tbuckley/cabot-search huggingface dataset:
HER2-Targeted Therapy Reduces Incidence and Progression of Midlife Mammary Tumors in Female Murine Mammary Tumor Virus huHER2-Transgenic Mice
Authors: David Finkle, Zhi Ricky Quan, Vida Asghari, Jessica Kloss, Nazli Ghaboosi, Elaine Mai, Wai Lee Wong, Philip Hollingshead, Ralph Schwall, Hartmut Koeppen, Sharon Erickson
Journal: Clinical Cancer Research (2004)

Abstract Purpose: This study examined the effectiveness of early and prolonged mu4D5 (the murine form of trastuzumab/Herceptin) treatment in transgenic mice that overexpress human HER2 (huHER2), under the murine mammary tumor virus promoter, as a model of huHER2-overexpressing breast cancer. Experimental Design: Mice were randomly assigned to one of three treatment groups and received i.p. injections from 17 weeks of age until either 52 weeks of age or morbidity. Fourteen mice received 100 mg/kg mu4D5, 14 mice received 100 mg/kg antiherpes simplex virus glycoprotein D control antibody, and 11 mice received a diluent control. Results: High levels of huHER2 expression were detectable in mammary glands of young virgin founder mice. Mammary adenocarcinomas were frequently found in female founders and progeny at an average age of 28 weeks, with some progressing to metastatic disease. The incidence of mammary tumors was significantly reduced, and tumor growth inhibition was observed in mice receiving mu4D5 compared with control mice. In addition, Harderian gland neoplasms, highly associated with overexpression of huHER2 in this transgenic line, were entirely absent in the mu4D5 treatment group, indicating down-regulation of huHER2 in vivo activity. Conclusions: Early intervention with mu4D5 was of benefit in our transgenic mice at high risk for developing huHER2-overexpressing breast cancer. This study suggests a potential benefit of early treatment with Herceptin in HER2-positive primary breast cancer.
A QUANTITATIVE THEORY OF THE PRECIPITIN REACTION
Authors: Michael Heidelberger, Forrest E. Kendall
Journal: The Journal of Experimental Medicine (1937)

1. The reaction between the specific polysaccharide of Type III pneumococcus and homologous antibody in rabbit sera is quantitatively accounted for by expressions similar to those derived from the mass law for the corresponding horse sera. Preliminary data are also given for the Type I reaction. 2. Differences and similarities of the reaction with antibodies produced by the two animals are discussed. 3. Calculations are made of the equivalent composition of the specific precipitate at various reference points in the reaction range. 4. Certain theoretical and practical implications of the findings are pointed out.
Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN
Authors: Klaas P.J.M. van Gisbergen, Marta Sanchez-Hernandez, Teunis B.H. Geijtenbeek, Yvette van Kooyk
Journal: The Journal of Experimental Medicine (2005)

Neutrophils are key players of the innate immune system that provide a first line of defense against invading pathogens. However, it is unknown whether neutrophils can interact with dendritic cells (DCs) to modulate adaptive immune responses. We demonstrate that neutrophils strongly cluster with immature DCs and that activated, not resting, neutrophils induce maturation of DCs that enables these DCs to trigger strong T cell proliferation and T helper type 1 polarization of T cells. This neutrophil–DC interaction is driven by the binding of the DC-specific, C-type lectin DC-SIGN to the β2-integrin Mac-1. Strikingly, DC-SIGN only interacts with Mac-1 from neutrophils, but not from other leukocytes, mainly because of specific Lewisx carbohydrates that are present on the αM chain of Mac-1 from neutrophils. Furthermore, we show that besides the formation of cellular contact, the tumor necrosis factor-α produced by activated neutrophils is essential for inducing DC maturation. Our data demonstrate that DC-SIGN and Mac-1 define a molecular pathway to establish cellular adhesion between DCs and neutrophils, thereby providing a novel cellular link between innate and adaptive immunity.
2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF
Authors: Nicola J. Mabjeesh, Daniel Escuin, Theresa M. LaVallee, Victor S. Pribluda, Glenn M. Swartz, Michelle S. Johnson, Margaret T. Willard, Hua Zhong, Jonathan W. Simons, Paraskevi Giannakakou
Journal: Cancer Cell (2003)
Risk factors for long-term renal survival after renal transplantation
Authors: J Broekroelofs, C A Stegeman, G Navis, A M Tegzess, D De Zeeuw, P E De Jong
Journal: Journal of the American Society of Nephrology (1998)

Chronic progressive renal function loss is a main cause of long-term graft loss after initially successful renal transplantation. Transplanted kidneys share some risk factors for renal function loss, such as hypertension or proteinuria, with diseased native kidneys. Recently, it has been shown that renal function loss is influenced by the angiotensin-converting enzyme (ACE) (insertion/deletion [I/D]) genotype in renal disease in diseased native kidneys. This study examines whether donor or recipient ACE (I/D) genotype is a risk factor for graft loss after renal transplantation. To avoid bias by acute events, graft survival was studied, with patients dying with a functioning graft censored, starting at 12 mo after transplantation in a cohort of 367 patients transplanted between 1987 and 1994 with at least 2 yr of follow-up. Mean follow-up was 58 mo. ACE (I/D) genotype was determined by PCR on stored donor and recipient lymphocytes. Neither donor nor recipient ACE (I/D) genotype was associated with graft survival. However, Cox proportional hazards analysis identified recipient, but not donor, ACE (I/D) genotype D-allele to be independently associated with a shorter time to graft loss in subgroups of patients at high risk for graft loss defined by a creatinine clearance <50 ml/min (n = 108, P = 0.017) or proteinuria > or =0.5 g/24 h at 12 mo (n = 97, P = 0.0051) after transplantation. In conclusion, recipient ACE (I/D) genotype was associated with time to graft loss in a specific high-risk subgroup of the study population. This suggests that the effect of ACE (I/D) genotype on graft survival only becomes apparent when other risk factors are simultaneously present.
The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT)
Authors: Andrew J Molyneux, Jacqueline Birks, Alison Clarke, Mary Sneade, Richard S C Kerr
Journal: The Lancet (2014)
Hospital Lymph Node Examination Rates and Survival After Resection for Colon Cancer
Authors: Sandra L. Wong, Hong Ji, Brent K. Hollenbeck, Arden M. Morris, Onur Baser, John D. Birkmeyer
Journal: JAMA (2007)

Several studies suggest improved survival among patients in whom a higher number of nodes are examined after colectomy for colon cancer. The National Quality Forum and other organizations recently endorsed a 12-node minimum as a measure of hospital quality.To assess whether hospitals that examine more lymph nodes after resection for colon cancer have superior late survival rates.Retrospective cohort study, using the national Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1995-2005), of US patients undergoing colectomy for nonmetastatic colon cancer (n = 30 625). Hospitals were ranked according to the proportion of their patients in whom 12 or more lymph nodes were examined and then were sorted into 4 evenly sized groups. Late survival rates were assessed for each hospital group, adjusting for potentially confounding patient and clinician characteristics.Hospitals' lymph node examination rates in association with cancer staging, use of adjuvant chemotherapy (indicated for patients with node-positive disease), and 5-year survival rate.Hospitals with the highest proportions of patients with examination of 12 or more lymph nodes tended to treat lower-risk patients and had substantially higher procedure volumes. After adjusting for these and other factors, there remained no statistically significant relationship between hospital lymph node examination rates and survival after surgery (adjusted hazard ratio, highest vs lowest hospital quartile, 0.95; 95% confidence interval, 0.88-1.03). Although the 4 hospital groups varied widely in the number of lymph nodes examined, they were equally likely to find node-positive tumors and had very similar overall unadjusted rates of adjuvant chemotherapy (26% vs 25%, highest vs lowest hospital quartile).The number of lymph nodes hospitals examine following colectomy for colon cancer is not associated with staging, use of adjuvant chemotherapy, or patient survival. Efforts by payers and professional organizations to increase node examination rates may have limited value as a public health intervention.
Differential Regulation of Elafin in Normal and Tumor-Derived Mammary Epithelial Cells Is Mediated by CCAAT/Enhancer Binding Protein β
Authors: Tomoya Yokota, Tuyen Bui, Yanna Liu, Min Yi, Kelly K. Hunt, Khandan Keyomarsi
Journal: Cancer Research (2007)

Abstract CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor implicated in the control of development, differentiation, and proliferation of mammary epithelial cells. However, it remains unclear how C/EBPβ is involved in tumor suppression through its interaction with specific downstream genes in breast cancer. Tumor cells overexpress serine proteases, which play crucial roles in tumor invasion and metastasis. Elafin is an endogenous serine protease inhibitor and is transcriptionally down-regulated in most tumor cell lines. In this study, we show that C/EBPβ is differentially expressed in normal versus tumor cell lines and normal adjacent versus tumor tissues obtained from breast cancer patients. We identified elafin as a downstream effector of C/EBPβ and show that elafin is also differentially regulated between normal and tumor cells. The mechanism by which C/EBPβ regulates elafin expression is through its direct interaction with the elafin promoter. There are three C/EBPβ binding sites involved in the elafin promoter activity, and the overexpression of C/EBPβ transactivates the elafin gene through these sites in tumor cells. RNA interference studies in normal cells further evidenced the requirement of the C/EBPβ for the elafin expression and negative feedback loop between C/EBPβ and elafin. We suggest that elafin is a novel substrate of C/EBPβ, and alterations in C/EBPβ isoforms result in their differential binding to the elafin promoter, leading to the altered expression of the elafin between normal and tumor cells. [Cancer Res 2007;67(23):11272–83]
Comparison of Fixed-Dose Weight-Adjusted Unfractionated Heparin and Low-Molecular-Weight Heparin for Acute Treatment of Venous Thromboembolism
Authors: Clive Kearon, Jeffrey S Ginsberg, Jim A Julian, James Douketis, Susan Solymoss, Paul Ockelford, Sharon Jackson, Alexander G Turpie, Betsy MacKinnon, Jack Hirsh, Michael Gent
Journal: JAMA (2006)

When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism.To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism.Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety.Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy.Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization.Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, -2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, -0.3%; 95% confidence interval, -2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group.Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment.clinicaltrials.gov Identifier: NCT00182403.
Infliximab for Diabetic Macular Edema Refractory to Laser Photocoagulation
Authors: Petros P. Sfikakis, Vlassis Grigoropoulos, Ioannis Emfietzoglou, George Theodossiadis, Nicholas Tentolouris, Evi Delicha, Christina Katsiari, Kleopatra Alexiadou, Erifili Hatziagelaki, Panayiotis G. Theodossiadis
Journal: Diabetes Care (2010)

OBJECTIVE Because many patients with diabetic macular edema (DME) do not respond to focal/grid laser photocoagulation, the only currently approved treatment, alternatives are needed. Based on encouraging preliminary findings, we aimed to assess efficacy and safety of the anti–tumor necrosis factor (TNF) monoclonal antibody infliximab in this condition. RESEARCH DESIGN AND METHODS This was a single-center, double-blind, randomized, placebo-controlled, crossover study. Eleven patients with sight-threatening DME persisting after two sessions of laser photocoagulation received infliximab (5 mg/kg) intravenously at weeks 0, 2, 6, and 14, followed by placebo at weeks 16, 18, 22, and 30, or vice versa. Blinding was maintained to week 32, when the final assessments were performed. Best corrected visual acuity evaluated by a mixed-models approach for imbalanced crossover design using the percentage difference as the outcome variable was the primary study end point. Data were analyzed on an intention-to-treat basis. RESULTS Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 ± 5.1 (mean ± SD) letters read at baseline to 28.8 ± 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 ± 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 ± 10.3 at baseline to 30.4 ± 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 ± 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8–43.7; P = 0.017). Infliximab treatment was well tolerated. CONCLUSIONS The positive results of this small phase III study suggest that larger and longer term trials should be conducted to assess the efficacy of systemic or intravitreal anti-TNF agent administration for primary treatment of DME.
Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes.
Authors: C M Ryan, M O Geckle
Journal: Diabetes Care (2000)

To examine the extent to which type 2 diabetes is associated with poorer performance on measures of learning, memory, psychomotor speed, and problem-solving in middle-aged adults.This cross-sectional study evaluated 50 adults (age range 34-65 years, mean 50.8) with type 2 diabetes and 50 demographically similar community control subjects without diabetes. Each subject received a thorough physical examination and a detailed neuropsychological assessment. Factor analysis was used to assign specific tests to 1 of 4 cognitive domains (learning, memory for stories, problem-solving, and psychomotor speed). Hierarchical regression analysis was used to identify demographic and biomedical variables associated with cognitive dysfunction.Learning, memory, and problem-solving skills were unaffected by type 2 diabetes. In contrast, psychomotor slowing was predicted by a diagnosis of diabetes (r2 change = 0.075, P < 0.002) with additional variance in psychomotor efficiency explained independently by HbA1 (r2 = 0.064, P < 0.003) and vibratory threshold (r2 = 0.112, P < 0.0001). The magnitude of psychomotor slowing on specific tests ranged from 12% (Digit Vigilance) to 23% (Grooved Pegboard).Middle-aged adults with type 2 diabetes manifest psychomotor slowing that is associated with poorer metabolic control, whereas learning, memory, and problem-solving skills appear to be largely intact. The development of psychomotor slowing may be a manifestation of a "central neuropathy" induced by chronic hyperglycemia.
Changing clinical behaviour by making guidelines specific
Authors: Susan Michie, Marie Johnston
Journal: BMJ (2004)

Efforts to get doctors to follow guidelines have overlooked the importance of clear and concise recommendationsThe problems of getting people to act on evidence based guidelines are widely recognised. 1 An overview of 41 systematic reviews found that the most promising approach was to use a variety of interventions including audit and feedback, reminders, and educational outreach. 1The effective interventions often involved complicated procedures and were always an addition to the provision of guidelines.None of the studies used the simplest intervention-that is, changing the wording of the guidelines.We examine the importance of precise behavioural recommendations and suggest how some current guidelines could be improved.
A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide and adapalene in the treatment of mild to moderate facial acne vulgaris
Authors: A. Langner, A. Chu, V. Goulden, M. Ambroziak
Journal: British Journal of Dermatology (2007)

Background Antibiotics are often combined with other agents to provide topical acne treatments that are effective against both inflammatory and noninflammatory lesions and minimize the development of antibiotic resistance. Retinoids and associated treatments also have anti-inflammatory activity and decrease microcomedo formation. To date, few direct comparisons of these different acne treatments have been conducted. Objectives To compare the clinical effectiveness of two treatments for facial acne: a ready-mixed once-daily gel containing clindamycin phosphate 10 mg mL−1 + benzoyl peroxide 50 mg mL−1 (CDP + BPO; Duac®; Stiefel, High Wycombe, U.K.) and a once-daily gel containing adapalene 0·1% (ADA; Differin®; Galderma, Watford, U.K.). Methods In this assessor-blind, randomized study; 65 patients were treated with CDP + BPO once daily and 65 patients with ADA once daily. The treatment period was 12 weeks and lesion counts, acne grade and global improvement were assessed at weeks 1, 2, 4, 8 and 12. Results CDP + BPO showed an earlier onset of action with a faster significant reduction in inflammatory and total lesion counts than ADA. A between-group comparison of the percentage change from baseline showed that CDP + BPO was statistically significantly superior to ADA from week 1 onwards both for inflammatory lesions (P ≤ 0·001) and for total lesions (P ≤ 0·004). While 76% of inflammatory lesions remained at week 2 for patients using ADA, in contrast, only 55% of inflammatory lesions remained at week 2 in the CDP + BPO group, resulting in a treatment effect of 1·38. Thus CDP + BPO removed 38% more inflammatory lesions than ADA at this timepoint. The trend in favour of CDP + BPO, although less marked, continued to the end of the study. CDP + BPO was better tolerated than ADA, with a greater proportion of ADA-treated patients experiencing treatment-related adverse events. Adjunctive topical or oral agents and their impact on acne were not studied in this trial. Due to product differences, this study could not be double blinded but was only single (assessor) blinded. Conclusions CDP + BPO and ADA are both effective treatments for acne, but CDP + BPO has a significantly earlier onset of action, is significantly more effective against inflamed and total lesions and is better tolerated, which should improve patient compliance.
Natural Killer and<i>NK-Like</i>T-Cell Activation in Colorectal Carcinoma Patients Treated with Autologous Tumor-Derived Heat Shock Protein 96
Authors: Lorenzo Pilla, Paola Squarcina, Jorgelina Coppa, Vincenzo Mazzaferro, Veronica Huber, Daniela Pende, Cristina Maccalli, Gloria Sovena, Luigi Mariani, Chiara Castelli, Giorgio Parmiani, Licia Rivoltini
Journal: Cancer Research (2005)

Abstract Heat shock proteins (HSPs) are involved in the activation of both adaptive and innate immune systems. Here, we report that vaccination with autologous tumor-derived HSP96 of colorectal cancer patients, radically resected for liver metastases, induced a significant boost of natural killer (NK) activity detected as cytokine secretion and cytotoxicity in the presence of NK-sensitive targets. Increased NK activity was associated with a raise in CD3−CD56+ NK and/or CD3+CD56+ NK-like T cells, displaying enhanced expression of NKG2D and/or NKp46 receptors. Up-regulated expression of CD83 and CD40 and increased interleukin-12 release on stimulation were observed in CD14+ cells from post-HSP96 peripheral blood mononuclear cells, suggesting an indirect pathway of NK stimulation by HSP96-activated monocytes. Additionally, CD3−CD56+ and CD3+CD56+ lymphocytes were found to undergo functional and phenotypic activation on in vitro exposure to HSP96 even in the absence of monocytes, supporting a potential direct activity of HSP96 on these cell subsets. This evidence was confirmed by the specific binding of FITC-conjugated HSP96 to a subset of both CD3−CD56+ and CD3+CD56+ cells in peripheral blood mononuclear cells from colorectal cancer patients. Altogether, these findings identify the activation of the NK compartment as an additional immunologic effect of autologous tumor-derived HSP96 administration in cancer patients.