tbuckley/cabot-search huggingface dataset:
Receptor for Activated C Kinase 1 (RACK1) and Src Regulate the Tyrosine Phosphorylation and Function of the Androgen Receptor
Authors: Sarah Kraus, Daniel Gioeli, Tomas Vomastek, Vicki Gordon, Michael J. Weber
Journal: Cancer Research (2006)

Abstract The androgen receptor (AR) remains functionally important in the development and progression of prostate cancer even when the disease seems androgen “independent.” Because signal transduction by growth factor receptors increases in advanced prostate cancer and is capable of sensitizing the AR to androgen, there is considerable interest in determining the mechanisms by which signaling systems can modulate AR function. We show herein that the adaptor/scaffolding protein receptor for activated C kinase 1 (RACK1), which was previously reported to interact with the AR, modulates the tyrosine phosphorylation of AR and its interaction with the Src tyrosine kinase. We also show that down-regulation of RACK1 by short interfering RNA inhibits growth and stimulates prostate-specific antigen transcription in androgen-treated prostate cancer cells. Our results suggest that RACK1 mediates the cross-talk of AR with additional binding partners, such as Src, and facilitates the tyrosine phosphorylation and transcriptional activity of the AR. (Cancer Res 2006; 66(22): 11047-54)
First report of Ehrlichia ewingii detected by molecular investigation in dogs from Brazil
Authors: L.S. Oliveira, K.A. Oliveira, L.C. Mourão, A.M. Pescatore, M.R. Almeida, L.G. Conceição, M.A.M. Galvão, C. Mafra
Journal: Clinical Microbiology and Infection (2009)
Airwaves
Authors: W. Wedzicha
Journal: Thorax (2003)

Traffic accidents are a major issue in patients with sleep apnoea and nasal CPAP (continuous positive airway pressure) therapy improves driving performance. However, information is required on the time course of improvement so that patients can be advised when to restart driving after starting CPAP or whether they can drive safely after missing treatment. Turkington and colleagues used a simulator to study the time course of driving performance after starting CPAP therapy. They found that driving performance had significantly improved by 7 days and that, after stopping CPAP therapy, the improvements were maintained for up to 1 week after withdrawal although the effect size was now smaller. This study provides some valuable information on driving performance for all of us who treat patients with sleep apnoea. See page 56
Prognostic factors influencing survival in patients with B‐cell small lymphocytic lymphoma
Authors: Marin Nola, Steven Z. Pavletic, Dennis D. Weisenburger, Lynette M. Smith, Martin A. Bast, Julie M. Vose, James O. Armitage
Journal: American Journal of Hematology (2004)

Abstract The term “B‐cell small lymphocytic lymphoma” (B‐SLL) is generally reserved for patients with lymph node masses that show the histology and immunophenotype of B‐cell chronic lymphocytic leukemia (B‐CLL) but who are not leukemic. The aim of our study was to define clinical factors that predict for survival in B‐SLL. Thirty‐nine patients with B‐SLL and with less than 5,000 mature‐appearing lymphocytes/μL in the peripheral blood were studied. The median follow‐up of survivors was 6.6 years (range, 1.6–12.3 years). The estimated 5‐year overall survival (OS) and failure‐free survival (FFS) were 66% and 23%, respectively. In the univariate analysis, significant adverse predictors for OS were age ≥60 years, B symptoms, elevated serum LDH, low hemoglobin (&lt;11 g/dL), and high International Prognostic Index (IPI) score (3–5). In multivariate analysis, the IPI score was the only significant predictor of OS. Anemia and B symptoms were additionally predictive of poor OS in patients with low IPI scores. Am. J. Hematol. 77:31–35, 2004. © 2004 Wiley‐Liss, Inc.
Paracrine changes in the peritoneal environment of women with endometriosis
Authors: W Kupker
Journal: Human Reproduction Update (1998)

During the past decade, macrophage-derived substances such as prostanoids, cytokines, growth factors and angiogenic factors have been detected in the peritoneal fluid of women with endometriosis. In particular, growth-promoting and angiogenic factors are considered to be substantially involved in the pathogenesis of endometriosis. In this study, vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta) and intercellular adhesion molecule 1 (ICAM-1), substances recently detected in the peritoneal fluid of women with endometriosis, were assessed with regard to their concentrations in different stages of endometriosis and changes of the peritoneal paracrine activity after medical treatment with a gonadotrophin releasing hormone agonist (GnRHa). Peritoneal fluid was obtained from patients with endometriosis during laparoscopy before and after a 4-month treatment with a GnRHa. VEGF, TGF-beta and ICAM-1 could be detected in all women presenting with various stages of active endometriosis. After GnRHa therapy, all patients showed significant decreases in mean concentrations of VEGF (194+/-77 pg/ml), TGF-beta (902+/-273 pg/ml) and ICAM-1 (157+/-52 ng/ml). Patients with stage III and IV endometriosis (according to the rAFS score) had much higher concentrations of VEGF and TGF-beta before treatment compared with those patients with mild endometriosis (rAFS stages I and II). The most striking decrease in concentration was for TGF-beta, from 902 pg/ml before to 273 pg/ml after therapy. These results indicate an important role for paracrine activity in the establishment and maintenance of endometriosis. Indeed, treatment with a GnRHa may reduce paracrine activity in the peritoneal cavity via hypo-oestrogenism and provide proof of successful therapy.
Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice
Authors: Mary K. Kennedy, Moira Glaccum, Sandra N. Brown, Eric A. Butz, Joanne L. Viney, Monica Embers, Naoto Matsuki, Keith Charrier, Lisa Sedger, Cynthia R. Willis, Kenneth Brasel, Philip J. Morrissey, Kim Stocking, JoAnn C. L. Schuh, Sebastian Joyce, Jacques J. Peschon
Journal: The Journal of Experimental Medicine (2000)

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.
Hemodynamic Changes in Trained Dogs During Experimental Renal Hypertension
Authors: FREDERICK OLMSTED, IRVINE H. PAGE
Journal: Circulation Research (1965)

The hemodynamic events, during onset of experimental renal hypertension, and during its progression to the chronic state, were recorded in 19 trained quiet dogs for 20 to 30 minutes daily for four to forty-two days. This was made possible by implanting a flow probe around the root of the aorta, and a catheter in the aortic arch for connection to an external pressure gauge. Continuous graphic recordings of blood pressure, cardiac output, stroke volume, heart rate, and peripheral resistance were made daily during a period of training to obtain control values, and after hypertension was initiated by partial occlusion of a renal artery and unilateral nephrectomy. The average mean arterial pressure in 34 unanesthetized dogs in this study was 85 mm Hg (range, 68 to 116 mm Hg). This is about 30% below values previously reported by others in unanesthetized dogs. These low pressures were ascribed to lack of restraint, to training, and to the natural posture of the dogs. At onset of hypertension a sharp rise in arterial pressure was accompanied by a decrease of cardiac output and heart rate, and by a large abrupt increase of peripheral resistance. After one to four days, the continued rise of arterial pressure was associated with return of cardiac output and heart rate toward normal. Peripheral resistance eventually stabilized at a level above that of the initial large rise. A chronic state of hypertension was reached by ten to twenty days after the initial rise of pressure. At this time cardiac output and heart rate were restored to normal, while peripheral resistance remained elevated. Studies lasting for as long as forty-two days did not show further changes. If the renal arterial constriction was severe, a third, "malignant" phase ensued with extreme elevation of diastolic pressure, reduction of cardiac output, and greatly increased peripheral resistance. This terminated in uremic death after a few days.
Blistering time as a parameter for the strength of dermoepidermal adhesion: a systematic review and meta-analysis
Authors: L.K. Hatje, C. Richter, U. Blume-Peytavi, J. Kottner
Journal: British Journal of Dermatology (2014)

Skin ageing is associated with a flattening of the dermoepidermal junction and a less effective anchoring system, predisposing to bulla formation, trauma and shear-type injuries. An artificial and controlled technique for standardized dermoepidermal separation is the suction blister method, whereby the strength of dermoepidermal adhesion is characterized by blistering time. To identify and quantify influencing factors on blistering time in healthy humans. A search in the Medline and Embase databases (1946 to June 2014) and in reference lists was conducted. In total, results of 146 suction blister experiments in 3418 individuals reported in 59 publications were analysed. The median blister diameter was 6 mm (IQR 5-6) and the median suction pressure was -210 mmHg (IQR -200 to -300), resulting in a median blistering time of 75 min (IQR 48-120). In the multivariate model, skin temperature and age were the strongest predictors for suction blistering time (P < 0·001, R(2) adjusted = 0·707). This strong association between temperature and suction blistering indicates that the dermoepidermal junction loses its strength with increasing skin temperature. This finding supports the practice of skin and tissue cooling to prevent injuries. The increased vulnerability of the skin seems to exist irrespectively of applied mechanical loads. We conclude that blistering time is an important and clinically relevant (outcome) parameter measuring the structural and mechanical integrity of deeper cutaneous layers.
AN ELECTRON MICROSCOPE STUDY ON THE ACANTHOLYTIC AND DYSKERATOTIC PROCESSES IN DARIER DISEASE
Authors: PATRICIA R. MANN, K. R. HAYE
Journal: British Journal of Dermatology (1970)

SUMMARY.— Electron microscope studies have been made on 2 patients suffering from Darier's disease. The changes observed in the desmosometonofilament complex in the acantholytic process differ from those previously reported. The structure and formation of “corps rond’ are described; similar changes also occur in groups of cells apparently involved together.
Collaborative Analysis of α-Synuclein Gene Promoter Variability and Parkinson Disease
Authors: Demetrius M. Maraganore
Journal: JAMA (2006)

Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking.To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset.We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally.Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset.Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55).This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.
Elements Related to Heterogeneity of Antibody-Dependent Cell Cytotoxicity in Patients Under Trastuzumab Therapy for Primary Operable Breast Cancer Overexpressing Her2
Authors: Stefania Varchetta, Nadia Gibelli, Barbara Oliviero, Elena Nardini, Roberto Gennari, Giovanna Gatti, Luzemira Santos Silva, Laura Villani, Elda Tagliabue, Sylvie Ménard, Alberto Costa, Francesco F. Fagnoni
Journal: Cancer Research (2007)

Abstract Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56+ T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16+ lymphocytes was influenced by 158 V/F polymorphism of FcγRIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16+ lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism. [Cancer Res 2007;67(24):11991–9]
Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer
Authors: Erick Gamelin, Remy Delva, Jacques Jacob, Yacine Merrouche, Jean Luc Raoul, Denis Pezet, Etienne Dorval, Gilles Piot, Alain Morel, Michele Boisdron-Celle
Journal: Journal of Clinical Oncology (2008)

A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival.Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m(2) FU plus 200 mg/m(2) folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg x h x L(-1)) previously established in other studies was reached.An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m(2)/wk in arm A and 1,790 +/- 386 mg/m(2)/wk (range, 900 to 3,300 mg/m(2)/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003).Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.
Clean living staves off autoimmunity
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

![Graphic][1] 

Fungal infections trigger arthritis in susceptible SKG mice (arrowheads indicate fungal spores in the lung).Autoreactive T cells are harmless until they are prodded into action by exposure to common microbes, according to Yoshitomi and colleagues on 

[page 949][2].
Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation
Authors: Henrik Ekberg, Helio Tedesco-Silva, Alper Demirbas, Štefan Vítko, Björn Nashan, Alp Gürkan, Raimund Margreiter, Christian Hugo, Josep M. Grinyó, Ulrich Frei, Yves Vanrenterghem, Pierre Daloze, Philip F. Halloran
Journal: New England Journal of Medicine (2007)

Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival.The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%).A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).
Preventing Coronary Attacks
Authors: D. Sharland
Journal: BMJ (1964)

BRIC JOS 1463 weight rapidly, which, curiously enough, has provoked some nurses and doctors to argue that this might in some way be detrimental, but the evident success of the method usually overcomes the objections.Certainly if one told a farmer that his young livestock were growing and gaining weight too fast he would laugh in one's face !But then, Sir, he has the advantage of having his feet placed firmly on the good earth.-Iam, etc., Stock, Essex.IAN G. WICKES.SIR,-I was astonished to see no reference at all to the development of the teeth in Dr. D. MacCarthy's article (21 November, p. 1309).Surely one of the main advantages of breast-feeding is that the teeth in later life will be harder and more durable than they would be with artificial feeding.Recently I went to see a girl who happened to be out.The mother said she had an appointment with her dentist; she complained that she was always there, whereas her two sons never needed any dental treatment.I said that was an easy one: the girl had been artificially fed and the boys had been breastfed.This proved to be the case.It would be interesting to have a dental surgeon's opinion.-Iam, etc.,