tbuckley/cabot-search huggingface dataset:
Mishandling Misconduct: The NSABP Lumpectomy Trial
Authors: Kay Dickersin
Journal: JAMA (1994)

To the Editor.  —Dr Rennie 1 was right on target in his editorial comments. His Editorial on what went wrong in the NSABP misconduct case highlights numerous areas, within the scientific process in general and the NSABP specifically, in need of critical examination and revision.  The process of understanding what happened in this unfortunate episode has strayed considerably from the mark, however. At a recent international professional meeting I attended, the head of the NSABP, Dr Bernard Fisher, was praised and the bully boys at the National Cancer Institute (NCI) were excoriated for their respective roles in spearheading important breast cancer trials and in impaling Fisher. The scientific and medical community appears all too ready to focus on the individuals involved and not the more critical issue of where the system broke down and the ways in which it should be modified so that similar problems do not occur in
Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial
Authors: S. Reitamo, P. Spuls, B. Sassolas, M. Lahfa, A. Claudy, C.E.M. Griffiths
Journal: British Journal of Dermatology (2001)

The identification of a highly potent immunosuppressive/antiproliferative agent with an acceptable toxicity profile has long been a goal for the management of severe plaque psoriasis.To investigate the efficacy and safety of sirolimus (Rapamune) for severe psoriasis when given alone or in association with cyclosporin.In a randomized, double-blind, eight parallel group, pilot study in 24 out-patient centres in seven European countries, 150 patients, 18 years and older, with severe chronic plaque psoriasis were given sirolimus 0.5, 1.5 and 3.0 mg m(-2) daily for 8 weeks, either alone or in association with a subtherapeutic dose of cyclosporin (1.25 mg kg(-1) daily). Cyclosporin 5 mg kg(-1) daily was the positive control and cyclosporin 1.25 mg kg(-1) daily the negative control. The primary efficacy variable was the mean percentage reduction in Psoriasis Area and Severity Index (PASI). Safety assessments included monitoring of adverse events, clinical laboratory parameters and sirolimus/cyclosporin blood concentrations.The greatest mean percentage decreases in PASI were seen with cyclosporin 5.0 mg kg(-1) daily (70.5%) and with sirolimus 3.0 mg m(-2) daily + cyclosporin 1.25 mg kg(-1) daily (63.7%). Both groups demonstrated significantly better results than cyclosporin 1.25 mg kg(-1) daily (mean decrease 33.4%). Serum creatinine levels were significantly lower for groups with sirolimus alone and sirolimus plus reduced-dose cyclosporin when compared with cyclosporin 5.0 mg kg(-1) daily. Adverse events associated with sirolimus included thrombocytopenia (5%), hyperlipidaemia (9%), aphthous stomatitis (9%) and acne (13%), whereas adverse events associated with cyclosporin included hot flushes (12%), hyperlipidaemia (9%) and increased serum creatinine (9%).The concomitant administration of sirolimus with a subtherapeutic dose of cyclosporin in severe psoriasis may permit a reduction in their respective toxicities, notably cyclosporin-induced nephrotoxicity.
Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7
Authors: Y. Yin, A. M. Grabowska, P. A. Clarke, E. Whelband, K. Robinson, R. H. Argent, A. Tobias, R. Kumari, J. C. Atherton, S. A. Watson
Journal: Gut (2010)

Helicobacter pylori (H pylori) infection is a major risk factor in the development of distal gastric adenocarcinoma. Development of the invasive phenotype is associated with the phenomenon of epithelial:mesenchymal transition (EMT). Soluble heparin-binding epidermal growth factor (HB-EGF) has been implicated in this process. A study was undertaken to investigate the possibility that matrix metalloproteinase (MMP)-7 is upregulated in H pylori infection as a result of hypergastrinaemia, which may enhance shedding of HB-EGF and contribute towards EMT in gastric adenocarcinoma cell lines.Three gastric epithelial cell lines (AGS, MGLVA1 and ST16) were co-cultured with the pathogenic H pylori strain 60190 and non-pathogenic strain Tx30a in an in vitro infection model. Gene expression was quantified by real-time PCR, HB-EGF shedding by ELISA and protein expression by immunofluorescence or immunohistochemistry. The INS-GAS mouse, a transgenic mouse model of gastric carcinogenesis which overexpresses amidated gastrin, was used to investigate the in vivo relationship between HB-EGF, MMP-7, gastrin and EMT.The pathogenic strain of H pylori significantly upregulated EMT-associated genes Snail, Slug and vimentin in all three gastric cell lines to a greater degree than the non-pathogenic strain. Pathogenic H pylori also upregulated HB-EGF shedding, a factor implicated in EMT, which was partially dependent on both gastrin and MMP-7 expression. Gastrin and MMP-7 siRNAs and MMP-7 neutralising antibody significantly reduced upregulation of HB-EGF shedding in H pylori infected gastric cell lines and reduced EMT gene expression. The effect of H pylori on EMT was also reversed by gastrin siRNA. Neutralisation of gastrin in the INS-GAS mouse model reduced expression of MMP-7, HB-EGF and key EMT proteins.The upregulation of MMP-7 by pathogenic H pylori is partially dependent on gastrin and may have a role in the development of gastric cancer, potentially through EMT, by indirectly increasing levels of soluble HB-EGF.
Beneficial effect of chronic bradycardial pacing on capillary growth and heart performance in volume overload heart hypertrophy.
Authors: A J Wright, O Hudlicka, M D Brown
Journal: Circulation Research (1989)

We have previously reported that chronic bradycardial pacing increases both capillary density/mm2 (CD) and maximal work output in normal rabbit hearts. This technique has now been applied to rabbits with volume-overload hypertrophy due to lesion of the aortic valve. Four groups of animals were studied: controls (C), paced (P), valve-lesioned (VL), and paced valve-lesioned (PVL). The aortic valve was lesioned 8 weeks before the acute experiments; pacing was started 4 weeks before the acute experiments, and thus, the PVL group had developed hypertrophy before pacing was started. The degree of hypertrophy was similar in VL hearts whether paced or not: heart wt/body wt ratio increased by 33.5 +/- 8.9% (mean +/- SEM) in VL and 25.2 +/- 8.2% in PVL versus control animals of similar body weight (p less than 0.001). The hearts of the PVL animals showed a higher CD (2,277 +/- 107) than VL hearts (1,383 +/- 43), CD in C hearts of similar weights being 1,595 +/- 103, and in P hearts 2,350 +/- 194. Thus, CD was lower by 14% in VL and higher by 43% in PVL than in C hearts. Valve-lesioning had a significant effect in reducing maximal cardiac minute work (p less than 0.001), whereas pacing significantly improved maximal cardiac minute work (p less than 0.001) to 2.467 +/- 0.206 J/g x 10(-4) in the P group versus 1.609 +/- 0.105 in the C group.(ABSTRACT TRUNCATED AT 250 WORDS)
Energy intake and energy expenditure in prepubertal males with asthma
Authors: C Maffeis, E Chiocca, M Zaffanello, M Golinelli, L Pinelli, AL Boner
Journal: European Respiratory Journal (1998)

This study aimed to measure energy intake (EI) and total energy expenditure (TEE) of asthmatic males and to validate diet history as a method of estimating their energy requirements. EI was assessed by dietary history and TEE by the heart-rate monitoring method in a group of asthmatic and nonasthmatic males. Resting energy expenditure (REE) adjusted for fat-free mass was higher in asthmatic than in nonasthmatic males (5,037 versus 4,839 kJ x day(-1), p&lt;0.05). TEE (93+/-1.8 versus 8.4+/-1.4 MJ x day(-1), respectively; p=NS) and EI (9.2+/-15 versus 8.8+/-15 MJ x day(-1), respectively, p=NS) were not statistically different in asthmatic and nonasthmatic male. EI was not statistically different from TEE in both groups of males. Asthmatic males showed an acceptable agreement between TEE and EI at the individual level (range of agreement: -3.2 to 2.9 MJ x day(-1)), and a good agreement at the group level (95% confidence interval for the bias, - 1.1 to 0.8 MJ x day(-1)). Males with mild-to-moderate asthma have a higher metabolic activity per unit fat-free mass than nonasthmatic males. This increased requirement is apparently well compensated by an adequate energy intake. Diet history is a suitable method for estimating energy requirements in males with mild-to-moderate asthma.
Comparative analysis of surface antigens in cultured human outer root sheath cells and epidermal keratinocytes: persistence of low expression of class I MHC antigens in outer root sheath cells in vitro
Authors: A. LIMAT, T. WYSS-CORAY, T. HUNZIKER, L.R. BRAATHEN
Journal: British Journal of Dermatology (2006)

In the anagen human hair follicle, the epithelial cells from the infrainfundibular portion and the hair matrix cells express markedly lower numbers of major histocompatibility complex class I molecules than interfollicular epidermal keratinocytes. During the catagen phase of the hair cycle, class I expression on these cells increases, and activated macrophages aggregate around the follicle, which has led to the hypothesis that the cells to be resorbed are recognized by virtue of their low class I antigen expression. In the present study, we showed that, in vitro, outer root sheath cells also maintain a lower constitutive expression of MHC class I molecules compared with epidermal keratinocytes. In contrast, other surface antigens such as HLA-DR, -DP and -DQ, ICAM-1, LFA-3 and CD29, which are all known to participate in leucocyte-keratinocyte interactions, were similarly expressed in both cell types. Furthermore, interferon gamma strongly upregulated MHC class I and II and ICAM-1 expression in both cell types, whereas CD29 and LFA-3 remained unaffected. Tumour necrosis factor alpha, to a lesser extent, also upregulated MHC class I and ICAM-1 expression, but not class II expression. The differences in constitutive surface antigen expression of infrainfundibular outer root sheath cells compared with interfollicular epidermal keratinocytes emphasizes a distinct role of this cell type in the hair cycle, and possibly also in alopecia areata.
Coexpression of Endothelin-Converting Enzyme-1 and Endothelin-1 in Different Stages of Human Atherosclerosis
Authors: Christian Ihling, Thomas Szombathy, Bernd Bohrmann, Manfred Brockhaus, Hans E. Schaefer, Bernd M. Loeffler
Journal: Circulation (2001)

Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis.To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1(+) cells were simultaneously ECE-1(+). Most importantly, there were significantly more ET-1(+) cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE(+) cells in the different compartments of the arterial wall.Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.
Binding of the Renal Epithelial Cell Line LLC-PK1 to Laminin Is Regulated by Protein Kinase C
Authors: RINA KAPADIA, PETER D. YURCHENCO, KURT AMSLER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The α6β1 integrin heterodimer has been implicated in the mediation of renal epithelial cell binding to laminin, and it has been suggested that this binding is important for renal morphogenesis and development. Studies of nonrenal cells have suggested that the functional activity of α6β1 integrin is regulated by protein kinase C (PKC) activity. In this study, the binding of a renal epithelial cell line, LLC-PK 1 , to laminin was characterized and the role of PKC activity in the modulation of binding was investigated. LLC-PK 1 cells bound to laminin-coated surfaces in a time- and laminin concentration-dependent manner. Binding was strongly inhibited by anti-β1 integrin antibodies and by anti-α6 integrin antibodies. Antibodies against α2 integrin and α3 integrin had little inhibitory effect. Cells bound to both whole laminin and laminin fragment E8, i.e. , the fragment to which the α6β1 integrin heterodimer binds. Exposure of cells to PKC activators for as little as 2 h enhanced cell binding to laminin approximately twofold, in a protein synthesis-dependent manner. PKC inhibitors antagonized this effect. PKC-stimulated binding was also inhibited by anti-β1 integrin and anti-α6 integrin antibodies. PKC activation did not alter expression of β1 integrin subunits at the cell surface after short time periods (2 to 4 h), but expression was increased after longer time periods (24 h). These results indicate that the renal epithelial cell line LLC-PK 1 binds to laminin via the α6β1 integrin heterodimer and binding is enhanced by PKC activation. The PKC-mediated enhancement of binding requires protein synthesis and is mediated in part by activation of surface α6β1 integrin.
Treatment of osteitis pubis and osteomyelitis of the pubic symphysis in athletes: a systematic review
Authors: Haemi Choi, Michael McCartney, Thomas M Best
Journal: British Journal of Sports Medicine (2008)

The authors examined the most current evidence for treatment options in athletes with osteitis pubis and osteomyelitis pubis, attempting to determine which options provide optimal pain relief with rapid return to sport and prevention of symptom reoccurrence.Three databases-MEDLINE, Cochrane Database of Systematic Reviews and CINAHL-were searched using the OVID interface for all years between 1985 and May 2008. References were analysed from included studies, and additional relevant articles were obtained for inclusion. Inclusion criteria included (1) humans only, (2) subjects had no apparent risk factors for development of osteitis pubis or osteomyelitis of the pubic symphysis other than athletic involvement, (3) both physical exam findings and diagnostic imaging were used to confirm either diagnosis, and (4) a definitive treatment strategy was identifiable for management of osteitis pubis or osteomyelitis of the pubic symphysis. In total, 25 articles were included in the review.There were no randomised controlled trials identified with this study's search strategy. A total of 195 athletes were diagnosed as having osteitis pubis (186 males, nine females) and treated with either conservative measures/physical therapy, local injection with corticosteroids and/or local anaesthetic, dextrose prolotherapy, surgery or antibiotic therapy. Six case reports/series described conservative treatment measures (physical therapy, rest, non-steroid anti-inflammatory drugs). Four case series explored the use of corticosteroid injections in treatment. One case series described the use of dextrose prolotherapy as a treatment modality. Six case series described various surgical techniques (pubic symphysis curettage, polypropylene mesh placement and pubic bone stabilisation) in treatment. Ten case reports/series (10 subjects) outlined antibiotic treatment of osteomyelitis of the pubic symphysis.The current medical literature shows only level 4 evidence of the treatment for osteitis pubis in 24 case reports/series in athletes. Without any direct comparison of treatment modalities, it is difficult to determine which individual treatment option is the most efficacious. Further study comparing the different treatment options is necessary to determine which modality provides the fastest return to sport.
Living With Prostate Cancer: Patients' and Spouses' Psychosocial Status and Quality of Life
Authors: Laurel L. Northouse, Darlene W. Mood, James E. Montie, Howard M. Sandler, Jeffrey D. Forman, Maha Hussain, Kenneth J. Pienta, David C. Smith, Martin G. Sanda, Trace Kershaw
Journal: Journal of Clinical Oncology (2007)

Despite the high prevalence of prostate cancer, little information is available on the quality of life of men and their spouses during the phases of illness. This study assessed patients' and spouses' quality of life, appraisal of illness, resources, symptoms, and risk for distress across three phases of prostate cancer: newly diagnosed, biochemical recurrence, and advanced.The sample consisted of 263 patient/spouse dyads. A stress-appraisal conceptual model guided the selection of variables which were then assessed with established instruments. Study variables were examined for phase effects (differences in dyads across three phases), role effects (patients v spouses), and phase-by-role interactions (differences within dyads across phases) using analysis of variance (ANOVA).More phase effects than role effects were found, indicating that the psychosocial experiences of patients and their spouses were similar, but differed from dyads in other phases. Dyads in the advanced phase were at highest risk for distress. These patients had the lowest physical quality of life, and their spouses had the lowest emotional quality of life of all participants. Dyads in the biochemical recurrence and advanced phases had more negative appraisals of illness and caregiving, greater uncertainty, and more hopelessness compared with dyads in the newly diagnosed phase. Spouses, in contrast to patients, had less confidence in their ability to manage the illness and perceived less support across all phases of illness.Phase-specific programs of care are needed to assist both men with prostate cancer and their spouses to manage the effects of illness.
Role of Exosomes in Myocardial Remodeling
Authors: Anders Waldenström, Gunnar Ronquist
Journal: Circulation Research (2014)

Exosomes are nanovesicles released from cells through exocytosis and are known to be mediators of proximal as well as distant cell-to-cell signaling. They are surrounded by a classical bilayered membrane with an exceptionally high cholesterol/phospholipid ratio. Exosomes were first described in 1977, then named prostasomes, and in 1987 the name exosome was coined. Exosomes contain surface proteins, some of which can act as labels in order to find their target cells. Exosomes also contain messages in the form of proteins and nucleic acids (RNA and DNA) that are transferable to target cells. Little is known and written about cardiac exosomes, although Gupta and Knowlton described exosomes containing HSP60 in 2007. It is now known that exosomes from cardiomyocytes can transfect other cells and that the metabolic milieu of the parental cell decides the quality of exosomes released such that they induce differential gene expression in transfected cells. Future clinical use of exosomes in diagnosis, monitoring disease progress, and treatment is promising.
The Na+/I− Symporter Mediates Iodide Uptake in Breast Cancer Metastases and Can Be Selectively Down-Regulated in the Thyroid
Authors: Irene L. Wapnir, Michael Goris, Anthony Yudd, Orsolya Dohan, Donna Adelman, Kent Nowels, Nancy Carrasco
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The Na+/I− symporter (NIS) is a key plasma membrane protein that mediates active iodide (I−) transport in the thyroid, lactating breast, and other tissues. Functional NIS expression in thyroid cancer accounts for the longstanding success of radioactive iodide (131I) ablation of metastases after thyroidectomy. Breast cancer is the only other cancer demonstrating endogenous functional NIS expression. Until now, NIS activity in breast cancer metastases (BCM) was unproven. Experimental Design: Twenty-seven women were scanned with 99mTcO4− or 123I− to assess NIS activity in their metastases. An 131I dosimetry study was offered to patients with I−-accumulating tumors. Selective down-regulation of thyroid NIS was tested in 13 patients with T3 and in one case with T3 + methimazole (MMI; blocks I− organification). NIS expression was evaluated in index and/or metastatic tumor samples by immunohistochemistry. Results: I− uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show NIS expression or activity. Thyroid I− uptakes were decreased to ≤2.8% at 24 h in T3-treated patients and 1/100 normal with T3/MMI. Uptake (2.9%) was calculated in a peribronchial metastasis on 131I dosimetry scans at 4 h with disappearance of the signal by 24 h. We estimated a therapeutic dose of 3000 cGy could be achieved in this metastasis with 100 mCi of 131I if the tumor exhibited the same dynamics as the T3/MMI-suppressed thyroid. Conclusions: This is the first article of in vivo, scintigraphically detected, NIS-mediated I− accumulation in human BCM. T3/MMI down-regulation of thyroid NIS makes 131I-radioablation of BCM possible with negligible thyroid uptake and radiation damage.
A Fully Human Antitumor ImmunoRNase Selective for ErbB-2-Positive Carcinomas
Authors: Claudia De Lorenzo, Angela Arciello, Rosanna Cozzolino, Donald B. Palmer, Paolo Laccetti, Renata Piccoli, Giuseppe D’Alessio
Journal: Cancer Research (2004)

Abstract We report the preparation and characterization of a novel, fully human antitumor immunoRNase (IR). The IR, a human RNase and fusion protein made up of a human single chain variable fragment (scFv), is directed to the ErbB-2 receptor and overexpressed in many carcinomas. The anti-ErbB-2 IR, named hERB-hRNase, retains the enzymatic activity of the wild-type enzyme (human pancreatic RNase) and specifically binds to ErbB-2-positive cells with the high affinity (Kd = 4.5 nm) of the parental scFv. hERB-hRNase behaves as an immunoprotoxin and on internalization by target cells becomes selectively cytotoxic in a dose-dependent manner at nanomolar concentrations. Administered in five doses of 1.5 mg/kg to mice bearing an ErbB-2-positive tumor, hERB-hRNase induced a dramatic reduction in tumor volume. hERB-hRNase is the first fully human antitumor IR produced thus far, with a high potential as a poorly immunogenic human drug devoid of nonspecific toxicity, directed against ErbB-2-positive malignancies.