deficient. Lung function measurements included forced expiratory volume in 1 s (FEV 1 ) % predicted, forced vital capacity (FVC) % predicted and FEV 1 /FVC ratio. Multiple linear regression models were used to estimate adjusted regression coefficients (β) and 95% confidence intervals. 44% of asthma adults had serum 25(OH)D levels &lt;50 nmol·L −1 . Its associations with lung function measures seemed to be modified by sex and allergic rhinitis (p&lt;0.03 for three-way interaction term). Overall, a serum 25(OH)D level &lt;50 nmol·L −1 was not associated with lung function measurements in subjects with allergic rhinitis in this asthma cohort. In men with asthma but without allergic rhinitis, however, a serum 25(OH)D level &lt;50 nmol·L −1 was significantly associated with lower FEV 1 /FVC ratio (β=−8.60%; 95% CI: −16.95%– −0.25%). Low serum 25(OH)D level was not associated with airway obstruction in most asthma adults with the exception of men with asthma but without allergic rhinitis.
Oversized AAV Transductifon Is Mediated via a DNA-PKcs-independent, Rad51C-dependent Repair Pathway
Authors: Matthew L Hirsch, Chengwen Li, Isabella Bellon, Chaoying Yin, Sai Chavala, Marina Pryadkina, Isabelle Richard, Richard Jude Samulski
Journal: Molecular Therapy (2013)

A drawback of gene therapy using adeno-associated virus (AAV) is the DNA packaging restriction of the viral capsid (<4.7 kb). Recent observations demonstrate oversized AAV genome transduction through an unknown mechanism. Herein, AAV production using an oversized reporter (6.2 kb) resulted in chloroform and DNase-resistant particles harboring distinct "fragment" AAV (fAAV) genomes (5.0, 2.4, and 1.6 kb). Fractionation experiments determined that only the larger "fragments" mediated transduction in vitro, and relatively efficient transduction was also demonstrated in the muscle, the eye, and the liver. In contrast with concatemerization-dependent large-gene delivery by split AAV, fAAV transduction is independent of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in vitro and in vivo while disproportionately reliant on the DNA strand-annealing protein Rad51C. Importantly, fAAV's unique dependence on DNA repair proteins, compared with intact AAV, strongly suggests that the majority of oversized AAV transduction is mediated by fragmented genomes. Although fAAV transduction is less efficient than intact AAV, it is enhanced fourfold in muscle and sevenfold in the retina compared with split AAV transduction. Furthermore, fAAV carrying codon-optimized therapeutic dysferlin cDNA in a 7.5 kb expression cassette restored dysferlin levels in a dystrophic model. Collectively, oversized AAV genome transduction requires unique DNA repair pathways and offers an alternative, more efficient strategy for large-gene therapy.
Benefits, Harms, and Cost-Effectiveness of Supplemental Ultrasonography Screening for Women With Dense Breasts
Authors: Brian L. Sprague, Natasha K. Stout, Clyde Schechter, Nicolien T. van Ravesteyn, Mucahit Cevik, Oguzhan Alagoz, Christoph I. Lee, Jeroen J. van den Broek, Diana L. Miglioretti, Jeanne S. Mandelblatt, Harry J. de Koning, Karla Kerlikowske, Constance D. Lehman, Anna N.A. Tosteson
Journal: Annals of Internal Medicine (2014)

Many states have laws requiring mammography facilities to tell women with dense breasts and negative results on screening mammography to discuss supplemental screening tests with their providers. The most readily available supplemental screening method is ultrasonography, but little is known about its effectiveness.To evaluate the benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts.Comparative modeling with 3 validated simulation models.Surveillance, Epidemiology, and End Results Program; Breast Cancer Surveillance Consortium; and medical literature.Contemporary cohort of women eligible for routine screening.Lifetime.Payer.Supplemental ultrasonography screening for women with dense breasts after a negative screening mammography result.Breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, biopsies recommended after a false-positive ultrasonography result, and costs.Supplemental ultrasonography screening after a negative mammography result for women aged 50 to 74 years with heterogeneously or extremely dense breasts averted 0.36 additional breast cancer deaths (range across models, 0.14 to 0.75), gained 1.7 QALYs (range, 0.9 to 4.7), and resulted in 354 biopsy recommendations after a false-positive ultrasonography result (range, 345 to 421) per 1000 women with dense breasts compared with biennial screening by mammography alone. The cost-effectiveness ratio was $325,000 per QALY gained (range, $112,000 to $766,000). Supplemental ultrasonography screening for only women with extremely dense breasts cost $246,000 per QALY gained (range, $74,000 to $535,000).The conclusions were not sensitive to ultrasonography performance characteristics, screening frequency, or starting age.Provider costs for coordinating supplemental ultrasonography were not considered.Supplemental ultrasonography screening for women with dense breasts would substantially increase costs while producing relatively small benefits.National Cancer Institute.
CONTROLLING THE CHRONICALLY DISTURBED PATIENT WITH MASSIVE PHENOTHIAZINE THERAPY
Authors: ROBIE T. CHILDERS
Journal: American Journal of Psychiatry (1961)

The successful management of an acutely disturbed ward rests in the control of the chronically disturbed and combative patients. A regimen utilizing an average 700 mg. Throzine (or equivalent ) daily resulted in marked improvement in the behaviour and ajustment of 8 "hard core" refactory patients. Multiple attempts by other means had failed to elicit a sustained improvement. An extremealy low incidence of side effects was encountered. The question of control of difficult patient is usually : 1. Which tranquilizer; 2. In what dosage; 3. Over what period of time.
Mismatch in elastic properties around anastomoses of interposition grafts for hemodialysis access.
Authors: L Hofstra, D C Bergmans, A P Hoeks, P J Kitslaar, K M Leunissen, J H Tordoir
Journal: Journal of the American Society of Nephrology (1994)

Arteriovenous (AV) fistulas for hemodialysis access, constructed with the use of interposition grafts, are often complicated by intimal hyperplastic stenosis, mainly occurring at the venous anastomosis. In this study, mismatch in elastic properties around the arterial and venous anastomoses of graft AV fistulas in humans was quantified in order to find clues for the predisposition of intimal hyperplasia to develop at the venous anastomosis. The elastic properties of graft AV fistulas in 31 hemodialysis patients were investigated by the use of vessel wall Doppler tracking, 2 wk after construction. Nine saphenous vein grafts, 8 expanded polytetrafluoroethylene (ePTFE) grafts, and 14 stretch-PTFE (sPTFE) grafts were measured at the arterial inflow segment, the proximal graft segment, the distal graft segment, and the venous outflow segment. Area increase (AI), representing the capacity of the vessel wall to store blood volume, and relative distension, representing the intrinsic elastic properties, were calculated from diameter and distension. A decrease in AI was observed in the arterial anastomoses of all graft types. An increase in AI was found in the venous anastomosis of ePTFE and sPTFE grafts. Higher values for AI and relative distension were found at the proximal and distal graft segments of the saphenous vein grafts when compared with the prosthetic grafts. In the sPTFE grafts, the level of AI was maintained along the graft, whereas in the ePTFE grafts, a decrease in AI was found. In the arterial anastomoses of AV fistulas, a decline in the capacity to store blood volume was observed. By contrast, an increase in the capacity to store blood volume was found in the venous anastomoses.(ABSTRACT TRUNCATED AT 250 WORDS)
Genotype–Phenotype Correlation in X-Linked Alport Syndrome
Authors: Mir Reza Bekheirnia, Berenice Reed, Martin C. Gregory, Kim McFann, Alireza Abdollah Shamshirsaz, Amirali Masoumi, Robert W. Schrier
Journal: Journal of the American Society of Nephrology (2010)

Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P < 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5' end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3' end; P < 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5; end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.
U.S. Food and Drug Administration Approval: Panitumumab for Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Carcinoma with Progression Following Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Containing Chemotherapy Regimens
Authors: Ruthann M. Giusti, Kaushikkumar Shastri, Anne M. Pilaro, Chana Fuchs, Ruth Cordoba-Rodriguez, Kallappa Koti, Mark Rothmann, Angela Yuxin Men, Hong Zhao, Monica Hughes, Patricia Keegan, Karen D. Weiss, Richard Pazdur
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To describe the Food and Drug Administration review and marketing approval considerations for panitumumab (Vectibix) for the third-line treatment of patients with epidermal growth factor receptor–expressing metastatic colorectal carcinoma. Experimental Design: Food and Drug Administration reviewed a single, open-label, multicenter trial in which 463 patients with epidermal growth factor receptor–expressing metastatic colorectal cancer who had progressed on or following treatment with a regimen containing a fluoropyrimidine, oxaliplatin, and irinotecan were randomized (1:1) to receive best supportive care (BSC) with or without panitumumab (6 mg/kg every other week) administered until disease progression or intolerable toxicity. Progression and response were confirmed by an independent review committee masked to treatment assignment. At progression, patients in the BSC-alone arm were eligible to receive panitumumab. Results: Although median progression-free survival (PFS) was similar in both treatment arms (∼8 weeks), the mean PFS was ∼50% longer among patients receiving panitumumab than among those receiving BSC alone (96 versus 60 days, respectively) and the objective response rate in patients receiving panitumumab was 8%. However, no difference in overall survival was shown between the two study arms. Conclusions: Panitumumab received accelerated approval based on improvement in PFS and an independently confirmed response rate of 8%, similar to that observed with other active agents at this advanced stage of disease. Confirmation of clinical benefit will be required for full approval.
Gastric, haematological, and immunological abnormalities in Hashimoto's thyroiditis.
Authors: K F Schiller, L M Snyder, M B Vallotton
Journal: Gut (1967)

EDITORIAL COMMENT Reduced gastric acidity and intrinsic factor production are common in Hashimoto's thyroiditis.This cannot be explained on the basis of changes with age but may be related to the presence of gastric parietal cell antibodies in the blood.
Effectiveness of First-Line Management Strategies for Stage I Follicular Lymphoma: Analysis of the National LymphoCare Study
Authors: Jonathan W. Friedberg, Michelle Byrtek, Brian K. Link, Christopher Flowers, Michael Taylor, John Hainsworth, James R. Cerhan, Andrew D. Zelenetz, Jamie Hirata, Thomas P. Miller
Journal: Journal of Clinical Oncology (2012)

Purpose The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT). Patients and Methods We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database. Results Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival. Conclusion In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.
Whose proton pumps are we inhibiting? a study of PPI prescribing in primary care in east glasgow
Authors: J. W. Winter, M. Sandle, U. McLeod, K. Grosset
Journal: Gut (2011)

<h3>Introduction</h3> Proton pump inhibitors (PPIs) are one of the most frequently prescribed classes of drug in the world, and their use has doubled in the last 8 years. Although highly effective in the management of peptic oesophagitis and ulcer disease, they are being increasingly employed for diverse indications, and studies have demonstrated that 25–70% of prescriptions are possibly inappropriate. Although generally regarded as safe, concerns have been raised regarding potential hazard, including possibly harmful interactions with cardiovascular medications. Furthermore, rebound acid hypersecretion following PPI use has been shown to induce the symptoms that these drugs are designed to treat. We aimed to review the characteristics of patients prescribed PPI in a primary care population. <h3>Methods</h3> Data was obtained from all patients in one GP practice who had been started on a PPI in 2008 who had no prior PPI use in the previous year. Computerised records of prescription and patient encounters, and correspondence with secondary care were analysed. Patients receiving PPI as part of eradication therapy for H pylori were excluded. <h3>Results</h3> 1292 patients (15% of practice population) were prescribed a PPI in 2008. 418 of these patients (4.8% of practice population) had not received a PPI in the previous year. 268/418 (64%) had never previously received PPI therapy. 80% of prescriptions were initiated in primary care and twenty different indications were recorded. The commonest documented indications were gastro-protection in NSAID use (20%), dyspepsia (18%) and reflux disease (16%). 44/418 (10.5%) patients were prescribed PPI for unlicensed indications and in 66/418 (16%) no indication was discernible. 48/81(59%) of patients prescribed a PPI with NSAID therapy had no risk factors for ulcer disease. 347/418 (83%) of patients received PPI on acute prescription and 4% of these patients remained on repeat prescription for PPI 2 years later. <h3>Conclusion</h3> PPI prescribing in primary care is highly prevalent and most commonly initiated by GPs. A quarter of patients received PPIs for unlicensed or unknown indications, and this was commonest for prescriptions initiated in hospital. Gastro-oesophageal reflux disease accounted for only 16% of prescriptions. The single commonest indication for PPI was gastro-protection in NSAID therapy, but most patients in this category had no evidence of risk factors for NSAID enteropathy. Despite the high incidence of PPI prescribing, prevalence of continued use at 2 years in this cohort was low.
Upregulation of junctional adhesion molecule-A is a putative prognostic marker of hypertension
Authors: Haibo Xu, Elizabeth B. Oliveira-Sales, Fiona McBride, Beihui Liu, James Hewinson, Marie Toward, Emma B. Hendy, Delyth Graham, Anna F. Dominiczak, Monica Giannotta, Hidefumi Waki, Raimondo Ascione, Julian F.R. Paton, Sergey Kasparov
Journal: Cardiovascular Research (2012)

AimsEstablishing biochemical markers of pre-hypertension and early hypertension could help earlier diagnostics and therapeutic intervention. We assess dynamics of junctional adhesion molecule-A (JAM-A) expression in rat models of hypertension and test whether JAM-A expression could be driven by angiotensin (ANG) II and whether JAM-A contributes to the progression of hypertension. We also compare JAM-A expression in normo- and hypertensive humans.