tbuckley/cabot-search huggingface dataset:
Acute spontaneous tumor lysis syndrome
Authors: Andrzej M. Jasek, H. James Day
Journal: American Journal of Hematology (1994)

Abstract An 83‐year‐old woman with no previous history of malignancy was admitted to our institution with weakness and anemia and subsequently developed acute tumor lysis syndrome secondary to newly diagnosed Burkitt's leukemia/lymphoma. This syndrome has been previously described in patients with hematologic malignancies; however, its development has been related to the administration of chemotherapy, steroids, or radiotherapy. The spontaneous occurrence of tumor lysis syndrome has not been previously reported; however, Cohen et al. [ Am J Med 58:486–491, 1980] report 8 of 37 patients with “clinically insignificant pretreatment derangements” of serum potassium, phosphate, and calcium. © 1994 Wiley‐Liss, Inc.
Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B <sub>2</sub> Kinin Receptor Gene Knockout Mice
Authors: Xiao-Ping Yang, Yun-He Liu, Dharmesh Mehta, Maria A. Cavasin, Edward Shesely, Jiang Xu, Fang Liu, Oscar A. Carretero
Journal: Circulation Research (2001)

Abstract —Using B 2 kinin receptor gene knockout mice (B 2 −/− ), we tested the hypothesis that (l) lack of B 2 receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT 1 -ant), whereas lack of B 2 receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B 2 −/− and 129/SvEvTac mice (wild-type control, B 2 +/+ ). An ACEi (ramipril, 2.5 mg/kg/d) or AT 1 -ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B 2 +/+ and B 2 −/− mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B 2 −/− mice (respective values for B 2 +/+ versus B 2 −/− mice: overall increase in ejection fraction, 64±10% versus 21±5% [ P &lt;0.01]; increase in CO, 69±17% versus 23±9% [ P &lt;0.01]; overall decrease in LVDd, −24±3% versus −7±4% [ P &lt;0.01]; and decrease in LV mass, −38±3% versus −6±6% [ P &lt;0.01]). AT 1 -ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B 2 −/− mice (respective values for B 2 +/+ versus B 2 −/− mice: overall increase in ejection fraction, 46±10% versus 25±9% [ P &lt;0.01]; increase in CO, 44±14% versus 15±5% [ P &lt;0.01]; overall decrease in LVDd, −14±4% versus −6±3% [ P &lt;0.01]; and decrease in LV mass, −33±4 versus −16±7% [ P &lt;0.01]). The effect of ACEi or AT 1 -ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B 2 −/− mice. We concluded that (1) lack of B 2 kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B 2 receptor play an important role in the cardioprotective effect of ACEi and AT 1 -ant.
Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific
Authors: Siew C Ng, Whitney Tang, Rupert W Leong, Minhu Chen, Yanna Ko, Corrie Studd, Ola Niewiadomski, Sally Bell, Michael A Kamm, H J de Silva, Anuradhani Kasturiratne, Yasith Udara Senanayake, Choon Jin Ooi, Khoon-Lin Ling, David Ong, Khean Lee Goh, Ida Hilmi, Qin Ouyang, Yu-Fang Wang, PinJin Hu, Zhenhua Zhu, Zhirong Zeng, Kaichun Wu, Xin Wang, Bing Xia, Jin Li, Pises Pisespongsa, Sathaporn Manatsathit, Satimai Aniwan, Marcellus Simadibrata, Murdani Abdullah, Steve W C Tsang, Tai Chiu Wong, Aric J Hui, Chung Mo Chow, Hon Ho Yu, Mo Fong Li, Ka Kei Ng, Jessica Ching, Justin C Y Wu, Francis K L Chan, Joseph J Y Sung
Journal: Gut (2014)

<h3>Objective</h3> The rising incidence of inflammatory bowel disease in Asia supports the importance of environmental risk factors in disease aetiology. This prospective population-based case-control study in Asia-Pacific examined risk factors prior to patients developing IBD. <h3>Design</h3> 442 incident cases (186 Crohn9s disease (CD); 256 UC; 374 Asians) diagnosed between 2011 and 2013 from eight countries in Asia and Australia and 940 controls (frequency-matched by sex, age and geographical location; 789 Asians) completed an environmental factor questionnaire at diagnosis. Unconditional logistic regression models were used to estimate adjusted ORs (aOR) and 95% CIs. <h3>Results</h3> In multivariate model, being breast fed &gt;12 months (aOR 0.10; 95% CI 0.04 to 0.30), antibiotic use (aOR 0.19; 0.07 to 0.52), having dogs (aOR 0.54; 0.35 to 0.83), daily tea consumption (aOR 0.62; 0.43 to 0.91) and daily physical activity (aOR 0.58; 0.35 to 0.96) decreased the odds for CD in Asians. In UC, being breast fed &gt;12 months (aOR 0.16; 0.08 to 0.31), antibiotic use (aOR 0.48; 0.27 to 0.87), daily tea (aOR 0.63; 0.46 to 0.86) or coffee consumption (aOR 0.51; 0.36 to 0.72), presence of hot water tap (aOR 0.65; 0.46 to 0.91) and flush toilet in childhood (aOR 0.71; 0.51 to 0.98) were protective for UC development whereas ex-smoking (aOR 2.02; 1.22 to 3.35) increased the risk of UC. <h3>Conclusions</h3> This first population-based study of IBD risk factors in Asia-Pacific supports the importance of childhood immunological, hygiene and dietary factors in the development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life.
Impact of Azacitidine Before Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes: A Study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies
Authors: Gandhi Damaj, Alain Duhamel, Marie Robin, Yves Beguin, Mauricette Michallet, Mohamad Mohty, Stephane Vigouroux, Pierre Bories, Alice Garnier, Jean El Cheikh, Claude-Eric Bulabois, Anne Huynh, Jacques-Olivier Bay, Faeyzeh Legrand, Eric Deconinck, Nathalie Fegueux, Laurence Clement, Charles Dauriac, Natacha Maillard, Jérôme Cornillon, Lionel Ades, Gaelle Guillerm, Aline Schmidt-Tanguy, Zora Marjanovic, Sophie Park, Marie-Thérèse Rubio, Jean-Pierre Marolleau, Federico Garnier, ierre Fenaux, Ibrahim Yakoub-Agha
Journal: Journal of Clinical Oncology (2012)

To investigate the impact of prior-to-transplantation azacitidine (AZA) on patient outcome after allogeneic stem-cell transplantation (alloSCT) for myelodysplastic syndrome (MDS).Of the 265 consecutive patients who underwent alloSCT for MDS between October 2005 and December 2009, 163 had received cytoreductive treatment prior to transplantation, including induction chemotherapy (ICT) alone (ICT group; n = 98), AZA alone (AZA group; n = 48), or AZA preceded or followed by ICT (AZA-ICT group; n = 17). At diagnosis, 126 patients (77%) had an excess of marrow blasts, and 95 patients (58%) had intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS). Progression to more advanced disease before alloSCT was recorded in 67 patients. Donors were sibling (n = 75) or HLA-matched unrelated (10/10; n = 88). They received blood (n = 142) or marrow (n = 21) grafts following either myeloablative (n = 33) or reduced intensity (n = 130) conditioning.With a median follow-up of 38.7 months, 3-year outcomes in the AZA, ICT, and AZA-ICT groups were 55%, 48%, and 32% (P = .07) for overall survival (OS); 42%, 44%, and 29% (P = .14) for event-free survival (EFS); 40%, 37%, and 36% (P = .86) for relapse; and 19%, 20%, and 35% (P = .24) for nonrelapse mortality (NRM), respectively. Multivariate analysis confirmed the absence of statistical differences between the AZA and the ICT groups in terms of OS, EFS, relapse, and NRM.With the goal of downstaging underlying disease before alloSCT, AZA alone led to outcomes similar to those for standard ICT.
Environmental Exposure to Lead and Progression of Chronic Renal Diseases
Authors: Chun-Chen Yu, Ja-Liang Lin, Dan-Tzu Lin-Tan
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Previous retrospective research suggests that low-level environmental lead exposure is associated with an acceleration of age-related impairment of renal function. For elucidating the long-term relationship between low-level environmental lead exposure and progression of chronic renal diseases in patients without diabetes, 121 patients who had chronic renal insufficiency, a normal body lead burden (BLB), and no history of exposure to lead were observed prospectively for 48 mo. Associations of both BLB and blood lead level (BLL) with renal function were evaluated, with reference to other covariates. The primary end point was an increase in the serum creatinine level to double the baseline value. Sixty-three patients had BLB ≥80 μg and <600 μg (high-normal group), and 58 patients had BLB <80 μg (low-normal group). The primary end point occurred in 17 patients. Fifteen of them had high-normal BLB, whereas two patients had low-normal BLB (hazard ratio [95% confidence interval]: 1.01 [1.00 to 1.01] for each increment of 1 μg; P = 0.002). The BLB and BLL at baseline were the most important risk factors to predict progression of renal insufficiency. Each increase of 10 μg in the BLB or 1 μg/dl in the BLL reduced the GFR by 1.3 (P = 0.002) or 4.0 ml/min (P = 0.01) during the study period. In conclusion, low-level environmental lead exposure is associated with accelerated deterioration of renal insufficiency. Even at levels far below the normal ranges, both increased BLL and BLB predict accelerated progression of chronic renal diseases.
Focal glomerulosclerosis and maximal glomerular hypertrophy in human nephronopenia.
Authors: D B Bhathena
Journal: Journal of the American Society of Nephrology (1996)

This study examines the relationship of the degree of glomerular hypertrophy in nephronopenia to the development of focal segmental glomerulosclerosis (FGS) in humans. To this end, group mean glomerular diameters in a variety of acquired and congenital nephronopenic states in native kidneys and long-surviving renal allografts with and without FGS were analyzed and compared. The results indicate that all groups of native nephronopenic kidneys without FGS develop significant and equivalent glomerular hypertrophy. By contrast, long-surviving renal allografts without FGS do not undergo glomerular hypertrophy. For groups with FGS, long-surviving renal homografts had a significantly smaller mean glomerular diameter when compared with any other group of native nephronopenic kidneys. There was no significant difference among group mean glomerular diameters of native nephronopenic kidneys with FGS. Pairwise comparisons in each category of nephronopenia indicated that, except in the groups with uninephrectomy, the mean glomerular diameters were significantly larger in those with FGS than without. These observations are interpreted to indicate that nephronopenic individuals with native kidneys, by undergoing glomerular hypertrophy, consume much or all their capacity for glomerular enlargement. This brings them closer to their maximal diameters at which FGS develops. Finally, long-surviving renal allografts without nephronopenic FGS do not undergo glomerular hypertrophy. However, when FGS develops in long-surviving allografts, it does so at glomerular diameters significantly smaller than in native nephronopenic kidneys, reflecting their decreased capacity to undergo glomerular hypertrophy, acquiring maximal diameters at a smaller dimension than native nephronopenic kidneys.
Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity of Non–Small-Cell Lung Carcinoma Cell Lines and Xenografts to Epidermal Growth Factor Receptor Inhibition
Authors: Stuart Thomson, Elizabeth Buck, Filippo Petti, Graeme Griffin, Eric Brown, Nishal Ramnarine, Kenneth K. Iwata, Neil Gibson, John D. Haley
Journal: Cancer Research (2005)

Abstract Treatment of second- and third-line patients with non–small-cell lung carcinoma (NSCLC) with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib significantly increased survival relative to placebo. Whereas patient tumors with EGFR mutations have shown responses to EGFR inhibitors, an exclusive role for mutations in patient survival benefit from EGFR inhibition is unclear. Here we show that wild-type EGFR–containing human NSCLC lines grown both in culture and as xenografts show a range of sensitivities to EGFR inhibition dependent on the degree to which they have undergone an epithelial to mesenchymal transition (EMT). NSCLC lines which express the epithelial cell junction protein E-cadherin showed greater sensitivity to EGFR inhibition in vitro and in xenografts. In contrast, NSCLC lines having undergone EMT, expressing vimentin and/or fibronectin, were insensitive to the growth inhibitory effects of EGFR kinase inhibition in vitro and in xenografts. The differential sensitivity of NSCLC cells with epithelial or mesenchymal phenotypes to EGFR inhibition did not correlate with cell cycle status in vitro or with xenograft growth rates in vivo, or with total EGFR protein levels. Cells sensitive to EGFR inhibition, with an epithelial cell phenotype, did exhibit increased phosphorylation of EGFR and ErbB3 and a marked increase in total ErbB3. The loss of E-cadherin and deregulation of β-catenin associated with EMT have been shown to correlate with poor prognosis in multiple solid tumor types. These data suggest that EMT may be a general biological switch rendering non–small cell lung tumors sensitive or insensitive to EGFR inhibition.
A Novel Diagnostic Target in the Hepatitis C Virus Genome
Authors: Jan Felix Drexler, Bernd Kupfer, Nadine Petersen, Rejane Maria Tommasini Grotto, Silvia Maria Corvino Rodrigues, Klaus Grywna, Marcus Panning, Augustina Annan, Giovanni Faria Silva, Jill Douglas, Evelyn S. C Koay, Heidi Smuts, Eduardo M Netto, Peter Simmonds, Maria Inês de Moura Campos Pardini, W. Kurt Roth, Christian Drosten
Journal: PLoS Medicine (2009)

Detection and quantification of hepatitis C virus (HCV) RNA is integral to diagnostic and therapeutic regimens. All molecular assays target the viral 5'-noncoding region (5'-NCR), and all show genotype-dependent variation of sensitivities and viral load results. Non-western HCV genotypes have been under-represented in evaluation studies. An alternative diagnostic target region within the HCV genome could facilitate a new generation of assays.In this study we determined by de novo sequencing that the 3'-X-tail element, characterized significantly later than the rest of the genome, is highly conserved across genotypes. To prove its clinical utility as a molecular diagnostic target, a prototype qualitative and quantitative test was developed and evaluated multicentrically on a large and complete panel of 725 clinical plasma samples, covering HCV genotypes 1-6, from four continents (Germany, UK, Brazil, South Africa, Singapore). To our knowledge, this is the most diversified and comprehensive panel of clinical and genotype specimens used in HCV nucleic acid testing (NAT) validation to date. The lower limit of detection (LOD) was 18.4 IU/ml (95% confidence interval, 15.3-24.1 IU/ml), suggesting applicability in donor blood screening. The upper LOD exceeded 10(-9) IU/ml, facilitating viral load monitoring within a wide dynamic range. In 598 genotyped samples, quantified by Bayer VERSANT 3.0 branched DNA (bDNA), X-tail-based viral loads were highly concordant with bDNA for all genotypes. Correlation coefficients between bDNA and X-tail NAT, for genotypes 1-6, were: 0.92, 0.85, 0.95, 0.91, 0.95, and 0.96, respectively; X-tail-based viral loads deviated by more than 0.5 log10 from 5'-NCR-based viral loads in only 12% of samples (maximum deviation, 0.85 log10). The successful introduction of X-tail NAT in a Brazilian laboratory confirmed the practical stability and robustness of the X-tail-based protocol. The assay was implemented at low reaction costs (US$8.70 per sample), short turnover times (2.5 h for up to 96 samples), and without technical difficulties.This study indicates a way to fundamentally improve HCV viral load monitoring and infection screening. Our prototype assay can serve as a template for a new generation of viral load assays. Additionally, to our knowledge this study provides the first open protocol to permit industry-grade HCV detection and quantification in resource-limited settings.
Inhibition of IL-1<b>β</b> Improves Fatigue in Type 2 Diabetes
Authors: Claudia Cavelti-Weder, Romana Furrer, Cornelia Keller, Andrea Babians-Brunner, Alan M. Solinger, H. Gast, A. Fontana, Marc Y. Donath, Iris K. Penner
Journal: Diabetes Care (2011)

Several diseases including microbial infection, rheumatoid arthritis, multiple sclerosis, and cancer have been linked to fatigue. They all have in common an upregulation of cytokines, including interleukin (IL)-1β and tumor necrosis factor-α (TNF-α), which may interfere with clock gene functions (1). Increasing evidence associates type 2 diabetes with inflammatory processes characterized by elevated production of proinflammatory cytokines and infiltration of immune cells. Reducing IL-1 activity in prediabetes and diabetes improves insulin secretion, glycemic control, and markers of systemic inflammation (2–4). Given this background, we hypothesized that fatigue levels may be increased in type 2 diabetes and may be improved by IL-1β antagonism.

Within a placebo-controlled, double-blind study of IL-1β antagonism with a monoclonal anti–IL-1β …
Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo
Authors: Paramita Chakrabarty, Amanda Herring, Carolina Ceballos-Diaz, Pritam Das, Todd E Golde
Journal: Molecular Neurodegeneration (2011)

Fibrillar amyloid β (fAβ) peptide is the major component of Aβ plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of Aβ pathology in AD patients by increasing amyloidogenic processing of APP and promoting Aβ accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates Aβ pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on Aβ pathology in vivo, we explored the effect of murine Tumor Necrosis Factor α (mTNFα) in regulating Aβ accumulation. Recombinant adeno-associated virus serotype 1 (AAV2/1) mediated expression of mTNFα in the hippocampus of 4 month old APP transgenic TgCRND8 mice resulted in significant reduction in hippocampal Aβ burden. No changes in APP levels or APP processing were observed in either mTNFα expressing APP transgenic mice or in non-transgenic littermates. Analysis of Aβ plaque burden in mTNFα expressing mice showed that even after substantial reduction compared to EGFP expressing age-matched controls, the Aβ plaque burden levels of the former do not decrease to the levels of 4 month old unmanipulated mice. Taken together, our data suggests that proinflammatory cytokine expression induced robust glial activation can attenuate plaque deposition. Whether such an enhanced microglial response actually clears preexisting deposits without causing bystander neurotoxicity remains an open question.
Preclinical Profile of a Potent γ-Secretase Inhibitor Targeting Notch Signaling with <i>In vivo</i> Efficacy and Pharmacodynamic Properties
Authors: Leopoldo Luistro, Wei He, Melissa Smith, Kathryn Packman, Maria Vilenchik, Daisy Carvajal, John Roberts, James Cai, Windy Berkofsky-Fessler, Holly Hilton, Michael Linn, Alexander Flohr, Roland Jakob-Røtne, Helmut Jacobsen, Kelli Glenn, David Heimbrook, John F. Boylan
Journal: Cancer Research (2009)

Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way.
CPAP suppression of awake right-to-left shunting through patent foramen ovale in a patient with obstructive sleep apnoea
Authors: C Pinet
Journal: Thorax (2005)

The prevalence of an echocardiographically visible patent foramen ovale (PFO) is higher in patients with obstructive sleep apnoea syndrome (OSAS) than in normal controls. We report a patient who presented with OSAS and right-to-left shunting (RLS) through the PFO in whom the RLS disappeared after treatment for 1 week with nocturnal continuous positive airway pressure (CPAP). This case shows the role of OSA in generating an awake RLS through a PFO and its possible reversibility by CPAP. The mechanism of reversible awake RLS through PFO in OSAS is discussed.