tbuckley/cabot-search huggingface dataset:
A Germline Variant in the Interferon Regulatory Factor 4 Gene as a Novel Skin Cancer Risk Locus
Authors: Jiali Han, Abrar A. Qureshi, Hongmei Nan, Jiangwen Zhang, Yiqing Song, Qun Guo, David J. Hunter
Journal: Cancer Research (2011)

Genome-wide association studies on pigmentary phenotypes provide a pool of candidate genetic markers for skin cancer risk. The SNPs identified from a genome-wide association study of natural hair color were assessed for associations with the risk of three types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study [218 melanoma, 285 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 870 common controls]. Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (P value, 6.6 × 10(-4) for melanoma, 7.0 × 10(-7) for SCC, and 0.04 for BCC). This association was further replicated in additional samples (190 melanoma, 252 SCC, and 634 common controls). The P value in the replication set was 0.03 for melanoma and 4.2 × 10(-3) for SCC. The risk of BCC was replicated in an independent set of 213 cases and 718 controls (P value, 0.02). The combined results showed that the association with SCC reached the genome-wide significance level [odds ratio (OR) for additive model = 1.61, 95%CI, 1.36-1.91, P = 3.2 × 10(-8)]. The OR was 1.49 for melanoma (95%CI, 1.23-1.80; P = 4.5 × 10(-5)), and 1.32 for BCC (95%CI, 1.11-1.57; P = 1.6 × 10(-3)). Given that the T allele was shown previously to be associated with increased expression of IRF4 locus, further studies are warranted to elucidate the role of the IRF4 gene in human pigmentation and skin cancer development.
Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death
Authors: Lishu Duan, Bula J Bhattacharyya, Abdelhak Belmadani, Liuliu Pan, Richard J Miller, John A Kessler
Journal: Molecular Neurodegeneration (2014)

An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a constant feature of Alzheimer’s disease (AD) and is associated with deficits in spatial learning and memory. Induced pluripotent stem cells (iPSCs) derived from patients with AD as well as from normal controls could be efficiently differentiated into neurons with characteristics of BFCNs. We used BFCNs derived from iPSCs to model sporadic AD with a focus on patients with ApoE3/E4 genotypes (AD-E3/E4). BFCNs derived from AD-E3/E4 patients showed typical AD biochemical features evidenced by increased Aβ42/Aβ40 ratios. AD-E3/E4 neurons also exhibited altered responses to treatment with γ-secretase inhibitors compared to control BFCNs or neurons derived from patients with familial AD. BFCNs from patients with AD-E3/E4 also exhibited increased vulnerability to glutamate-mediated cell death which correlated with increased intracellular free calcium upon glutamate exposure. The ability to generate BFCNs with an AD phenotype is a significant step both for understanding disease mechanisms and for facilitating screening for agents that promote synaptic integrity and neuronal survival.
GP consortiums will need first class management support, says Nuffield Trust
Authors: A. O'Dowd
Journal: BMJ (2011)

England’s GP commissioning consortiums will fail without substantial investment in management and technology that is driven by capable leaders, a study of systems in the United States has warned.

Strong management will be vital when the new GP consortiums take charge of most of the NHS budget from 2013, says the report from the health policy think tank the Nuffield Trust.

The report examines the US experience of handing the equivalent of commissioning budgets to doctors over the past 20 years—which has met with mixed success.

Senior researchers from the trust visited four medical groups led by doctors in California. Around 2000 doctor led networks and groups emerged across the US from the mid-1980s. …
Gene-body mass index interactions are associated with methotrexate toxicity in rheumatoid arthritis: Table 1
Authors: Stella Aslibekyan, Jin Sha, David T Redden, Larry W Moreland, James R O'Dell, Jeffrey R Curtis, Ted R Mikuls, Richard J Reynolds, Maria I Danila, S Louis Bridges
Journal: Annals of the Rheumatic Diseases (2013)

Despite the introduction of multiple biological agents for the treatment of rheumatoid arthritis (RA), methotrexate (MTX) remains the initial drug of choice.1 Response to MTX therapy is highly heterogeneous between individuals. An extensive body of work illustrates the complexity of MTX response architecture, which includes genetic polymorphisms, environmental factors and gene-gene interactions.2 Among environmental contributors, elevated body mass index (BMI) has emerged as an important predictor of MTX toxicity.3 Using data from the Treatment of Aggressive Rheumatoid Arthritis (TEAR) trial,4 we present first evidence linking the risk of MTX-associated toxicity to interactions between genotype and BMI.

The TEAR trial, described in previous publications,4 compared two strategies (early intensive …
Cellobiose/mannitol sugar test--a sensitive tubeless test for coeliac disease: results on 1010 unselected patients.
Authors: L D Juby, J Rothwell, A T Axon
Journal: Gut (1989)

The cellobiose/mannitol (Ce/Ma) test is a non-invasive technique for investigating intestinal permeability. In coeliac disease there is a decreased absorption of small molecules and paradoxically increased absorption of large molecules. The simultaneous administration of cellobiose and mannitol as two probe molecules allows the permeability of the small bowel mucosa to be studied, eliminating extraneous factors such as gastric emptying, and incomplete urine collection. One thousand and ten patients presenting to a gastroenterology clinic with symptoms, signs, or biochemical indices compatible with coeliac disease had a Ce/Ma test. Eight hundred and seventeen had a normal test and of these 197 had a jejunal biopsy showing 148 normal mucosa, two coeliac disease, 43 non-specific abnormalities, four giardiasis. One hundred and ninety three had an abnormal test; of these 132 had a jejunal biopsy showing 62 normal mucosa, 48 coeliac disease, and 22 other abnormalities. Considering those who had jejunal biopsies, the sensitivity of the test for coeliac disease is 96%, specificity 70%, the predictive value of the positive 36%, and predictive value of the negative 99%. Eleven per cent of the patients with a 9false positive9 test had abnormalities in the jejunal biopsy or a diagnosis which could explain the abnormal permeability.
Cellular Retinol-Binding Protein I, a Regulator of Breast Epithelial Retinoic Acid Receptor Activity, Cell Differentiation, and Tumorigenicity
Authors: E. F. Farias, D. E. Ong, N. B. Ghyselinck, S. Nakajo, Y. S. Kuppumbatti, R. Mira y Lopez
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: Retinoic acid receptor (RAR) activation induces cell differentiation and may antagonize cancer progression. Cellular retinol-binding protein I (CRBP-I) functions in retinol storage and its expression is lower in human cancers than in normal cells. We hypothesized that retinol storage might be linked to RAR activation and thus that lowered CRBP-I function might impair RAR activity and cell differentiation. Methods: Sarcoma virus 40-immortalized human mammary epithelial cells (MTSV1-7) devoid of CRBP-I were transfected with wild-type CRBP-I or CRBP-I point mutants with low RA binding affinity. The subcellular localization of CRBP-I was investigated in these cells and in wild-type or CRBP-I null mouse mammary epithelial cells (MECs), using indirect immunofluorescence and sucrose gradient fractionation. RAR activity was assessed using reporter gene assays. Acinar differentiation and in vivo tumor growth were assessed in reconstituted basement membrane and athymic mice, respectively. Results: In cells expressing wild-type CRBP-I but not the CRBP-I mutants, CRBP-I was found mainly in lipid droplets, the retinol storage organelle, and this localization was associated with promotion of retinol storage by wild-type CRBP-I only. RAR activity was higher and acinar differentiation was observed in cells expressing wild-type but not mutant CRBP-I. RAR antagonist treatment blocked and chronic RA treatment mimicked, the CRBP-I induction of cell differentiation. Finally, CRBP-I suppressed tumorigenicity in athymic mice. Conclusions: Physiologic RAR activation is dependent on CRBP-I-mediated retinol storage, and CRBP-I downregulation chronically compromises RAR activity, leading to loss of cell differentiation and tumor progression.
Dicumarol Therapy
Authors: E. A. MURPHY, J. F. MUSTARD
Journal: Circulation Research (1960)

One of the problems of Dicumarol administration has been determination of the adequacy of therapy. A fundamental stage in thrombus formation in the circulation is platelet clumping. Since platelets are involved in both hemostasis and thrombosis, a study of changes in platelet function may prove useful. The effects of Dicumarol on platelet clumping and adhesiveness have, therefore, been studied and related to changes in other clotting mechanisms. Comparison of platelet function in control periods and during Dicumarol administration shows that this drug lowers the adhesive index and prolongs the platelet clumping time to a highly significant degree. The accuracy of estimates of these 2 platelet functions given by 3 other tests, prothrombin time, whole blood clotting time and plasma activity in the thromboplastin generation tests have been compared. By any criterion, degree of correlation, consistency of regression slopes, intercepts or scatter about regression lines, clotting time was the most efficient of the 3 tests for evaluting platelet function. The prothrombin time was the least efficient. Furthermore, hemorrhage from excessive dosage was closely related to the platelet clumping time and clotting time. It should be pointed out, however, that in about one-third of the patients the prothrombin time was as good an index of platelet clumping time as clotting time. While prothrombin times done with 2 different sources of thromboplastin may give congruous results in untreated patients, considerable discrepancies may appear during Dicumarol therapy. If prothrombin time is to be used as a guide to Dicumarol therapy, it is important to establish in each patient separately its reliability as a measure of the behavior of the clotting mechanism as a whole. For those in whom it seems reliable, an individual "therapeutic range" should be determined. For other cases, some other suitable test should be employed. It is emphasized that regulation of Dicumarol dosage is an individual problem and that only those tests shown to be reliable indices of safe effective modifications of clotting mechanism in the individual patient should be used.
Characterization of Asthma Exacerbations by Arg16Gly Genotype in Subjects with Asthma Receiving Salmeterol Alone or with Fluticasone Propionate
Authors: H NELSON, E BLEECKER, J CORREN, S YANCEY, H ORTEGA, D REILLY, A EMMETT, W ANDERSON
Journal: Journal of Allergy and Clinical Immunology (2008)
Acute exacerbation of chronic obstructive pulmonary disease and antibiotics: what studies are still needed?
Authors: C. Sohy, C. Pilette, M.S. Niederman, Y. Sibille
Journal: European Respiratory Journal (2002)

The use of antibiotics in acute exacerbations of chronic bronchitis (AECBs) remains the subject of controversy despite considerable medical and socioeconomic implications. First, the contribution of bacterial infection to AECBs is difficult to assess in patients with chronic obstructive pulmonary disease (COPD) who are chronically colonized with respiratory pathogens. In addition, several studies suggest a major role of viral infections in AECBs. Secondly, it is unlikely that all COPD patients will benefit from antibiotics during AECBs. In particular, the benefit in mild COPD remains uncertain. Unfortunately, the number of studies complying with evidence-based medicine requirements is too small for definite recommendations in AECBs to be drawn up. Considering the impact of acute exacerbations of chronic bronchitis on chronic obstructive pulmonary disease patients, as well as the community, and the impact of antibiotic therapy on the development of bacterial resistance, there is an urgent need for the design of appropriate multicentric studies to define the usefulness of this type of treatment in acute exacerbations of chronic bronchitis.
Immunomodulation by Electrically Enhanced Delivery of Plasmid DNA Encoding IL-12 to Murine Skeletal Muscle
Authors: M.Lee Lucas, Richard Heller
Journal: Molecular Therapy (2001)

Recent reports have shown the successful delivery of plasmid DNA to skeletal muscle by in vivo electroporation. However, most of these reports have used what has been characterized as low-voltage, millisecond pulses. One of the purposes of this study was to examine a wide range of parameters to establish a better understanding of the effects of field strength and pulse length. Two electroporation conditions, one utilizing low-voltage millisecond pulses and the other high-voltage microsecond pulses, were compared for their ability to deliver a molecule that can be measured systemically, IL-12. Not only was this molecule efficiently delivered, but one of the molecules it induces (IFN-γ) was also measured systemically, with expression peaking at greater than 200 pg/ml serum levels on day 7 and still as high as 40 pg/ml on day 21 when using electrical parameters of 100 V/cm, 20-ms pulses. Of the two types of parameters tested, low-voltage, millisecond pulses resulted in higher, prolonged expression of plasmid DNA than high-voltage, microsecond pulses. In summary, this report provides evidence that in vivo electroporation is an efficient method for the delivery of plasmid DNA, and its use in immunotherapy protocols should be furthered examined.
The serum levels of the cytokines involved in the Th17 and Th1 cell commitment are increased in individuals with borderline thrombocytopenia
Authors: Andreia Maria Camargos Rocha, Cláudia Souza, Gifone Aguiar Rocha, Fabrício Freire de Melo, Nelma Cristina Diogo Clementino, Marília Campos Abreu Marino, Dulciene Maria Magalhães Queiroz
Journal: Journal of Hematology & Oncology (2013)

Abstract The definition of immune Thrombocytopenia (ITP) as a peripheral blood platelet count less than 100 × 10 9 /L instead of the historical criteria of 150 × 10 9 /L renders subjects with platelets between 100 and 150 × 10 9 /L without a diagnosis. Here, we demonstrated that these subjects have enhanced levels of proinflammatory cytokines linked to Th1 and Th17 cell response, and are more frequently carriers of polymorphisms in genes that code cytokines involved in the commitment of Th1 and Th17 immune response, when compared with controls, similarly to that observed in patients with ITP.
IMMUNOPATHOGENICITY AND ONCOGENICITY OF MURINE LEUKEMIA VIRUSES
Authors: Byron P. Croker, Bert C. del Villano, Fred C. Jensen, Richard A. Lerner, Frank J. Dixon
Journal: The Journal of Experimental Medicine (1974)

This report clearly demonstrates that a systemic lupus erythematosus (SLE)-like syndrome and lymphoma can be induced in immunologically normal (BALB/c x NZB)F(1) mice by infection of neonates with a murine leukemia virus (MuLV) (Scripps leukemia virus [SLV] 60A) isolated from NZB lymphoblasts. SLV 60A was titered in vitro (XC test) and administered to newborn and adult (BALB/c x NZB)F(1) mice over six log(10) dilutions. Propagation of MuLV in the newborn recipients was indicated by greatly elevated serum Mu gs-1 levels which were proportional to the dose of virus given. The SLE-like syndrome was characterized by antinuclear antibodies (ANA) and immune complex-type glomerulonephritis. ANA production was related to the dose of virus and reached the highest levels at 8-16 wk. The incidence of glomerulonephritis was also correlated with the dose of virus and reached nearly 50% in the animals given the highest virus dose. Both titers of ANA and incidence of glomerulonephritis were greater in females than in males, although the amounts of Mu gs-1 in sera of both sexes were equal. The incidence of direct Coombs' positivity was not significantly affected by inoculation of this virus. The incidence and time of onset of thymocytic lymphoma were linearly related to the amount of virus inoculated. High serum Mu gs-1 levels predicted lymphoma development and reflected increases in the amount of infectious virus in the spleen. No induction of tumors, autoimmunity, or high serum Mu gs-1 levels followed administration of SLV 60A to 6-wk old (BALB/c x NZB)F(1) mice or inactivated 60A or active AKR virus to newborns.
THE ANTIGENS AND AUTOANTIGENS OF THE SEMINAL VESICLE
Authors: Frank Orsini, Sidney Shulman
Journal: The Journal of Experimental Medicine (1971)

Guinea pig vesicular fluid was characterized both biochemically and immunologically. Biochemical analyses showed this fluid to be homogeneous by ultracentrifugal analyses, revealing a single boundary with a sedimentation coeflicient of 1.5 S. In contrast, electrophoretic separation methods revealed six components, of which three were major components, of approximately equal proportions. They were termed I, II, and III. One of these components (II) was shown to be strongly antigenic in heteroimmunization, whereas components I and III failed to show any antigenicity, even after diverse attempts. This antigen (component II) was found to be highly tissue specific and species specific. Through procedures of isoimmunization, component II was also found to be immunogenic, giving rise (in male animals) to autoantibodies, A high proportion of injected guinea pigs showed positive skin tests and many revealed tissue lesions when the seminal vesicles were examined histologically. It is therefore concluded that experimental autoimmune disease of the seminal vesicle has been induced.
Phase II Trial of High-Dose Intermittent Interleukin-2 in Metastatic Renal Cell Carcinoma: A Southwest Oncology Group Study
Authors: R. M. Bukowski, P. Goodman, E. D. Crawford, J. S. Sergi, B. G. Redman, R. P. Whitehead
Journal: JNCI Journal of the National Cancer Institute (1990)

A phase II trial of intermittent highdose recombinant interleukin-2 (rIL-2) was initiated to evaluate the response rate, remission duration, and toxic effects in patients with measurable metastatic renal cell carcinoma. The rIL-2 was administered as a bolus intravenous infusion at a dose level of 10.0 × 10 6 U/m 2 three times weekly, preceded by indomethacin (50 mg orally). Dose reductions of rIL-2 for hypotension and other grade 3 or 4 toxic effects were permitted. Forty-four patients were entered and 41 were eligible. Previous treatment included nephrectomy (23 patients), radiation therapy (seven), and hormone therapy (three). Most toxic effects observed were moderate and included nausea, vomiting, anorexia (85%); hypotension (85%); fever, chills (78%); central nervous system changes (24%); myelosuppression (27%); and creatinine elevation (15%). Four instances of grade 4 toxicity were observed and included nausea, vomiting with dehydration; hypotension; and myocardial infarction. Thirty patients (73%) required dose adjustments because of toxicity. Five responses (12%) were seen, which included one complete and four partial. Sites of response included lung, liver, and soft tissue; the duration of response ranged from 2 to 20+ months. These results demonstrate that this schedule of rIL-2 can be administered in an outpatient setting, and can produce tumor regression in patients with metastatic renal cell carcinoma, including durable complete responses. [J Natl Cancer Inst 82: 143–146, 1990]
Opportunistic pulmonary strongyloidiasis complicating asthma treated with steroids.
Authors: T W Higenbottam, B E Heard
Journal: Thorax (1976)

A man aged 57 years who had lived most of his life in London, suffered from asthma which had begun during army service in Burma 37 years previously. Latterly he was treated with increasing doses of corticosteroids but his symptoms continued to worsen and he died of asthma. Necropsy revealed a heavy opportunistic infection of the bronchi and lungs by the nematode Strongyloides stercoralis which he had presumably acquired while on service abroad. The case illustrates the need, even in non-endemic areas, to suspect opportunistic pulmonary strongyloidiasis when a patient9s asthma worsens despite treatment with increasing doses of corticosteroids. Although it is a potentially lethal iatrogenic opportunistic infection, it is amenable to treatment with anthelminthic agents if recognized in time.
Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration
Authors: Jessica C. A. Bouma-ter Steege, Coen I. M. Baeten, Victor L. J. L. Thijssen, Sietske A. Satijn, Inge C. L. Verhoeven, Harry F. P. Hillen, John Wagstaff, Arjan W. Griffioen
Journal: Clinical Cancer Research (2004)

Abstract To study the relationship between the angiogenic profile and leukocyte infiltration of tumors, single cell suspensions of archival frozen medullary and ductal breast cancer tissues were analyzed by flow cytometry. The amount of leukocytes and endothelial cells was measured, as well as the expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell fraction. A significantly higher number (3.2-fold) of infiltrating leukocytes was observed in medullary carcinoma. The composition of this infiltrate was similar to that seen in ductal carcinomas. The more intense infiltrate was explained by the ∼3-fold enhanced endothelial ICAM-1 expression in medullary carcinoma. The angiogenic profile of all tumors was assessed by quantitative real-time reverse transcription-PCR analysis. Vascular endothelial growth factor (VEGF)-C and VEGF-D, but not VEGF-A, basic fibroblast growth factor, placental growth factor, and angiopoietins 1, 2, and 3 showed a relatively higher level of expression in ductal carcinoma than in medullary carcinoma. In vitro, both VEGF-C and VEGF-D were found to decrease endothelial ICAM-1 expression in the presence of basic fibroblast growth factor. These data suggest that in vivo angiogenic stimuli prevent the formation of an effective leukocyte infiltrate in tumors by suppressing endothelial ICAM-1 expression.
Changes in respiratory muscle function after neostigmine injection in patients with myasthenia gravis
Authors: L Radwan, M Strugalska, A Koziorowski
Journal: European Respiratory Journal (1988)

In sixteen patients with myasthenia gravis, the weakness of respiratory muscles, especially of expiratory, caused some disturbances in lung function. Thirty minutes after injection of neostigmine, general improvement of muscle function was accompanied by an increase of strength and endurance of respiratory muscles. The mean value of maximal inspiratory mouth pressure (PImax) increased by 33%, maximal expiratory mouth pressure (PEmax) by 23.5% and maximal voluntary ventilation (MVV) by 21%. As a consequence of these changes amelioration of lung function indices was found, vital capacity increasing on average by 13% and residual volume decreasing by 12.5%. We concluded that patients with generalized myasthenia gravis have disturbances in lung function which may be partially improved by neostigmine injection or other anticholinesterase agents.