tbuckley/cabot-search huggingface dataset:
Treatment of imported malaria in an ambulatory setting: prospective study * Commentary: Should patients with imported malaria routinely be admitted?
Authors: V. D'Acremont
Journal: BMJ (2002)

<h3>Abstract</h3> Plant pathogenic <i>Ralstonia</i> cause wilt diseases by colonizing xylem vessels and disrupting water transport. Due to the abundance of <i>Ralstonia</i> cells in vessels, the dogma is that bacterial biomass clogs vessels and reduces the flow of xylem sap. However, the physiological mechanism of xylem disruption during bacterial wilt disease is untested. Using a tomato and <i>Ralstonia pseudosolanacearum</i> GMI1000 model, we visualized and quantified the spatiotemporal dynamics of xylem disruption during bacterial wilt disease. First, we measured stomatal conductance of leaflets on mock-inoculated and wilt-symptomatic plants. Wilted leaflets had reduced stomatal conductance, as did turgid leaflets located on the same petiole as wilted leaflets. Next, we used X-ray microcomputed tomography (X-ray microCT) and light microscopy to differentiate between mechanisms of xylem disruption: blockage by bacterial biomass, blockage by vascular tyloses, or sap displacement by gas embolisms. We imaged stems on plants with intact roots and leaves to quantify embolized vessels. Embolized vessels were rare, but there was a slight trend of increased vessel embolisms in infected plants with low bacterial population sizes. To test the hypothesis that vessels are clogged during bacterial wilt, we imaged excised stems after allowing the sap to evaporate during a brief dehydration. Most xylem vessels in mock-infected plants emptied their contents after excision, but non-conductive clogged vessels were abundant in infected plants by 2 days post infection. At wilt onset when bacterial populations exceeded 5×10<sup>8</sup> cfu/g stem tissue, approximately half of the xylem vessels were clogged with electron-dense bacterial biomass. We found no evidence of tyloses in the X-ray microCT reconstructions or light microscopy on the preserved stems. Bacterial blockage of vessels appears to be the principal cause of vascular disruption during <i>Ralstonia</i> wilt.
Rituximab Treatment of Patients with Severe, Corticosteroid-Resistant Thyroid-Associated Ophthalmopathy
Authors: Dinesh Khanna, Kelvin K.L. Chong, Nikoo F. Afifiyan, Catherine J. Hwang, Diana K. Lee, Helene Chokron Garneau, Robert A. Goldberg, Christine H. Darwin, Terry J. Smith, Raymond S. Douglas
Journal: Ophthalmology (2009)
<i>CHEK2</i>-Positive Breast Cancers in Young Polish Women
Authors: Cezary Cybulski, Bohdan Górski, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Tadeusz Dębniak, Dominika Wokołorczyk, Anna Jakubowska, Elżbieta Kowalska, Oleg Oszurek, Steven A. Narod, Jan Lubiński
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To investigate the contribution of CHEK2 mutations to early-onset breast cancer in Poland and to establish the characteristic features of these cancers. Experimental Design: We studied 3,228 women diagnosed with breast cancer under the age of 51 years and 5,496 population controls. CHEK2 mutations were detected by RFLP-PCR or allele-specific oligonucleotide-PCR assays. Clinical and pathologic features of CHEK2-positive cases and CHEK2-negative cases were compared. Results: A truncating CHEK2 mutation (1100delC or IVS2+1G&amp;gt;A) was seen in 47 of 3,228 cases and in 34 of 5,496 controls (odds ratio, 2.4; P = 0.0001). The CHEK2 I157T missense mutation was present in 207 of 3,228 cases, compared with 264 of 5,496 controls (odds ratio, 1.4; P = 0.002). Breast cancers in women with a CHEK2 mutation were more commonly of lobular histology (21.5% versus 15.8%; P = 0.05), of size &amp;gt;2 cm (54.8% versus 43.5%; P = 0.01), or of multicentric origin (28.7% versus 19.5%; P = 0.01) than were cancers from women without a CHEK2 mutation. Bilateral cancers were equally common in both subgroups. Conclusion: Three founder alleles in CHEK2 contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of CHEK2 mutations seem to be similar to those of breast cancers in the population at large.
Loss in Chromosome 11q Identifies Tumors with Increased Risk for Metastatic Relapses in Localized and 4S Neuroblastoma
Authors: Ruediger Spitz, Barbara Hero, Thorsten Simon, Frank Berthold
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To improve risk prediction in neuroblastoma and to specify the type of a possible relapse, alterations in the long arm of chromosome 11 were analyzed. Experimental Design: A representative cohort of 611 neuroblastomas was investigated for deletion events in distal chromosome 11q using interphase fluorescence in situ hybridization. Results: Alterations in 11q were found in 159 of 611 tumors in the whole cohort (26%) and were associated with stage 4 disease (P &amp;lt; 0.001) and age at diagnosis of &amp;gt;2.5 years (P &amp;lt; 0.001). Event-free survival and overall survival were significantly poorer for patients with 11q loss in the whole cohort (event-free survival and overall survival, P &amp;lt; 0.001) and in different subsets: neuroblastoma without MYCN amplification (MNA) (event-free survival and overall survival, P &amp;lt; 0.001), with MNA (event-free survival, P = 0.03; overall survival, P = 0.02), and MYCN-nonamplified stage 1, 2, 3, and 4S tumors with and without del 1p (event-free survival and overall survival, P &amp;lt; 0.001). In stage 4, the 11q status did not discriminate outcome. By multivariate analysis, the 11q status proved prognostic for event-free survival in the whole cohort (P = 0.008; hazard ratio, 1.573) and in the subgroup of stages 1, 2, 3, and 4S without MNA (P &amp;lt; 0.001; hazard ratio, 3.534). Moreover, 11q alterations were strongly correlated with the occurrence of metastatic relapses (P &amp;lt; 0.001). Conclusion: In addition to the current risk stratification, the status of 11q enables the identification of patients with an increased risk for relapses in general and metastatic relapses in particular.
ALTERATION OF RESISTANCE OF THE RAT TO TUBERCULOSIS WHEN MAINTAINED ON AN ATHEROGENIC DIET
Authors: Richard L. Costello, Loyd W. Hedgecock, Tom R. Hamilton
Journal: The Journal of Experimental Medicine (1962)

Albino rats maintained for 50 to 60 days on rations containing cholesterol, sodium cholate, and thiouracil were found to be highly susceptible to the lethal effects of infection with Mycobacterium tuberculosis. Maximum loss of resistance occurred only when all three components were present in a single ration. A lesser degree of susceptibility resulted from the deletion of one or more of the factors from the diet. Animals maintained on control rations never died of the infection. Histopathological studies of stained sections of tissues of infected animals revealed that the reaction of the host to the bacillus was more extensive and less well contained in animals fed the complete atherogenic ration than in the controls.
Prognostic Value of Desaturation during a 6-Minute Walk Test in Idiopathic Interstitial Pneumonia
Authors: Vibha N. Lama, Kevin R. Flaherty, Galen B. Toews, Thomas V. Colby, William D. Travis, Qi Long, Susan Murray, Ella A. Kazerooni, Barry H. Gross, Joseph P. Lynch, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.
Racial/Ethnic Differences in Inpatient Palliative Care Consultation for Patients With Advanced Cancer
Authors: Rashmi K. Sharma, Kenzie A. Cameron, Joan S. Chmiel, Jamie H. Von Roenn, Eytan Szmuilowicz, Holly G. Prigerson, Frank J. Penedo
Journal: Journal of Clinical Oncology (2015)

Purpose Inpatient palliative care consultation (IPCC) may help address barriers that limit the use of hospice and the receipt of symptom-focused care for racial/ethnic minorities, yet little is known about disparities in the rates of IPCC. We evaluated the association between race/ethnicity and rates of IPCC for patients with advanced cancer. Patients and Methods Patients with metastatic cancer who were hospitalized between January 1, 2009, and December 31, 2010, at an urban academic medical center participated in the study. Patient-level multivariable logistic regression was used to evaluate the association between race/ethnicity and IPCC. Results A total of 6,288 patients (69% non-Hispanic white, 19% African American, and 6% Hispanic) were eligible. Of these patients, 16% of whites, 22% of African Americans, and 20% of Hispanics had an IPCC (overall P &lt; .001). Compared with whites, African Americans had a greater likelihood of receiving an IPCC (odds ratio, 1.21; 95% CI, 1.01 to 1.44), even after adjusting for insurance, hospitalizations, marital status, and illness severity. Among patients who received an IPCC, African Americans had a higher median number of days from IPCC to death compared with whites (25 v 17 days; P = .006), and were more likely than Hispanics (59% v 41%; P = .006), but not whites, to be referred to hospice. Conclusion Inpatient settings may neutralize some racial/ethnic differences in access to hospice and palliative care services; however, irrespective of race/ethnicity, rates of IPCC remain low and occur close to death. Additional research is needed to identify interventions to improve access to palliative care in the hospital for all patients with advanced cancer.
Inconsistencies in Estimating the Age of HIV-1 Subtypes Due to Heterotachy
Authors: J. O. Wertheim, M. Fourment, S. L. Kosakovsky Pond
Journal: Molecular Biology and Evolution (2011)

Rate heterogeneity among lineages is a common feature of molecular evolution, and it has long impeded our ability to accurately estimate the age of evolutionary divergence events. The development of relaxed molecular clocks, which model variable substitution rates among lineages, was intended to rectify this problem. Major subtypes of pandemic HIV-1 group M are thought to exemplify closely related lineages with different substitution rates. Here, we report that inferring the time of most recent common ancestor of all these subtypes in a single phylogeny under a single (relaxed) molecular clock produces significantly different dates for many of the subtypes than does analysis of each subtype on its own. We explore various methods to ameliorate this problem. We conclude that current molecular dating methods are inadequate for dealing with this type of substitution rate variation in HIV-1. Through simulation, we show that heterotachy causes root ages to be overestimated.
Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance
Authors: Pei-Yin Lin, Susan P Fosmire, See-Hyoung Park, Jin-Young Park, Shairaz Baksh, Jaime F Modiano, Robert H Weiss
Journal: Molecular Cancer (2007)

Abstract Background The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN . While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (~90% in metastatic cases), and these tumors frequently contain PTEN abnormalities. Results Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.
PROGNOSTIC MODEL OF RESIDUAL RISK FOR MAJOR CARDIOVASCULAR EVENTS IN STATIN-TREATED CORONARY PATIENTS: A COMBINED ANALYSIS OF THE IDEAL AND TNT TRIALS
Authors: Ingar Holme, Ole Faergeman, Rana Fayyad, Chuan-Chuan Wun, John Kastelein, Anders Olsson, Matti Tikkanen, Mogens Larsen, Christina Lindahl, Terje Pedersen, Matthijs Boekholdt, Nanette Wenger, Phillip Barter
Journal: Journal of the American College of Cardiology (2012)
Molecular Imaging Insights Into Early Inflammatory Stages of Arterial and Aortic Valve Calcification
Authors: Sophie E.P. New, Elena Aikawa
Journal: Circulation Research (2011)

Traditional imaging modalities such as computed tomography, although perfectly adept at identifying and quantifying advanced calcification, cannot detect the early stages of this disorder and offer limited insight into the mechanisms of mineral dysregulation. This review presents optical molecular imaging as a promising tool that simultaneously detects pathobiological processes associated with inflammation and early stages of calcification in vivo at the (sub)cellular levels. Research into treatment of cardiovascular calcification is lacking, as shown by clinical trials that have failed to demonstrate the reduction of calcific aortic stenosis. Hence, the need to elucidate the pathways that contribute to cardiovascular calcification and to develop new therapeutic strategies to prevent or reverse calcification has driven investigations into the use of molecular imaging. This review discusses studies that have used molecular imaging methods to advance knowledge of cardiovascular calcification, focusing in particular on the inflammation-dependent mechanisms of arterial and aortic valve calcification.
266RBM20-dependent regulation of organized myofilament structure and titin splicing in induced pluripotent stem cell-derived cardiomyocytes from patients with dilative cardiomyopathy
Authors: K Streckfuss-Boemeke, C Fischer, M Stauske, A Perret, C Oezcelic, S Wagner, L Maier, G Hasenfuss, K Guan
Journal: Cardiovascular Research (2014)

Purpose: The ability to generate patient-specific human induced pluripotent stem cells (ps-iPSCs) provides a unique opportunity for modeling heart disease. Dilated cardiomyopathy (DCM) is due to a progressive enlargement of the heart leading finally to heart failure. Mutations in many genes have been implicated in the pathogenesis of DCM including the RNA-binding motif 20 (RBM20). We aimed to generate iPSCs from DCM patients with a RBM20 mutations, and to analyze the functionality and cell biology of cardiomyocytes derived from these ps-iPSCs (ps-iPSC-CM) with regard to the cardiac DCM phenotype. Methods and Results: Dermal fibroblasts from two patients (34y; 75y) with DCM harboring different RBM20 mutations were reprogrammed to ps-iPSCs via lentiviral infection using the STEMCCA system. The ps-iPSCs show pluripotent characteristics by expressing pluripotency markers on mRNA and protein level similar to human embryonic stem cells. Furthermore, bisulfite sequencing analysis showed that the OCT4 and NANOG promoters were significantly demethylated in ps-iPSCs compared to their parental cells. In addition, the generated RBM20-iPSCs are able to differentiate in vitro and in vivo into derivatives of all three germ layers. The cardiac in vitro differentiation efficiency into beating cardiomyocytes of the RBM20-iPSCs is similar to control iPSCs. Electrophysiological studies showed that under basal conditions ps-iPSC-CM exhibited spontaneous action potentials characteristic for pacemaker-, atrial-, ventricular- and Purkinje-like cells in a similar manner as control iPSC-CM. Using Fast Fourier Transformation the sarcomere-associated periodic signal amplitude was analyzed for α-actinin. A significant higher percentage of RBM20-iPSC-CM showed abnormal sarcomeric α-actinin distribution compared to control CM, suggesting disorganized myofilament structure. But no significant difference was observed in cell size between RBM20-iPSC-CMs and control cells. Further, we found a different isoform expression pattern of the cardiac titin in the mutant ps-iPSC-CM compared to the control cells. This demonstrates a RBM20-dependent regulation of organized myofilament structure and titin splicing in an in vitro ps-DCM-iPSC-model. Conclusion: We demonstrate that iPSC-derived cardiomyocytes from young and old DCM patients harboring a RBM20 mutation recapitulate the abnormalities that were found in individuals with DCM caused by the same mutation. The differentiated cardiomyocytes may be used for individual drug testing and development of novel treatments for this inherited disorder.
Abstract 1787: Identification of factors governing sensitivity of NSCLC cell lines to inhibition of Poly (ADP-Ribose) Polymerase (PARP).
Authors: Naveen Kommajosyula, Ye Cao, Lisa Moreau, Alan D'Andrea, Geoffrey I. Shapiro
Journal: Cancer Research (2013)

Abstract PARP inhibitors are emerging as important new anticancer agents, especially in cancers defective in homologous recombination (HR) repair, such as those lacking BRCA1 or BRCA2. To date, the potential role of PARP inhibition in NSCLC has not been extensively studied. As previously reported, we examined a panel of 26 genotypically-defined NSCLC cell lines for sensitivity to the PARP-1 inhibitor AG014699 (rucaparib) using colony formation assays. We identified 5 cell lines that are exquisitely sensitive (IC50 ≈ 50nM), 9 cell lines that are moderately sensitive (IC50 ≈ 60-500nM) and 12 cell lines that are resistant (IC50 &amp;gt; 5 μM). These data were confirmed with a second PARP inhibitor, AZD2281 (Olaparib). To determine whether sensitive cell lines have defective HR compared to resistant cell lines, we examined the formation of RAD51 foci. Both sensitive and resistant cell lines demonstrated efficient formation of RAD51 foci as well as gamma-H2AX foci in response to DNA damaging treatments, indicating correct initiation of HR. In resistant cell lines, the repair process following PARP inhibition is completed within 24 hours, with resolution of RAD51 and gamma-H2AX foci. However, in sensitive cell lines, these foci persist greater than 30 hours following DNA damaging treatments. These results suggest that although sensitive lines are able to initiate HR repair, they are unable to complete the process, so that RAD51 foci are not resolved. The persistence of DNA damage in these cell lines is confirmed by persistent gamma-H2AX focus formation as well as S/G2 arrest, the latter representing intact checkpoint control. Our results suggest that proteins required downstream of RAD51, including helicases and Holliday junction resolvases, are lacking in the sensitive lines. Consistent with this hypothesis, NCI-H520 cells, a highly PARP inhibitor-sensitive cell line, lacks expression of WRN, RECQL4 and RECQL5. siRNA-mediated depletion of these proteins individually sensitizes the resistant A549 cell line to PARP inhibition, with reduction in rucaparib IC50 by 100 fold. Our results may define a novel subset of NSCLCs with a late-step defect in HR that can be approached with PARP inhibition as a novel treatment strategy. Citation Format: Naveen Kommajosyula, Ye Cao, Lisa Moreau, Alan D'Andrea, Geoffrey I. Shapiro. Identification of factors governing sensitivity of NSCLC cell lines to inhibition of Poly (ADP-Ribose) Polymerase (PARP). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1787. doi:10.1158/1538-7445.AM2013-1787
Neuromuscular function of the human lower oesophageal sphincter in reflux disease and Barrett's oesophagus
Authors: S D Smid
Journal: Gut (2000)

<h3>BACKGROUND</h3> Columnar lined (Barrett9s) oesophagus is often considered a sequel to chronic severe reflux disease. Aberrant lower oesophageal sphincter (LOS) motility associated with Barrett9s oesophagus includes reduced basal LOS pressures. The aim of this study was to characterise neuromuscular function of the LOS in normal (squamous cell carcinoma (SCC) with uninvolved LOS) and reflux affected (Barrett9s) oesophagus in vitro. <h3>METHODS</h3> Strips of LOS muscle were prepared at biopsy following oesophagectomy from 16 patients with SCC and seven patients with oesophageal adenocarcinoma and Barrett9s oesophagus associated with a history of reflux disease. LOS smooth muscle responses were recorded in response to electrical field stimulation (EFS), potassium chloride (KCl), DMPP, isoprenaline, capsaicin, bethanechol, and tachykinins. <h3>RESULTS</h3> Basal LOS tone and LOS relaxations in response to isoprenaline, EFS, and DMPP were not significantly altered in the Barrett9s group. After tetrodotoxin pretreatment, responses to KCl and DMPP were significantly reduced in the SCC but not in Barrett9s LOS. Maximal contraction in response to bethanechol was significantly decreased in Barrett9s LOS while substance P and NK-2 receptor mediated contraction was unaltered. Capsaicin, NK-1, and NK-3 receptor agonists exerted negligible effects on LOS tone. <h3>CONCLUSIONS</h3> LOS muscle strips from patients with reflux associated Barrett9s oesophagus exhibit a reduction in cholinergic muscle contraction while retaining similar features of basal tone, responses to tachykinins, and inhibitory muscle and neural function. Enteric inhibitory neurones in LOS muscle strips from patients with reflux associated Barrett9s oesophagus display resistance to axonal sodium channel blockade. No evidence for functional NK-1 or NK-3 receptors or capsaicin sensitive axon collateral reflexes was observed in the human LOS.