tbuckley/cabot-search huggingface dataset:
Epigenetic reprogramming induces the expansion of cord blood stem cells
Authors: Pratima Chaurasia, David C. Gajzer, Christoph Schaniel, Sunita D’Souza, Ronald Hoffman
Journal: Journal of Clinical Investigation (2014)

Cord blood (CB) cells that express CD34 have extensive hematopoietic capacity and rapidly divide ex vivo in the presence of cytokine combinations; however, many of these CB CD34+ cells lose their marrow-repopulating potential. To overcome this decline in function, we treated dividing CB CD34+ cells ex vivo with several histone deacetylase inhibitors (HDACIs). Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune–deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.
Does the Manic/Mixed Episode Distinction in Bipolar Disorder Patients Run True Over Time?
Authors: Scott W. Woods, Roy Money, C. Bruce Baker
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors sought to determine whether the manic/mixed episode distinction in patients with bipolar disorder runs true over time. METHOD: Over an 11-year period, the observed distribution of manic and mixed episodes (N=1,224) for patients with three or more entries in the management information system of a community mental health center (N=241) was compared to the expected distribution determined by averaging 1,000 randomly generated simulations. RESULTS: Episodes were consistent (all manic or all mixed) in significantly more patients than would be expected by chance. CONCLUSIONS: These data suggest a pattern of diagnostic stability over time for manic and mixed episodes in patients with bipolar disorder. Careful prospective studies of this issue are needed.
Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial
Authors: Walter Stummer, Uwe Pichlmeier, Thomas Meinel, Otmar Dieter Wiestler, Friedhelm Zanella, Hans-Jürgen Reulen
Journal: The Lancet Oncology (2006)
Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France
Authors: T Lequerre, P Quartier, D Rosellini, F Alaoui, M De Bandt, O Mejjad, I Kone-Paut, M Michel, E Dernis, M Khellaf, N Limal, C Job-Deslandre, B Fautrel, X Le Loet, J Sibilia
Journal: Annals of the Rheumatic Diseases (2007)

Anakinra treatment has been reported to be effective in some patients with systemic-onset juvenile idiopathic arthritis (SoJIA) or adult-onset Still disease (AoSD).To assess the efficacy and the safety of anakinra treatment in SoJIA and AoSD.SoJIA and AoSD patients were treated with anakinra (1-2 mg/kg/day in children, 100 mg/day in adults); we analysed its effect on fever, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, numbers of swollen and tender joints, the assessment of disease activity (by physician and parent/patient) and pain (by parent/patient), and American College of Rheumatology (ACR) pediatric core set criteria for JIA activity.A total of 35 patients were included, 20 with SoJIA and 15 with AoSD. Their mean age (range) at the onset of treatment was 12.4 (3-23) and 38.1 (22-62) years, respectively; disease duration was 7.0 (1-16) and 7.8 (2-27) years, respectively. Active arthritis was present in all cases but one. Of the 20 SoJIA patients, 5 achieved ACR 50% improvement in symptoms (ACR50) response criteria at 6 months. Steroid dose had been decreased by 15% to 78% in 10 cases. A total of 11 of the 15 AoSD patients achieved at least a 50% improvement for all disease markers (mean follow-up: 17.5 (11-27) months). Steroids had been stopped in two cases and the dose was decreased by 45% to 95% in 12 patients. Two patients stopped anakinra due to severe skin reaction, and two patients due to infection: one visceral leishmaniasis and one varicella.Anakinra was effective in most AoSD patients, but less than half SoJIA patients achieved a marked and sustained improvement.
Cyclin-Dependent Kinase 5 Activity Controls Cell Motility and Metastatic Potential of Prostate Cancer Cells
Authors: Christopher J. Strock, Jong-In Park, Eric K. Nakakura, G. Steven Bova, John T. Isaacs, Douglas W. Ball, Barry D. Nelkin
Journal: Cancer Research (2006)

Abstract We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than one-fourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer. (Cancer Res 2006; 66(15): 7509-15) (Cancer Res 2006; 66(15): 7509-15)
Smooth Muscle Cells Orchestrate the Endothelial Cell Response to Flow and Injury
Authors: Mercedes Balcells, Jordi Martorell, Carla Olivé, Marina Santacana, Vipul Chitalia, Angelo A. Cardoso, Elazer R. Edelman
Journal: Circulation (2010)

Local modulation of vascular mammalian target of rapamycin (mTOR) signaling reduces smooth muscle cell (SMC) proliferation after endovascular interventions but may be associated with endothelial cell (EC) toxicity. The trilaminate vascular architecture juxtaposes ECs and SMCs to enable complex paracrine coregulation but shields SMCs from flow. We hypothesized that flow differentially affects mTOR signaling in ECs and SMCs and that SMCs regulate mTOR in ECs.SMCs and/or ECs were exposed to coronary artery flow in a perfusion bioreactor. We demonstrated by flow cytometry, immunofluorescence, and immunoblotting that EC expression of phospho-S6 ribosomal protein (p-S6RP), a downstream target of mTOR, was doubled by flow. Conversely, S6RP in SMCs was growth factor but not flow responsive, and SMCs eliminated the flow sensitivity of ECs. Temsirolimus, a sirolimus analog, eliminated the effect of growth factor on SMCs and of flow on ECs, reducing p-S6RP below basal levels and inhibiting endothelial recovery. EC p-S6RP expression in stented porcine arteries confirmed our in vitro findings: Phosphorylation was greatest in ECs farthest from intact SMCs in metal stented arteries and altogether absent after sirolimus stent elution.The mTOR pathway is activated in ECs in response to luminal flow. SMCs inhibit this flow-induced stimulation of endothelial mTOR pathway. Thus, we now define a novel external stimulus regulating phosphorylation of S6RP and another level of EC-SMC crosstalk. These interactions may explain the impact of local antiproliferative delivery that targets SMC proliferation and suggest that future stents integrate design influences on flow and drug effects on their molecular targets.
Validation of a Postresection Pancreatic Adenocarcinoma Nomogram for Disease-Specific Survival
Authors: Cristina R. Ferrone, Michael W. Kattan, James S. Tomlinson, Sarah P. Thayer, Murray F. Brennan, Andrew L. Warshaw
Journal: Journal of Clinical Oncology (2005)

Nomograms are statistically based tools that provide the overall probability of a specific outcome. They have shown better individual discrimination than the current TNM staging system in numerous patient tumor models. The pancreatic nomogram combines individual clinicopathologic and operative data to predict disease-specific survival at 1, 2, and 3 years from initial resection. A single US institution database was used to test the validity of the pancreatic adenocarcinoma nomogram established at Memorial Sloan-Kettering Cancer Center.The nomogram was created from a prospective pancreatic adenocarcinoma database that included 555 consecutive patients between October 1983 and April 2000. The nomogram was validated by an external patient cohort from a retrospective pancreatic adenocarcinoma database at Massachusetts General Hospital that included 424 consecutive patients between January 1985 and December 2003.Of the 424 patients, 375 had all variables documented. At last follow-up, 99 patients were alive, with a median follow-up time of 27 months (range, 2 to 151 months). The 1-, 2-, and 3-year disease-specific survival rates were 68% (95% CI, 63% to 72%), 39% (95% CI, 34% to 44%), and 27% (95% CI, 23% to 32%), respectively. The nomogram concordance index was 0.62 compared with 0.59 with the American Joint Committee on Cancer (AJCC) stage (P = .004). This suggests that the nomogram discriminates disease-specific survival better than the AJCC staging system.The pancreatic cancer nomogram provides more accurate survival predictions than the AJCC staging system when applied to an external patient cohort. The nomogram may aid in more accurately counseling patients and in better stratifying patients for clinical trials and molecular tumor analysis.
Symptom variability in patients with severe COPD: a pan-European cross-sectional study
Authors: R. Kessler, M.R. Partridge, M. Miravitlles, M. Cazzola, C. Vogelmeier, D. Leynaud, J. Ostinelli
Journal: European Respiratory Journal (2010)

In between exacerbations, chronic obstructive pulmonary disease (COPD) is usually regarded as a stable condition, but there is increasing recognition of variability in this state. This cross-sectional study assessed patients' perception of symptom variability. Participants were outpatients > 45 yrs old with COPD, current or ex-smokers, forced expiratory volume in 1 s (FEV₁) <50% predicted, FEV₁/forced vital capacity < 0.7 and no exacerbation leading to therapeutic intervention in the previous 3 months. Patients' perceptions of COPD symptoms and their impact on daily life activities were recorded. Alterations in therapy use in response to COPD worsening were also recorded. COPD symptoms were experienced by 2,258 (92.5%) out of 2,441 patients during the 7 days before interview. Breathlessness was the most common symptom (72.5%). Daily and/or weekly symptom variability was reported by 62.7% of symptomatic patients; the morning was the worst time of day. Factors associated with perception of variability of breathlessness included younger age, symptom severity and recruitment to the study by general practitioners. The perception of variability was significantly different between European countries or regions. Patient-perceived COPD symptoms vary over the day and the week, and impact on daily activities; morning being the worst time of day. The majority of patients appear not to adjust treatment when symptoms worsen.
Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited: Updated Results of the CAO/ARO/AIO-94 Trial
Authors: Emmanouil Fokas, Torsten Liersch, Rainer Fietkau, Werner Hohenberger, Tim Beissbarth, Clemens Hess, Heinz Becker, Michael Ghadimi, Karl Mrak, Susanne Merkel, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, Claus Rödel
Journal: Journal of Clinical Oncology (2014)

We previously described the prognostic impact of tumor regression grading (TRG) on the outcome of patients with rectal carcinoma treated with preoperative chemoradiotherapy (CRT) in the CAO/ARO/AIO-94 trial. Here we report long-term results after a median follow-up of 132 months.TRG after preoperative CRT was determined in 386 surgical specimens by the amount of viable tumor cells versus fibrosis, ranging from TRG 4 (no viable tumor cells) to TRG 0 (no signs of regression). Clinicopathologic parameters and TRG were correlated to the cumulative incidence of local recurrence, distant metastasis, and disease-free survival (DFS).Ten-year cumulative incidence of distant metastasis and DFS were 10.5% and 89.5% for patients with TRG 4 (complete regression), 29.3% and 73.6% for TRG 2 and 3 (intermediate regression), and 39.6% and 63% for TRG 0 and 1 (poor regression), respectively (P = .005 and P = .008, respectively). On multivariable analysis, residual lymph node metastasis (ypN+) and TRG were the only independent prognostic factors for cumulative incidence of distant metastasis (P < .001 and P = .035, respectively) and DFS (P < .001 and P = .039, respectively), whereas local recurrence was significantly affected by ypN status (P < .001) and lymphatic invasion (P = .026).Complete and intermediate tumor regressions were associated with improved long-term outcome in patients with rectal carcinoma after preoperative CRT independent of clinicopathologic parameters. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting.
Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression
Authors: Takashi Matsushita, Koichi Yanaba, Jean-David Bouaziz, Manabu Fujimoto, Thomas F. Tedder
Journal: Journal of Clinical Investigation (2008)

EAE is a mouse T cell–mediated autoimmune disease of the CNS used to model the human condition MS. The contributions of B cells to EAE initiation and progression are unclear. In this study, we have shown that EAE disease initiation and progression are differentially influenced by the depletion of B cells from mice with otherwise intact immune systems. CD20 antibody–mediated B cell depletion before EAE induction substantially exacerbated disease symptoms and increased encephalitogenic T cell influx into the CNS. Increased symptom severity resulted from the depletion of a rare IL-10–producing CD1dhiCD5+ regulatory B cell subset (B10 cells), since the adoptive transfer of splenic B10 cells before EAE induction normalized EAE in B cell–depleted mice. While transfer of regulatory B10 cells was maximally effective during early EAE initiation, they had no obvious role during disease progression. Rather, B cell depletion during EAE disease progression dramatically suppressed symptoms. Specifically, B cells were required for the generation of CD4+ T cells specific for CNS autoantigen and the entry of encephalitogenic T cells into the CNS during disease progression. These results demonstrate reciprocal regulatory roles for B cells during EAE immunopathogenesis. The therapeutic effect of B cell depletion for the treatment of autoimmunity may therefore depend on the relative contributions and the timing of these opposing B cell activities during the course of disease initiation and pathogenesis.
Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes
Authors: J. B. Kuemmerle-Deschner, E. Hachulla, R. Cartwright, P. N. Hawkins, T. A. Tran, B. Bader-Meunier, J. Hoyer, M. Gattorno, A. Gul, J. Smith, K. S. Leslie, S. Jimenez, S. Morell-Dubois, N. Davis, N. Patel, A. Widmer, R. Preiss, H. J. Lachmann
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> Longer-term effects of prolonged selective interleukin-1β blockade with canakinumab were evaluated in the largest cohort of cryopyrin-associated periodic syndrome (CAPS) patients studied to date. <h3>Methods</h3> Adult and paediatric CAPS patients (n=166, including canakinumab-naive and pretreated patients from previous studies) received canakinumab subcutaneously 150 mg or 2 mg/kg (≤40 kg) every 8 weeks for up to 2 years. Response and relapse was assessed using scores for disease activity, skin rash and C-reactive protein (CRP) and/or serum amyloid A (SAA) levels. <h3>Results</h3> Complete response was achieved in 85 of 109 canakinumab-naive patients (78%; 79/85 patients within 8 days, and five patients between days 10 and 21). Of 141 patients with an available relapse assessment, 90% did not relapse, their CRP/SAA levels normalised (&lt;10 mg/l) by day 8, and remained in the normal range thereafter. Median treatment duration was 414 days (29–687 days). Upward adjustments of dose or frequency were needed in 24.1% patients; mostly children and those with severe CAPS. Predominant adverse events (AE) were infections (65.7%) of mostly mild-to-moderate severity. Serious AE reported in 18 patients (10.8%) were mainly infections and were responsive to standard treatment. The majority of patients (92%) reported having no injection-site reactions and only 8% patients reported mild-to-moderate reactions. Patients receiving vaccination (15%) showed normal immune response. <h3>Conclusions</h3> Subcutaneous canakinumab 150 mg every 8 weeks was well tolerated and provided substantial disease control in children and adults across all CAPS phenotypes. Higher canakinumab doses in younger patients and more severe CAPS disease were efficacious in achieving complete responses without evidence of increased AE. Trial registration number: NCT00685373 (clinicaltrials.gov)
Use of cimetidine and other peptic ulcer drugs in Denmark 1977-1990 with analysis of the risk of gastric cancer among cimetidine users.
Authors: H Moller, A Nissen, J Mosbech
Journal: Gut (1992)

The prevalence of use of peptic ulcer drugs in the Danish population is described at two points in time using registrations of applications for reimbursement. In 1977-81, the prevalence of use of cimetidine was 0.4% in men and 0.2% in women. In 1989-90, the prevalence of use of peptic ulcer drugs was 1.3% in men and 1.2% in women. The increase in prevalence was apparent in all age groups, but most pronounced at relatively old age. The median age of users increased from 55 years in 1977-81 to 63 years in 1989-90. The data indicated that a third of those who used peptic ulcer drugs in 1977-81 also used these drugs in 1989-90, conditional on surviving this period. The probability of becoming a long term user was highest for those who were 50-69 years in 1977-81. The incidence of gastric cancer was investigated in the cohort of persons who used cimetidine in 1977-81. An excess risk of gastric cancer was apparent in the first years after start of cimetidine use. This is thought to reflect a selection bias. Significantly increased incidence was also observed in women seven years or longer after start of cimetidine use (RR = 4.7; 95% CI: 1.7-10.3). This estimate was, however, based on only six cases, and a similar pattern was not observed in men.
Is 13 g{middle dot}dL 1 the threshold to correct anaemia in COPD?
Authors: A. Singh
Journal: European Respiratory Journal (2007)

respiration [2].My major concern relates to large-scale screening programmes for sleep apnoea in patients with heart failure before solid evidence of treatment effect on central sleep apnoea regarding patient-related outcomes is obtained, i.e. survival, symptoms or quality of life.O. Oldenburg and co-workers argue that the apnoea/hypopnoea index could be used as a surrogate end-point, since a diagnosis of central sleep apnoea is associated with an impaired prognosis [3][4][5].Oxygen, continuous positive airway pressure and ventilators all reduce the frequency of central apnoeas, i.e. the central apnoea/hypopnoea index.However, other authors have not observed any increased mortality among patients with central sleep apnoea [6, 7].Surrogate endpoints also infer a risk of false interpretation.One such example was anti-arrhythmic treatment studies on patients suffering acute myocardial infarction with arrhythmia as the outcome.Reduction of the number of ventricular arrhythmia was later shown to be associated with an increased mortality rate [8].I am certainly in agreement with O. Oldenburg and co-workers that we need high-quality treatment studies in patients with congestive heart failure and sleep apnoea.My concern is that we should wait for the results of these studies before starting large-scale screening programmes.
Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension
Authors: V.S. Nikam, R.T. Schermuly, R. Dumitrascu, N. Weissmann, G. Kwapiszewska, N. Morrell, W. Klepetko, L. Fink, W. Seeger, R. Voswinckel
Journal: European Respiratory Journal (2010)

A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.
Triple crystal disease: monosodium urate monohydrate, calcium pyrophosphate dihydrate, and basic calcium phosphate in a single joint.
Authors: P B Halverson, L M Ryan
Journal: Annals of the Rheumatic Diseases (1988)

A 49 year old man is described with a polyarticular arthritis. Synovial fluid aspirated from the knee joint showed monosodium urate monohydrate and calcium pyrophosphate dihydrate by polarised light microscopy. Additionally, diphosphonate binding and scanning electron microscopy with energy dispersive analysis showed that basic calcium phosphate crystals were also present. This appears to be the first report of three crystals occurring simultaneously in a single joint.