tbuckley/cabot-search huggingface dataset:
Application of the tyrosinase assay to normal melanocytes in culture*
Authors: J. AUBOCK, D. KOFLER, M. SIFTER, P. FRITSCH
Journal: British Journal of Dermatology (1983)

Using a special selection technique, normal guinea‐pig melanocytes were maintained in highly purified but sparse cultures (˜104 cells/25 cm2 culture vessel) which showed little proliferative activity. The applicability of the Pomerantz tyrosinase assay was tested in this in vitro model system using three different approaches, namely crude cell extracts and viable cell cultures either in situ or in suspension. The latter modifications both proved too insensitive, whereas crude cell extracts allowed accurate measurements of the basal tyrosinase activity and its stimulation by various agents. In unstimulated cultures basal tyrosinase activities ranged from 3O% to 7OO%(mean 260%) above the blank values; intra‐assay and inter‐assay variability were 4.2% and 77.5% respectively. Stimulation with α‐MSH (10‐5m, 10‐6m), β‐MSH (10‐5 m), choleratoxin(10‐11 M)and cAMP(10‐4M) plus theophylline(10‐4 m) resulted in an increase of tyrosinase activity 30–65% above basal values. Melanotropin potentiating factor (10‐8m) enhanced the effects of α‐MSH (10‐6 m) by 20%. This assay modification provides a sensitive tool for comparative studies of melanogenesis in normal melanocytes, malignant melanocytes and otherwise altered melanocytes.
Nurses' Health Study: Log-Incidence Mathematical Model of Breast Cancer Incidence
Authors: Bernard Rosner, Graham A. Colditz
Journal: JNCI Journal of the National Cancer Institute (1996)

In 1983, Pike et al. developed a mathematical model to quantify the effects of reproductive risk factors on the incidence of breast cancer. In 1994, we modified that model to correct some deficiencies in the original model, including a lack of terms for spacing of births and an inability to easily accommodate births after age 40 years. Our extended Pike model, while improving on the original, still has serious disadvantages, such as difficulty in translating model parameters into relative risks (RRs) and an incomplete fit to data that slightly overestimated incidence for premenopausal women with an early age at first birth and that underestimated incidence for post-menopausal women with a late age at first birth.We undertook both the development of a new mathematical model to quantify the effects of reproductive risk factors on breast cancer incidence and validation of the model.A new log-incidence model of breast cancer incidence was developed using nonlinear regression methods, and a study population consisting of 89,132 women in the Nurses' Health Study from which a total of 2249 incident cases of breast cancer were identified. Subjects were followed from the return of the 1976 Nurses' Health Study questionnaire until June 1, 1990, or until the last questionnaire was returned, until the development of any cancer, or until death, yielding 1,148,593 person-years of follow-up. The log-incidence models were fitted using iteratively reweighted least squares analysis.The log-incidence model provided a better fit to that data than the extended Pike model, with parameter estimates interpretable in terms of RRs. This new model can be fitted using standard commercially available statistical software. In the model, younger parous women are generally at slightly higher risk than nulliparous women, which is true for both the observed and expected RRs, and older parous women, aged 55-64 years with an early age at first birth, are at lower risk than nulliparous women,while older women with a late age at first birth are at substantially higher risk than nulliparous women.Log-incidence models, such as this one, provide an efficient framework for modeling the effect of lifestyle risk factors on breast cancer incidence that may be specifically targeted to certain time periods of a woman's reproductive life.
BRAF mutation and gene methylation frequencies of colorectal tumours with microsatellite instability increase markedly with patient age
Authors: B Iacopetta
Journal: Gut (2005)

The microsatellite instability phenotype (MSI+) is observed in approximately 25% of colon cancers and 2% of rectal cancers. MSI+ is a hallmark of almost all hereditary non-polyposis colorectal cancers (HNPCC) where it is associated with germline mutations in one of the DNA mismatch repair genes.1 However, the large majority of MSI+ cancers occur as sporadic cases that arise following methylation induced silencing of the hMLH1 gene promoter. Sporadic MSI+ tumours are believed to originate in serrated polyps and display frequent and concurrent methylation of gene promoter regions but low frequencies of KRAS and TP53 mutations.2 In contrast, HNPCC associated MSI+ tumours originate in conventional adenomas and show frequent APC and KRAS mutations but infrequent methylation. Another striking difference is that BRAF mutations occur in most …
Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection.
Authors: M B Dunlop, R V Blanden
Journal: The Journal of Experimental Medicine (1977)

The cytotoxic T-cell response to lymphocytic choriomeningitis (LCM) virus infection was suppressed either in vitro or in vivo by addition of a high level of syngeneic virus-infected cells or syngeneic cells from congenital LCM virus carriers to the environment of the responding cells. This effect was not duplicated by formaldehyde-fixed carrier cells, nor could it be accounted for by 'cold' target competition by carrier cells at the level of the cytotoxicity assay. Conversely, suppression was produced in vivo by water-lysed, ultrasonically treated carrier cell suspensions, or by a large dose of LCM virus equivalent to that contained in the carrier cells. Thus a high level of infectious virus was a common factor in all observed examples of suppression. Based upon this, the following hypothesis, a form of 'forbidden clone deletion,' was proposed to account for virus-specific cytotoxic T-cell tolerance in LCM virus congenital carriers, or in high dose suppression. A high level of virus in lymphoid tissues, while not cytopathic per se, may result in infection of all or most T cells; this then may lead to deletion either via 'suicide' of individual, infected, cytotoxic T cells with receptors specific for virus-induced antigenic patterns on their own surface membranes, or by mutual lysis of two adjacent T cells.
Fluid Shift by Lower Body Positive Pressure Increases Pharyngeal Resistance in Healthy Subjects
Authors: Kuo-Liang Chiu, Clodagh M. Ryan, Satomi Shiota, Pimon Ruttanaumpawan, Michael Arzt, James S. Haight, Christopher T. Chan, John S. Floras, T. Douglas Bradley
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Fluid displacement into nuchal and peripharyngeal soft tissues while recumbent may contribute to narrowing and increased airflow resistance of the pharynx (Rph), and predispose to pharyngeal collapse in patients at risk for obstructive sleep apnea.To determine whether displacement of fluid from the lower body to the neck will increase both neck circumference and Rph in healthy subjects.In 11 healthy, nonobese subjects, studied while awake and supine, leg fluid volume, neck circumference, and Rph were measured at baseline. Subjects were then randomized to a control period or to application of lower body positive pressure (LBPP) of 40 mm Hg via antishock trousers to displace fluid from the legs, after which they crossed over to the other arm. Baseline measurements were repeated at 1 and 5 min during the control and LBPP periods.Compared with the control period, application of LBPP caused a significant reduction in leg fluid volume (p < 0.001) and a significant increase in neck circumference (p = 0.004). Rph remained stable during the control period, but increased significantly from baseline after 1 and 5 min of LBPP (from 0.43 +/- 0.10 to 0.60 +/- 0.11 cm H(2)O/L/s, p = 0.034, and to 0.87 +/- 0.19 cm H(2)O/L/s, p < 0.001, compared with baseline, respectively).Fluid displacement from the legs by LBPP increases neck circumference and Rph in healthy subjects. These findings suggest the hypothesis that fluid displacement to the upper body during recumbency may predispose to pharyngeal obstruction during sleep, especially in fluid overload states, such as heart and renal failure.
Influence of beta-adrenergic and cholinergic blockade on the electrophysiological effects of melperone in the dog heart in situ
Authors: E. S PLATOU, H. REFSUM, J. P AMLIE, K. LANDMARK
Journal: Cardiovascular Research (1981)

Melperone (0.5 to 12.5 mg.kg-1) reduced mean aortic blood pressure in pentobarbital anaesthetised dogs to a greater extent after beta1-adrenergic receptor blockade with atenolol than after cholinergic blockade with atropine. Electrophysiological studies demonstrated that increased heart rate and decreased atrioventricular nodal refractoriness after lower doses of melperone (0.5 to 2.5 mg.kg-1), could be prevented by pretreatment with atenolol. The melperone-induced decrease in atrioventricular nodal conduction time was, however, not affected by pretreatment with atenolol or atropine. Intra-atrial and His-Purkinje conduction times and QRS width were not affected by atenolol or atropine plus melperone. Melperone caused a dose-dependent and very pronounced increase in ventricular and, even more, atrial refractoriness after atenolol. The ventricular and atrial refractoriness increased less after pretreatment with atropine. Some of the cardiac electrophysiological effects of melperone thus depend on the degree of beta-adrenergic stimulation. The overall cardiac electrophysiological effects of melperone results from a combination of direct and indirect actions of the drug.
Microvascular Dysfunction in Chronic Total Coronary Occlusions
Authors: Gerald S. Werner, Markus Ferrari, Barbara M. Richartz, Oliver Gastmann, Hans R. Figulla
Journal: Circulation (2001)

Microvascular dysfunction is defined as reduced coronary flow reserve in the absence of an epicardial stenosis. This study determined its prevalence and relation to regional myocardial function in chronic total coronary occlusions (TCO).After recanalization and stenting of a TCO (duration, >4 weeks) in 42 patients, coronary flow velocity reserve (CFVR) was measured by intracoronary Doppler. In a subset of 27 patients, intracoronary pressure was recorded to obtain the fractional flow reserve (FFR). In 21 patients, the CFVR was reassessed after 24 hours. CFVR was <2.0 in 55% of all patients. In the subgroup with simultaneous pressure recordings, 52% of patients showed a CFVR<2.0 and a FFR>/=0.75, indicating microvascular dysfunction. Both reduced CFVR and reduced FFR occurred in only 2 patients (7.7%). CFVR and FFR were not correlated (r=0.03). A low CFVR was associated with a higher baseline average peak velocity (35.6+/-16.6 versus 22.4+/-11.5 cm/s; P=0.006). Doppler parameters did not change within 24 hours. Regional dysfunction had no influence on CFVR. Patients with diabetes and/or hypertension had a lower CFVR than those without this comorbidity (1.86+/-0.69 versus 2.36+/-0.45; P<0.05).Microvascular dysfunction was observed in 55% of TCOs, independent of the impairment of regional myocardial function. Dysfunction was observed more often in patients with diabetes and hypertension. Neither CFVR or FFR alone is appropriate for assessing angioplasty results in patients with a TCO; CFVR should be combined with FFR to differentiate microvascular dysfunction from residual coronary stenosis or diffuse disease.
ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation
Authors: Marit Westerterp, Andrea E. Bochem, Laurent Yvan-Charvet, Andrew J. Murphy, Nan Wang, Alan R. Tall
Journal: Circulation Research (2014)

Although recent genome-wide association studies have called into question the causal relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular disease, ongoing research in animals and cells has produced increasing evidence that cholesterol efflux pathways mediated by ATP-binding cassette (ABC) transporters and HDL suppress atherosclerosis. These differing perspectives may be reconciled by a modified HDL theory that emphasizes the antiatherogenic role of cholesterol flux pathways, initiated in cells by ABC transporters. ABCA1 and ABCG1 control the proliferation of hematopoietic stem and multipotential progenitor cells in the bone marrow and hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis in the spleen. Thus, activation of cholesterol efflux pathways by HDL infusions or liver X receptor activation results in suppression of hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis, leading to decreased production of monocytes and neutrophils and suppression of atherosclerosis. In addition, macrophage-specific knockout of transporters has confirmed their role in suppression of inflammatory responses in the arterial wall. Recent studies have also shown that ABCG4, a close relative of ABCG1, controls platelet production, atherosclerosis, and thrombosis. ABCG4 is highly expressed in megakaryocyte progenitors, where it promotes cholesterol efflux to HDL and controls the proliferative responses to thrombopoietin. Reconstituted HDL infusions act in an ABCG4-dependent fashion to limit hypercholesterolemia-driven excessive platelet production, thrombosis, and atherogenesis, as occurs in human myeloproliferative syndromes. Activation of ABC transporter-dependent cholesterol efflux pathways in macrophages, hematopoietic stem and multipotential progenitor cells, or platelet progenitors by reconstituted HDL infusion or liver X receptor activation remain promising approaches to the treatment of human atherothrombotic diseases.
Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies.
Authors: R J Murray, M G Kurilla, J M Brooks, W A Thomas, M Rowe, E Kieff, A B Rickinson
Journal: The Journal of Experimental Medicine (1992)

Epstein-Barr virus (EBV), a human herpes virus with oncogenic potential, persists in B lymphoid tissues and is controlled by virus-specific cytotoxic T lymphocyte (CTL) surveillance. On reactivation in vitro, these CTLs recognize EBV-transformed lymphoblastoid cell lines (LCLs) in an HLA class I antigen-restricted fashion, but the viral antigens providing target epitopes for such recognition remain largely undefined. Here we have tested EBV-induced polyclonal CTL preparations from 16 virus-immune donors on appropriate fibroblast targets in which the eight EBV latent proteins normally found in LCLs (Epstein-Barr nuclear antigen [EBNA] 1, 2, 3A, 3B, 3C, leader protein [LP], and latent membrane protein [LMP] 1 and 2) have been expressed individually from recombinant vaccinia virus vectors. Most donors gave multicomponent responses with two or more separate reactivities against different viral antigens. Although precise target antigen choice was clearly influenced by the donor's HLA class I type, a subset of latent proteins, namely EBNA 3A, 3B, and 3C, provided the dominant targets on a range of HLA backgrounds; thus, 15 of 16 donors gave CTL responses that contained reactivities to one or more proteins of this subset. Examples of responses to other latent proteins, namely LMP 2 and EBNA 2, were detected through specific HLA determinants, but we did not observe reactivities to EBNA 1, EBNA LP, or LMP 1. The bulk polyclonal CTL response in one donor, and components of that response in others, did not map to any of the known latent proteins, suggesting that other viral target antigens remain to be identified. This work has important implications for CTL control over EBV-positive malignancies where virus gene expression is often limited to specific subsets of latent proteins.
Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma
Authors: Wen-Jen Hwu, Susan E. Krown, Jennifer H. Menell, Katherine S. Panageas, Janene Merrell, Lynne A. Lamb, Linda J. Williams, Carolyn J. Quinn, Theresa Foster, Paul B. Chapman, Philip O. Livingston, Jedd D. Wolchok, Alan N. Houghton
Journal: Journal of Clinical Oncology (2003)

Purpose: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases. Patients and Methods: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m 2 /d × 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients &lt; 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients ≥ 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred. Results: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months’ duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. Conclusion: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.
Downregulation and altered spatial pattern of caveolin-1 in chronic plaque psoriasis
Authors: L. Campbell, P. Laidler, R.E.B. Watson, B. Kirby, C.E.M. Griffiths, M. Gumbleton
Journal: British Journal of Dermatology (2002)

Summary Background Caveolin‐1 is a key structural and functional protein for plasmalemmal invaginations termed caveolae. Caveolin‐1 is known to modulate multiple signal‐transducing pathways involved in cell differentiation and proliferation. Psoriasis is viewed as a multifactorial pathology characterized by keratinocyte hyperproliferation and abnormal cell maturation. We hypothesized that loss of caveolin‐1 within epidermal keratinocytes may contribute to the development and/or progression of the psoriatic phenotype. Objectives To examine the expression and spatial distribution of caveolin‐1 in skin biopsies from normal subjects and in patients with psoriasis. Methods Using immunohistochemical methods caveolin‐1 protein expression was assayed in two independent patient groups. Firstly, a retrospective analysis was conducted on archival skin samples obtained from nine normal subjects and from involved tissue of 12 patients with psoriasis. Following this, a prospectively designed study was conducted in 10 further patients with active psoriasis and involving caveolin‐1 staining of biopsy tissue from the uninvolved, advancing edge and lesional skin tissue from within the same subject. Results In normal skin or uninvolved skin from psoriasis patients intense caveolin‐1 staining was present throughout full‐thickness epidermis. In 20 of the 22 patient cases (combined retrospective and prospective samples) caveolin‐1 protein was significantly reduced and consistently showed very weak or absent staining within the hyperproliferative basal cell layers of the psoriatic plaque (P < 0·002 for retrospective archival study and P < 0·01 for prospectively designed study). Comparisons between caveolin‐1 staining in uninvolved tissue and at the advancing edge of a migrating plaque were more equivocal (P > 0·05). Conclusions The findings of this study are consistent with a downregulation of caveolin‐1 that may serve as an aetiological factor in the development and/or progression of psoriasis. Further mechanistic investigations are required with the potential that caveolin‐1 protein may be a novel target for therapy of psoriasis.
Why registries analysing cruciate ligament surgery are important
Authors: Lars Engebretsen, Magnus Forssblad, Martin Lind
Journal: British Journal of Sports Medicine (2015)

Postmortem microbiology (PMM) is a valuable tool in the identification of the cause of death and of factors contributory to death where death has been caused by infection. The value of PMM is dependent on careful autopsy planning, appropriate sampling, minimisation of postmortem bacterial translocation and avoidance of sample contamination. Interpretation of PMM results requires careful consideration in light of the clinical history, macroscopic findings and the histological appearances of the tissues. This consensus statement aims to highlight the importance of PMM in the hospital setting and to give microbiological and pathological advice on sampling in deaths occurring in hospital.
Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets
Authors: Vera Miranda-Gonçalves, Mrinalini Honavar, Céline Pinheiro, Olga Martinho, Manuel M. Pires, Célia Pinheiro, Michelle Cordeiro, Gil Bebiano, Paulo Costa, Isabel Palmeirim, Rui M. Reis, Fátima Baltazar
Journal: Neuro-Oncology (2012)

Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD147 and to assess the therapeutic impact of MCT inhibition in gliomas.MCTs and CD147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models.MCT1, MCT4, and CD147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed.This is the most comprehensive study reporting the expression of MCTs and CD147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment.