tbuckley/cabot-search huggingface dataset:
Pagetic hydrocephalus treated with zoledronate
Authors: A Morton
Journal: Annals of the Rheumatic Diseases (2005)

This case illustrates the usefulness of a therapeutic trial of colchicine monitored objectively by frequent acute phase protein measurements in patients with undiagnosed periodic fever syndromes.It also raises the possibility that a low threshold for analysing the FMF gene might disclose a wider spectrum of associated disease.
Etsrp/Etv2 Is Directly Regulated by <i>Foxc1a/b</i> in the Zebrafish Angioblast
Authors: Matthew B. Veldman, Shuo Lin
Journal: Circulation Research (2011)

Endothelial cells are developmentally derived from angioblasts specified in the mesodermal germ cell layer. The transcription factor etsrp/etv2 is at the top of the known genetic hierarchy for angioblast development. The transcriptional events that induce etsrp expression and angioblast specification are not well understood.We generated etsrp:gfp transgenic zebrafish and used them to identify regulatory regions and transcription factors critical for etsrp expression and angioblast specification from mesoderm.To investigate the mechanisms that initiate angioblast cell transcription during embryogenesis, we have performed promoter analysis of the etsrp locus in zebrafish. We describe three enhancer elements sufficient for endothelial gene expression when place in front of a heterologous promoter. The deletion of all 3 regulatory regions led to a near complete loss of endothelial expression from the etsrp promoter. One of the enhancers, located 2.3 kb upstream of etsrp contains a consensus FOX binding site that binds Foxc1a and Foxc1b in vitro by EMSA and in vivo using ChIP. Combined knockdown of foxc1a/b, using morpholinos, led to a significant decrease in etsrp expression at early developmental stages as measured by quantitative reverse transcriptase-polymerase chain reaction and in situ hybridization. Decreased expression of primitive erythrocyte genes scl and gata1 was also observed, whereas pronephric gene pax2a was relatively normal in expression level and pattern.These findings identify mesodermal foxc1a/b as a direct upstream regulator of etsrp in angioblasts. This establishes a new molecular link in the process of mesoderm specification into angioblast.
Differential localisation of the renin–angiotensin system in de-novo lesions and in-stent restenotic lesions in in-vivo human coronary arteries
Authors: L Wagenaar
Journal: Cardiovascular Research (2003)

Different components of the renin-angiotensin system (RAS) have been demonstrated in atherosclerotic plaques. However, the involvement of the RAS in in-stent restenosis is not clear. We studied the differential immunolocalisation of angiotensin converting enzyme (ACE) and the angiotensin II type 1 (AT1) receptor in de-novo stenotic lesions and in-stent restenotic lesions in human coronary arteries.Using a pullback atherectomy catheter, biopsies from de-novo coronary lesions (n=19) and in-stent restenotic lesions (n=19) were obtained. The biopsies were immunostained for vascular smooth muscle cells (VSMCs), macrophages, ACE and the AT1 receptor.In biopsies from de-novo stenotic lesions ACE-positive macrophages were more numerous than in in-stent restenotic lesions (P=0.002). Moreover, in the latter lesions, ACE-positive macrophages decreased when the time interval of stent implantation was longer. On the other hand, in-stent restenotic lesions contained predominantly young VSMCs, which abundantly expressed AT1 receptors.Lesional ACE expression is not a prominent feature of in-stent restenotic lesions. In contrast, AT1 receptors are abundantly expressed on young VSMCs. In de-novo lesions ACE and AT1 receptors were found on macrophages and VSMCs, which were present in all specimens.
The ATP-Competitive mTOR Inhibitor INK128 Enhances <i>In Vitro</i> and <i>In Vivo</i> Radiosensitivity of Pancreatic Carcinoma Cells
Authors: Thomas J. Hayman, Amy Wahba, Barbara H. Rath, Heekyong Bae, Tamalee Kramp, Uma T. Shankavaram, Kevin Camphausen, Philip J. Tofilon
Journal: Clinical Cancer Research (2013)

Radiotherapy remains a primary treatment modality for pancreatic carcinoma, a tumor characterized by aberrant mTOR activity. Given the regulatory role of mTOR in gene translation, in this study, we defined the effects of the clinically relevant, ATP-competitive mTOR inhibitor, INK128 on the radiosensitivity of pancreatic carcinoma cell lines.Clonogenic survival was used to determine the effects of INK128 on in vitro radiosensitivity of three pancreatic carcinoma cell lines and a normal fibroblast cell line with mTOR activity defined using immunoblots. DNA double-strand breaks were evaluated according to γH2AX foci. The influence of INK128 on radiation-induced gene translation was determined by microarray analysis of polysome-bound mRNA. Leg tumor xenografts grown from pancreatic carcinoma cells were evaluated for mTOR activity, eIF4F cap complex formation, and tumor growth delay.INK128, while inhibiting mTOR activity in each of the cell lines, enhanced the in vitro radiosensitivity of the pancreatic carcinoma cells but had no effect on normal fibroblasts. The dispersal of radiation-induced γH2AX foci was inhibited in pancreatic carcinoma cells by INK128 as were radiation-induced changes in gene translation. Treatment of mice with INK128 resulted in an inhibition of mTOR activity as well as cap complex formation in tumor xenografts. Whereas INK128 alone had no effect of tumor growth rate, it enhanced the tumor growth delay induced by single and fractionated doses of radiation.These results indicate that mTOR inhibition induced by INK128 enhances the radiosensitivity of pancreatic carcinoma cells and suggest that this effect involves the inhibition of DNA repair.
Abnormal lactic dehydrogenase isoenzyme patterns in ulcerative colitis with precancerous change
Authors: B. Lewis, B. C. Morson, A. W. February, J. H. Jones, J. J. Misiewicz
Journal: Gut (1971)

The isoenzyme pattern of lactic dehydrogenase was measured in rectal biopsies from six patients with ulcerative colitis in whom precancerous histological changes had been independently recognized. There was a highly significant increase in the ratio of isoenzymes IV + V to I + II. This suggests that lactic dehydrogenase isoenzyme measurement may prove a valuable addition to histology in the recognition of precancer in ulcerative colitis.
Intratumoral Vascular Changes With Increased Size of a Mammary Adenocarcinoma: New Method and Results
Authors: A W VOGEL
Journal: JNCI Journal of the National Cancer Institute (1965)

Changes with growth of vascular surface area and length per unit volume of tissue were estimated in a transplantable mammary adenocarcinoma, 72j. Over-all mean vascular volume of 16 percent did not change with tumor growth. The vessel diameters widened as the tumor grew, with a consequent drop in the over-all vessel length (820 mm/mm3 in tumors weighing 5 to 30 mg, to 47 mm/mm3 in tumors greater than 1100 mg) and surface area (34 to 7 mm2/mm3). Regional estimates of capillary or sinusoidal areas showed striking differences, i.e., capillary vessel length of 1700 mm per mm3 versus sinusoidal vessel length of 50 mm per mm3 and capillary surface area of 45 mm2 per mm3 versus sinusoidal surface area of 11 mm2 per mm3. The method for preparation of the specimens and calculation of the vascular surface area and length are presented.
Prevalence of abnormal lung volumes, DLCO and chest HRCT in smokers with normal spirometry
Authors: Sebastian Ahumada, Pablo Betancour, Mario Santamarina, Juan Pablo Huidobro, Monica Gutierrez, Manuel Barros
Journal: European Respiratory Journal (2013)

Smoking is the leading cause of COPD, but only some smokers acquired the disease. Diagnosis of COPD needs confirmation with spirometry, but it has been reported that lung and bronchial damage may be present before abnormalities in this test can be observed.

The aim of this study was to explore the prevalence of lung volumes (LV), DLCO and Chest HRCT (CT) abnormalities in smokers with normal spirometry.

We did a retrospective analysis in outpatients routinely sent for pulmonary function tests, which were done between March 2010 and November 2011. Inclusion criteria: current/ex-smokers with normal spirometry and CT done within 6 months (m). Exclusion criteria: chronic respiratory disease or acute respiratory symptoms ≤6 m. Associations were analyzed with Fisher's exact test.

We collected data from 50 subjects (24 M), 65±11 years old. They have smoked a median of 17 pack years (range 3 to 48); 33 were current smokers. Respiratory symptoms were present in 38 (26 had chronic cough, 8 chronic sputum, 17 dyspnoea). 48 patients have abnormalities in either LV, DLCO or CT. LV were normal in 33, showed air trapping (AT) in 14 and low residual volume in 3. DLCO was normal in 14 and abnormal in 36 (mild 27, moderate 7, severe 2); CT was normal in 10, showed emphysema (E) in 1, AT in 21 and both E and AT in 18. We did not find any association between abnormalities in LV, DLCO and CT, neither between AT diagnosed by LV and CT (p=0.29).

We found in this group of smokers with normal spirometry a high prevalence of DLCO abnormalities and AT measured by LV and CT. Although none of these subjects meet criteria for COPD as currently defined, damage to airways and/or lung parenchyma was present in most of them.
COPD and air travel: does hypoxia-altitude simulation testing predict in-flight respiratory symptoms?
Authors: Anne Edvardsen, Morten Ryg, Aina Akerø, Carl Christian Christensen, Ole H. Skjønsberg
Journal: European Respiratory Journal (2012)

The reduced pressure in an aircraft cabin may cause significant hypoxaemia and respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD). The current study evaluated whether there is a relationship between hypoxaemia obtained during hypoxia-altitude simulation testing (HAST), simulating an altitude of 2438 m, and the reporting of respiratory symptoms during air travel. 82 patients with moderate to very severe COPD answered an air travel questionnaire. Arterial oxygen tensions during HAST ( P aO 2HAST ) in subjects with and without in-flight respiratory symptoms were compared. The same questionnaire was answered within 1 year after the HAST. Mean± sd P aO 2HAST was 6.3±0.6 kPa and 62 (76%) of the patients had P aO 2HAST &lt;6.6 kPa. 38 (46%) patients had experienced respiratory symptoms during air travel. There was no difference in P aO 2HAST in those with and those without in-flight respiratory symptoms (6.3±0.7 kPa versus 6.3±0.6 kPa, respectively; p=0.926). 54 (66%) patients travelled by air after the HAST, and patients equipped with supplemental oxygen (n=23, 43%) reported less respiratory symptoms when flying with than those without such treatment (four (17%) versus 11 (48%) patients; p=0.039). In conclusion, no difference in P aO 2HAST was found between COPD patients with and without respiratory symptoms during air travel.
Postanoxic T Lymphocyte–Endothelial Cell Interactions Induce Tumor Necrosis Factor-α Production and Neutrophil Adhesion
Authors: Satoshi Kokura, Robert E. Wolf, Toshikazu Yoshikawa, D. Neil Granger, Tak Yee Aw
Journal: Circulation Research (2000)

Abstract —The objective of this study was to define the influence of postanoxic T-lymphocyte–endothelial cell interactions on anoxia-reoxygenation (A/R)–induced neutrophil–endothelial cell adhesion and cell adhesion molecule (CAM) expression on human umbilical vein endothelial cells (HUVECs). HUVEC monolayers were exposed to 60 minutes of anoxia, followed by 24 hours of reoxygenation, wherein freshly isolated human T lymphocytes were added at 6 hours during reoxygenation. After an additional 18 hours of incubation (ie, total of 24 hours of reoxygenation), the T-cell/endothelial cell (TC/EC) coculture media were collected and added to naive HUVEC monolayers incubated with neutrophils. Although the A/R-conditioned media per se had no effect on neutrophil adhesion, the media from TC/EC cocultures significantly increased the adhesion response. This enhanced adhesive interaction was associated with significant increases in tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) levels in the TC/EC coculture media and was accompanied by a pronounced increase in endothelial E-selectin expression. Treatment of the TC/EC coculture media with anti–TNF-α or anti-IL-8 antibodies reduced the media-induced neutrophil adhesion response. The enhanced neutrophil adhesion and the elevated medium levels of TNF-α, but not IL-8, were markedly reduced by inserts that prevented direct TC/EC contact and by monoclonal antibodies directed against vascular cell adhesion molecule-1 (VCAM-1) or very late antigen-4 (VLA-4). Collectively, these findings show that VLA-4–/VCAM-1–mediated interactions between T lymphocytes and postanoxic endothelial cells stimulates TNF-α production, which in turn elicits endothelial cell adhesion molecule expression and a corresponding increase in neutrophil adhesion.
Toxic Effects of Depression on Brain Function: Impairment of Delayed Recall and the Cumulative Length of Depressive Disorder in a Large Sample of Depressed Outpatients
Authors: Philip Gorwood, Emmanuelle Corruble, Bruno Falissard, Guy M Goodwin
Journal: American Journal of Psychiatry (2008)

Objective: An important current hypothesis suggests that the relationship between severe depression and the hippocampus is essentially toxic. The purpose of this study was to assess the generalizability of the impact of depression on hippocampal function. Method: Participants were 8,229 outpatients who 1) fulfilled DSM-IV criteria for major depressive disorder based on clinical assessment and 2) were tested for delayed recall, a memory function that is particularly related to hippocampal integrity in humans, during two visits several weeks apart. Results: As expected, at presentation with depression, the subjects’ current illness severity was the major determinant of performance, as opposed to the intensity of their previous depressive history (the number and length of past episodes). However, following clinical response at the second visit, the length of previous depressive history became more significant than current symptoms. The following factors had significant, independent impact: age, education level, and profession. Conclusions: Previous studies of small samples assessed for memory function, more or less specific to the hippocampus, have shown great variability in age, gender, education level, and the length and intensity of depressive episode. Hence, a very large sample was required to disentangle the central effect of previous depressive history. As demonstrated in a general practice sample in this study, the hypothesis that the length of past depression impairs memory performance is supported, suggesting that there is a toxic link between the burden of depression and cognition. This finding has important implications for public health.
Paired Toll-like Receptor Agonists Enhance Vaccine Therapy through Induction of Interleukin-12
Authors: Rongxiu Zheng, Peter A. Cohen, Christopher A. Paustian, Terrence D. Johnson, Walter T. Lee, Suyu Shu, Gary K. Koski
Journal: Cancer Research (2008)

Minimal requirements for generating effective immunity include the delivery of antigenic (signal 1) and costimulatory (signal 2) signals to T lymphocytes. Recently, a class of third signals, often delivered by antigen-presenting dendritic cells, has been shown to greatly enhance immune responses, especially against tumors. Among signal 3 factors, interleukin (IL)-12 is particularly effective and can be conditionally induced by agonists of Toll-like transmembrane receptors (TLR). In this study, we assessed the therapeutic effect of adjuvant TLR agonist administration upon the capacity of dendritic cell (DC)-tumor electrofusion hybrids to eradicate established MCA205 sarcomas in syngeneic mice. Paired, but not solitary combinations of polyinosine:polycytadilic acid (P[I:C]; TLR3 agonist) and CpG DNA (ODN1826l; TLR9 agonist) stimulated IL-12 secretion from DCs in vitro and synergized with vaccination to achieve potent tumor rejection. Therapeutic effects, however, required coadministration of paired TLR agonists and DC-tumor fusion hybrids. The administration of TLR agonists alone or with fusion vaccine induced transient splenomegaly but without apparent toxicity. The therapeutic effects of this immunization regimen were significantly abrogated through the neutralization of IL-12p70, indicating that production of this third signal was essential to the observed tumor regression. These results show the profound functional consequences of TLR cooperativity and further highlight the critical role of IL-12 in antitumor immunity.
Longitudinal assessment of lung function in children and adolescents with sickle cell anaemia
Authors: Alan Lunt, Gerrard F. Rafferty, David Rees, Sue Height, Anne Greenough
Journal: European Respiratory Journal (2011)

Aim: Lung function studies in children with sickle cell disease (SCD) have not identified consistent abnormalities. The results, however, of two cross-sectional studies suggest restrictive abnormalities become more prominent with increasing age. Our aim was, by undertaking serial comprehensive assessments in SCD children, to further characterize any changes in lung function with increasing age.

Methods: Two cohorts of SCD children were recruited. Cohort 1: 21 children, mean age at baseline 8.1 (range 2.9-12.0) years and mean length of follow-up 1.9 (1.7-2.1) years. Cohort 2: 28 children and adolescents, mean age at baseline 10.0 (6.0-15.5) years and mean length follow-up 9.0 (8.1-9.8) years. Lung function was assessed by spirometry and body plethysmography.

Results: Lung function declined significantly in both cohorts. The results are expressed as median (IQR) and percentage predicted for height.

View this table:

Table 1. Lung function at baseline and follow-up for cohort 1





View this table:

Table 2. Lung function at baseline and follow-up for cohort 2





Comparison of the data from the two cohorts demonstrates a faster decline in cohort one.

Conclusion: Children and adolescents with SCD suffer deterioration in lung function with increasing age; the speed of decline is greatest in young children.
Inhibition of antibody-dependent cellular cytotoxicity and immunoglobulin synthesis by an antiserum prepared against a human B-cell Ia-like molecule.
Authors: L Chess, R Evans, R E Humphreys, J L Strominger, S F Schlossman
Journal: The Journal of Experimental Medicine (1976)

Rabbit antisera to the human B-cell-specific antigen complex, p23,30, was used to define further the functional heterogeneity of isolated human lymphocyte subpopulations. Specific depletion of p23,30-bearing cells from Ig-negative cell populations and Ig-negative, E rosette-negative (Null) populations by either complement-mediated lysis or by physical separation on goat antirabbit Fab immunoabsorbent columns, eliminates the antibody-dependent cellular cytotoxic (ADCC) function. Furthermore, binding of anti-p23,30 serum to the effector cell surface inhibits ADCC but does not interfere with EA rosette formation. Apparently p23,30 represents a cell surface site which is distinct from the Fc receptor but which is important in the triggering of ADCC. In addition, depletion of p23,30-bearing cells from unfractionated cell populations, Ig-positive B-cell populations and Ig-negative, E rosette-negative (Null) populations eliminates the capacity of these populations to secrete immunoglobulin during subsequent culturing. Thus both the Ig-secreting cells and the ADCC effector cells within the Ig-negative, E rosette-negative (Null) population reside in the same population of cells which bears the p23,30 antigen.
Gliadin induced changes in the expression of MHC-class II antigens by human small intestinal epithelium. Organ culture studies with coeliac disease mucosa.
Authors: S Fais, L Maiuri, F Pallone, M De Vincenzi, G De Ritis, R Troncone, S Auricchio
Journal: Gut (1992)

Jejunal biopsies from 16 treated coeliac disease patients and from nine controls were cultured with and without a peptic-tryptic digest of gliadin. Cultures with a peptic-tryptic digest of maize prolamins were also undertaken. Frozen sections of baseline and cultured mucosa were stained by immunofluorescence with an anti-HLA-DR monoclonal antibody. Before culture the villous epithelium from both controls and treated coeliac disease expressed DR molecules while the crypt epithelium did not. When biopsies from treated coeliac disease were cultured with gliadin the expression of DR was enhanced in the crypt epithelium in eight of 14 cultures and in 11 of 14 was reduced or absent on the villous epithelium. No change was observed in control cultures. We conclude that gliadin is capable of inducing HLA-DR on the crypt epithelium of in vitro cultured coeliac disease mucosa, providing indirect evidence that gliadin may activate cell mediated immune mechanisms within the small bowel mucosa. This model could prove useful in identifying the immunogenic sequence(s) of gliadins and related prolamins.
Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer
Authors: Eric Chen, Derek Jonker, Isabelle Gauthier, Martha MacLean, Julie Wells, Jean Powers, Lesley Seymour
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer. Experimental Design: Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles. Results: Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1 patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9%; 95% confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin. Conclusions: Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.