tbuckley/cabot-search huggingface dataset:
Prognostic Significance of Human Epidermal Growth Factor Receptor Positivity for the Development of Brain Metastasis After Newly Diagnosed Breast Cancer
Authors: Zsolt Gabos, Richie Sinha, John Hanson, Nitin Chauhan, Judith Hugh, John R. Mackey, Bassam Abdulkarim
Journal: Journal of Clinical Oncology (2006)

Purpose As survival in breast cancer patients is improving, brain metastases are becoming increasingly prevalent. The risk of brain metastases in newly diagnosed human epidermal growth factor receptor 2 (HER-2) –overexpressing breast cancer patients is not yet fully defined. We aimed to analyze the risk of brain metastasis in newly diagnosed HER-2–positive breast cancer patients in comparison with HER-2–negative patients. Patients and Methods To determine the incidence of brain metastases in HER-2–overexpressing patients, we analyzed a cohort of newly diagnosed 301 HER-2–positive and 363 HER-2–negative patients identified between January 1998 and December 2003. The association between histologic features and the occurrence of brain metastases was evaluated with univariate and multivariate Cox regression analysis. Results Median follow-up was 3.9 years. Brain metastases were identified in 9% (27 patients) with HER-2–overexpressing breast cancer compared with only 1.9% (7 patients) in the HER-2 negative patients (hazard ratio 4.23 [1.84-9.74], P = .0007). HER-2 overexpression, tumor size larger than 2 cm, at least one positive node, and grade 2/3 disease were predictors of brain metastases in univariate analysis. In multivariate analysis, HER-2 overexpression, tumor size larger than 2 cm, and hormone-receptor negativity were independent prognostic factors for the development of brain metastases, whereas hormone-receptor expression was protective. Conclusion Our study shows that newly diagnosed HER-2–overexpressing breast cancer patients are at increased risk for brain metastases. Because most brain metastases occur after the development of systemic disease, these findings prompt consideration of brain prophylaxis strategies with HER-2–inhibiting small molecules able to cross the blood-brain barrier and/or radiologic screening to detect asymptomatic brain metastases.
CELL INTERACTIONS IN THE IMMUNE RESPONSE IN VITRO
Authors: Marc Feldmann
Journal: The Journal of Experimental Medicine (1972)

The mechanism of interaction of T and B lymphocytes was investigated in an in vitro hapten carrier system using culture chambers with two compartments separated by a cell impermeable nucleopore membrane. Because specific cell interaction occurred efficiently across this membrane, contact of T and B lymphocytes was not essential for cooperation which must have been mediated by a subcellular component or "factor." By using different lymphoid cell populations in the lower culture chamber and activated thymus cells in the upper chamber (with antigen present in both), it was found that the antigen-specific mediator acted indirectly on B cells, through the agency of macrophages. Macrophages which had been cultured in the presence of activated T cells and antigen acquired the capacity to specifically induce antibody responses in B cell-containing lymphoid populations. Trypsinization of these macrophages inhibited their capacity to induce immune responses, indicating that the mediator of cell cooperation is membrane bound. By using antisera to both the haptenic and carrier determinants of the antigen as blocking reagents, it was demonstrated that the whole antigen molecule was present on the surface of macrophages which had been exposed to activated T cells and antigen. Because specifically activated T cells were essential a component of the antigen-specific mediator must be derived from these cells. By using anti-immunoglobulin sera as inhibitors of the binding of the mediator to macrophages, the T cell component was indeed found to contain both kappa- and micro-chains and was thus presumably a T cell-derived immunoglobulin. It was proposed that cell cooperation is mediated by complexes of T cell IgM and antigen, bound to the surface of macrophage-like cells, forming a lattice of appropriately spaced antigenic determinants. B cells become immunized by interacting with this surface. With this mechanism of cell cooperation, the actual pattern of antigen-B cell receptor interactions in immunization would be the same with both thymus-dependent and independent antigens. An essential feature of the proposed mechanism of cell cooperation is that macrophage-B cell interaction must occur at an early stage of the antibody response, a concept which is supported by many lines of evidence. Furthermore this mechanism of cell interaction can be elaborated to explain certain phenomena such as the highly immunogenic macrophage-bound antigen, antigenic competition, the distinction between immunity and tolerance in B lymphocytes, and the possible mediation of tolerance by T lymphocytes.
Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study
Authors: Irene M Ghobrial, Edie Weller, Ravi Vij, Nikhil C Munshi, Ranjit Banwait, Meghan Bagshaw, Robert Schlossman, Renee Leduc, Stacey Chuma, Janet Kunsman, Jacob Laubach, Andrzej J Jakubowiak, Patricia Maiso, Aldo Roccaro, Philippe Armand, Akari Dollard, Diane Warren, Brianna Harris, Tiffany Poon, Amy Sam, Scott Rodig, Kenneth C Anderson, Paul G Richardson
Journal: The Lancet Oncology (2011)
Non-hydrostatic pulmonary edema after coronary artery ligation in dogs. Protective effect of indomethacin.
Authors: J F Richeson, C Paulshock, P N Yun
Journal: Circulation Research (1982)

Pulmonary edema which develops during acute myocardial infarction is generally believed to result solely from pulmonary microvascular hypertension. However, patient with myocardial infarction and pulmonary edema occasionally are found to have normal pulmonary wedge pressure. We report data indicating that pulmonary edema develops after coronary artery ligation despite stable microvascular pressure. Four groups of open-chest dogs were studied: (1) nine dogs with left anterior descending coronary artery ligation, (2) seven dogs with sham coronary ligation, (3) seven dogs ligated after beginning an infusion of indomethacin (5 mg/kg per hr), and (4) five dogs ligated after an infusion of the drug's vehicle was begun. Extravascular lung water and pulmonary blood volume were measured at hourly intervals during the 2 hours before and after coronary ligation or sham ligation. Gravimetric lung water was measured immediately thereafter. Changes of net pulmonary intravascular driving force (the difference of microvascular hydrostatic and oncotic pressure) after ligation or sham ligation were small and comparable in all groups. Pulmonary blood volume did not change in any group. Pulmonary extravascular water volume remained constant in the sham group but rose significantly in the ligated group. Gravimetric lung water also was significantly higher in the latter group. We interpret these results to indicate that factors other than microvascular pressure can mediate the formation of these results to indicated that factors other than microvascular pressure can mediate the formation of edema during acute myocardial infarction; increased pulmonary microvascular permeability may be responsible. Indomethacin infusion blocked the formation of edema after coronary ligation, even though net microvascular driving force was highest in this group. Infusion of the vehicle alone did not prevent edema. The mechanism by which indomethacin exerts this protective effect is unclear but is probably a result of its inhibition of cyclo-oxygenase or cyclic nucleotide phosphodiesterase.
LIVER INJURY, LIVER PROTECTION, AND SULFUR METABOLISM
Authors: L. L. Miller, G. H. Whipple
Journal: The Journal of Experimental Medicine (1942)

Protein-depleted dogs are very susceptible to injurious agents-in particular, chloroform. Methionine given shortly before chloroform anesthesia will give complete protection against chloroform. Methionine (or cysteine plus choline) given 3 or 4 hours after chloroform anesthesia will give significant protection against the liver injury of chloroform anesthesia. Methionine given more than 4 hours after chloroform anesthesia gives no protection against liver injury. Choline alone given before chloroform gives no protection against liver injury. The protein-depleted dogs have livers which are deficient in both nitrogen and sulfur, but sulfur is depleted more than is the nitrogen. The N/S ratio therefore rises. Methionine or cystine feeding promptly makes up this liver sulfur deficit. Viable liver cells are necessary for this uptake of sulfur. Livers of fetuses in utero or of newborn pups tolerate a chloroform anesthesia which will cause fatal liver injury in adults. The nitrogen and sulfur values of these fetus or pup livers are within the high normal values for adults. Blood-forming cells are present in the fetus or pup livers during this period. When these blood islands are eliminated during the 3rd or 4th week of life, the liver then becomes normally susceptible to chloroform liver injury. Methionine or methionine-rich protein digests (e.g. casein) or various proteins by mouth or by vein should prove useful to protect the liver against certain types of injury and to aid in organ repair.
Ganoderma lucidum polysaccharides can induce human monocytic leukemia cells into dendritic cells with immuno-stimulatory function
Authors: Wing Keung Chan, Christopher Ching Hang Cheung, Helen Ka Wai Law, Yu Lung Lau, Godfrey Chi Fung Chan
Journal: Journal of Hematology & Oncology (2008)

Previous studies demonstrated Ganoderma lucidum polysaccharides (GL-PS), a form of bioactive β-glucan can stimulate the maturation of monocyte-derived dendritic cells (DC). The question of how leukemic cells especially in monocytic lineage respond to GL-PS stimuli remains unclear. In this study, we used in vitro culture model with leukemic monocytic cell-lines THP-1 and U937 as monocytic effectors cells for proliferation responses and DCs induction. We treated the THP-1 and U937 cells with purified GL-PS (100 μg/mL) or GL-PS with GM-CSF/IL-4. GL-PS alone induced proliferative response on both THP-1 and U937 cells but only THP-1 transformed into typical DC morphology when stimulated with GL-PS plus GM-CSF/IL-4. The transformed THP-1 DCs had significant increase expression of HLA-DR, CD40, CD80 and CD86 though not as high as the extent of normal monocyte-derived DCs. They had similar antigen-uptake ability as the normal monocyte-derived DCs positive control. However, their potency in inducing allogeneic T cell proliferation was also less than that of normal monocyte-derived DCs. Our findings suggested that GL-PS could induce selected monocytic leukemic cell differentiation into DCs with immuno-stimulatory function. The possible clinical impact of using this commonly used medicinal mushroom in patients with monocytic leukemia (AML-M4 and M5) deserved further investigation.
Macrophage migration inhibitory factor in myocardial ischaemia/reperfusion injury
Authors: T. Rassaf, C. Weber, J. Bernhagen
Journal: Cardiovascular Research (2014)

Acute myocardial infarction (AMI) remains one of the leading causes of death in the developed world. There is emerging evidence that the cytokine macrophage migration inhibitory factor (MIF) is a crucial player in AMI. Cardioprotection by MIF is likely to be a multifactorial phenomenon mediated by receptor-mediated signalling processes, intracellular protein–protein interactions, and enzymatic redox regulation. Co-ordinating several pathways in the ischaemic heart, MIF contributes to receptor-mediated regulation of cardioprotective AMP-activated protein kinase signalling, inhibition of pro-apoptotic cascades, and the reduction of oxidative stress in the post-ischaemic heart. Moreover, the cardioprotective properties of MIF are modulated by S-nitros(yl)ation. These effects in the pathophysiology of myocardial ischaemia/reperfusion injury qualify MIF as a promising therapeutic target in the future. We here summarize the findings of experimental and clinical studies and emphasize the therapeutic potential of MIF in AMI.
Two essential regulatory elements in the human interferon gamma promoter confer activation specific expression in T cells.
Authors: L Penix, W M Weaver, Y Pang, H A Young, C B Wilson
Journal: The Journal of Experimental Medicine (1993)

Like interleukin 2 (IL-2), interferon gamma (IFN-gamma) is an early response gene in T cells and both are prototypical T helper cell type 1 (Th-1) lymphokines. Yet IL-2 and IFN-gamma production are independently regulated, as demonstrated by their differential expression in certain T cell subsets, suggesting that the regulatory elements in these two genes must differ. To explore this possibility, the 5' flank of the human IFN-gamma gene was analyzed. Expression of IFN-gamma promoter-driven beta-galactosidase reporter constructs containing 538 bp of 5' flank was similar to that by constructs driven by the IL-2 promoter in activated Jurkat T cells; expression nearly as great was observed with the construct containing only 108 bp of IFN-gamma 5' flank. These IFN-gamma promoter constructs faithfully mirrored expression of the endogenous gene, in that expression required activation both with ionomycin and PMA, was inhibited by cyclosporin A, and was not observed in U937 or THP-1 cells. The region between -108 and -40 bp in the IFN-gamma promoter was required for promoter function and contained two elements that are conserved across species. Deletion of 10 bp within either element reduced promoter function by 70%, whereas deletions in nonconserved portions of this region had little effect on promoter function. The distal conserved element (-96 to -80 bp) contained a consensus GATA motif and a potential regulatory motif found in the promoter regions of the GM-CSF and macrophage inflammatory protein (MIP) genes. Factors binding to this element, including GATA-3, were found in Jurkat nuclear extracts by electromobility shift assays and two of the three complexes observed were altered in response to activation. One or both of these motifs are present in the 5' flank of multiple, other lymphokine genes, including IL-3, IL-4, IL-5, and GM-CSF, but neither is present in the promoter of the IL-2 gene. The proximal conserved element (-73 to -48 bp) shares homology with the NFIL-2A element in the IL-2 promoter; these elements compete for binding of factors in Jurkat nuclear extracts, although the NFIL-2A element but not the IFN-gamma element binds Oct-1. Factors binding to this element in the IFN-gamma gene were present in extracts from resting and activated Jurkat T cells. However, by in vivo footprinting of intact cells, this element was protected from methylation only with activation.(ABSTRACT TRUNCATED AT 400 WORDS)
Atlas of care shows poor performance in treating diabetes in England
Authors: A. O'Dowd
Journal: BMJ (2014)

Only a third of people with diabetes are having their treatment targets met properly, shows a new online tool for displaying levels and quality of care across England.

Public Health England launched its Healthier Lives: Diabetes, Hypertension and NHS Health Check online tool on 30 October (http://healthierlives.phe.org.uk). The tool, in the form of an atlas of England, allows users to look up information in any geographical area about the prevalence of the conditions and their complications, levels of care provided, and quality of care achieved in each area. Results are shown as comparison with the England average and …
Longterm outcome after injection sclerotherapy for oesophageal varices in children with extrahepatic portal hypertension.
Authors: M D Stringer, E R Howard
Journal: Gut (1994)

A consecutive series of 36 children with bleeding from oesophageal varices secondary to extrahepatic portal hypertension was successfully treated by endoscopic injection sclerotherapy and followed up over a mean period of 8.7 years after variceal obliteration. There were no deaths from portal hypertension or its treatment and morbidity related to oesophageal sclerotherapy was minimal. Endoscopic injection sclerotherapy alone proved safe and effective in controlling variceal bleeding from portal hypertension in over 80% of the children. Recurrent variceal bleeding developed in 10 (31%) patients but half of these were effectively treated by further sclerotherapy. Gastric variceal bleeding unresponsive to sclerotherapy necessitated successful portosystemic shunt surgery in four (13%) patients. Two children required splenectomy for painful splenomegaly. In most children injection sclerotherapy is the best treatment for the primary management of bleeding oesophageal varices, reserving portosystemic shunting or other surgical procedures for those with bleeding from gastrointestinal varices.
S90 Role For Il-1alpha In Viral-induced Inflammatory Responses In A Co-culture Model Of The Airway Mucosa
Authors: A. Hill, L. Tezera, C. Blume, C. Grainge, D. Davies, E. Swindle
Journal: Thorax (2014)

<h3>Introduction</h3> Asthma is an inflammatory disease of the conducting airways which is exacerbated by environmental exposures, such as viral infections. Bronchial epithelial cells (BECs) together with underlying fibroblasts form an epithelial mesenchymal trophic unit (EMTU) that maintains normal tissue homeostasis. In asthma the EMTU is dysregulated. Recent evidence suggests that viral infections activate the epithelial barrier resulting in mediator release which could potentially activate fibroblasts. Therefore, we hypothesised that exposure to viruses activates inflammatory and anti-viral responses in the EMTU. <h3>Methods</h3> The EMTU was modelled using a co-culture system of polarised BECs (16HBE14o-) and fibroblasts (MRC5s) maintained on the apical and basolateral surface of a nanoporous membrane respectively. After 6 days the model was challenged apically with poly (I:C) (a viral mimetic) and barrier responses were determined by measuring transepithelial resistance (TER) while cytokine release was determined by ELISA. <h3>Results</h3> Following poly (I:C) stimulation a significant reduction in TER was observed in both the EMTU model and BEC monocultures. However, the EMTU model maintained a higher TER at 6–24 h after challenge. With regards to cytokine secretion, poly (I:C) stimulation significantly induced pro-inflammatory (IL-6, IL-8, GM-CSF and IL-1α) and anti-viral (IP-10) mediator release from BEC but not fibroblast monocultures. In the EMTU model, basolateral IL-6, IL-8, GM-CSF and IP-10 responses to poly (I:C) were significantly enhanced compared to BEC monocultures. In addition, basolateral pro-inflammatory (IL-6, IL-8 and GM-CSF) but not antiviral (IP-10) responses to poly (I:C) were abrogated in the EMTU model after pre-incubation with IL-1 receptor antagonist (IL-1ra). Furthermore, direct stimulation with IL-1α induced IL-6 and IL-8 release in the EMTU model and fibroblast monocultures but not in BEC monocultures. <h3>Conclusions</h3> Poly (I:C) activates inflammatory and anti-viral responses in BEC monocultures and fibroblast co-culture models of the EMTU. These responses were enhanced in the co-culture model suggesting that the EMTU is activated. Inflammatory but not anti-viral responses were mediated by epithelial-derived IL-1α acting on the underlying fibroblasts. This may have important consequences in promotion of inflammation and airway remodelling in viral-induced exacerbations of asthma.
A Phase I Study of PF-04449913, an Oral Hedgehog Inhibitor, in Patients with Advanced Solid Tumors
Authors: Andrew J. Wagner, Wells A. Messersmith, M. Naveed Shaik, Sherry Li, Xianxian Zheng, Karen R. McLachlan, Rossano Cesari, Rachel Courtney, Wendy J. Levin, Anthony B. El-Khoueiry
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors. Experimental Design: A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The starting dose was 80 mg. Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTD was estimated to be 320 mg once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) were grade 1–2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg once daily. No treatment-related grade 4–5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by &amp;gt;80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months). Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors. Clin Cancer Res; 21(5); 1044–51. ©2014 AACR.
Surfactant apoprotein-A concentration in airway secretions for the detection of pulmonary oedema
Authors: S Shimura, T Masuda, T Takishima, K Shirato
Journal: European Respiratory Journal (1996)

Patients with cardiogenic pulmonary oedema expectorate foamy sputum containing surfactant, which might be expected to include surfactant apoprotein A (SP-A). SP-A is specific for lung surfactant. We have measured the SP-A concentration in airway secretions to determine whether it is useful in distinguishing pulmonary oedema from other disorders. Samples of sputum and of aspirated airway secretion were obtained from 11 patients with cardiogenic pulmonary oedema, seven patients with clinically stable congestive heart failure, five patients with adult respiratory distress syndrome (ARDS) and 20 control patients (10 intubated) with other respiratory diseases. The samples were used for the measurement of SP-A concentration by a two-site simultaneous immunoassay with monoclonal antibodies against SP-A. SP-A concentrations, measured in samples of sputum and aspirated secretions, depended on the diagnosis of the patients from which they had come. In descending order these samples came from patients with: cardiogenic pulmonary oedema (1324 +/- 197 micrograms.mL-1; n = 33); ARDS (311 +/- 47 micrograms.mL-1; n = 23); clinically stable congestive heart failure (78 +/- 10 micrograms.mL-1; n = 21); and control conditions (3.0 +/- 0.6 micrograms.mL-1; n = 30). Concentrations from disease samples did not overlap with controls. In samples from patients with cardiogenic pulmonary oedema, the SP-A concentration correlated with mean pulmonary capillary wedge pressure (PCWP) (p < 0.001; n = 39). These findings indicate that the measurement of the surfactant apoprotein A concentration in airway secretions may be useful for the detection of pulmonary oedema.
A New Murine Model for Bronchiolitis Obliterans Post–Bone Marrow Transplant
Authors: Angela Panoskaltsis-Mortari, Kevin V. Tram, Andrew P. Price, Christine H. Wendt, Bruce R. Blazar
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Bronchiolitis obliterans (BO) is a major problem in lung transplantation and is also part of the spectrum of late-onset pulmonary complications that can occur after hematopoietic stem cell transplant. Better mouse models are needed to study the onset of this disease so that therapeutic interventions can be developed.