tbuckley/cabot-search huggingface dataset:
Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection
Authors: Robert I. Lehrer, Martin J. Cline
Journal: Journal of Clinical Investigation (1969)

The neutrophils and monocytes of a patient with disseminated candidiasis were found to lack detectable levels of the lysosomal enzyme myeloperoxidase (MPO), although they had normal levels of other granule-associated enzymes. Leukocytes from one of the patient's sisters also lacked detectable MPO; leukocytes from his four sons contained approximately one-third of mean normal peroxidase levels. Neither the patient nor his affected relatives had experienced frequent or unusual bacterial infections. The phagocytic activity of the patient's MPO-deficient neutrophils was intact, and the cells displayed normal morphologic and metabolic responses to phagocytosis. In contrast to normal leukocytes which killed 30.5+/-7.3% of ingested Candida albicans in 1 hr, however, the patient's neutrophils killed virtually none. His leukocytes also failed to kill the strain of C. albicans recovered from his lesions, as well as other Candida species. These MPO-deficient neutrophils killed Serratia marcescens and Staphylococens aureus 502A at an abnormally slow rate, requiring 3-4 hr to achieve the bactericidal effect attained by normal leukocytes after 45 min. No other abnormalities in his cellular or humoral immune responses were demonstrated. These findings suggest that hereditary MPO deficiency is transmitted as an autosomal recessive characteristic, that the homozygous state conveys enhanced susceptibility to disseminated candidiasis, and that MPO is necessary for candidacidal activity in human neutrophils. Although lending support to the suggested bactericidal role of MPO in leukocytes, the data indicate that alternative bactericidal mechanisms, effective in the absence of MPO, are functionally dominant in the human neutrophil.
S82 Airway Inflammation is Present by 4 Months in CF Infants Diagnosed on Newborn Screening
Authors: RM Thursfield, A Bush, EWFW Alton, JC Davies
Journal: Thorax (2012)

<h3>Introduction</h3> Cystic fibrosis (CF) newborn screening (NBS) allows early introduction of treatment, often before any symptoms arise with the aim of reducing airway infection and inflammation. UK nationwide screening began in 2007. <h3>Aims</h3> It is usual clinical practise at our centre to perform fibreoptic bronchoscopy (FOB) at the age of 3 months for all children with CF. The aim of this study was to establish the presence of infection and degree of inflammation in airways in the NBS cohort. Bronchoalveolar lavage fluid (BALF) was cultured and examined for cellular inflammation. <h3>Results</h3> Infants diagnosed by NBS undergoing routine FOB who had either BALF absolute cell count or differential cell count assessed were included in the study. 44 infants (48% female), median age (range) 15 (7–28) weeks met these criteria. The majority of these infants were symptom free however 13 (29%) had bacterial isolates from their BALF. Comparable data are also available for 71 children with established CF (median age 9.5 years; range 1.9–16.7 years) of whom 46 (65%) were BALF culture positive and for 6 healthy controls (median age 12.3 years, range 10.5–15.4 years). Cellular inflammation was present in the airways in infants diagnosed by NBS, both in those who were culture positive and negative in their BALF. Absolute BALF cell count and neutrophil differential were significantly higher in both NBS and established CF patients compared with healthy controls (p&lt;0.02). Median absolute cell counts and neutrophil differentials can be seen in table 1. For both NBS and established CF, in those who had bacteria isolated from their BALF, an increase in neutrophil differential was seen compared with those culture negative at the time of FOB although this did not reach significance in the NBS group. (NBS CF p= 0.05, established CF p&lt;0.01). <h3>Conclusion</h3> Our results demonstrate that inflammation is already present by 4 months of age in asymptomatic infants diagnosed through NBS, although at a lower level than seen in established CF. The results underscore the importance of early surveillance and lend support to the evolving focus on this age group for interventional trials.
Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
Authors: Michael E. Ward, Alice Taubes, Robert Chen, Bruce L. Miller, Chantelle F. Sephton, Jeffrey M. Gelfand, Sakura Minami, John Boscardin, Lauren Herl Martens, William W. Seeley, Gang Yu, Joachim Herz, Anthony J. Filiano, Andrew E. Arrant, Erik D. Roberson, Timothy W. Kraft, Robert V. Farese, Ari Green, Li Gan
Journal: The Journal of Experimental Medicine (2014)

Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3'-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.
Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Antiestrogen Therapy Failure
Authors: Amy R. Peck, Agnieszka K. Witkiewicz, Chengbao Liu, Ginger A. Stringer, Alexander C. Klimowicz, Edward Pequignot, Boris Freydin, Thai H. Tran, Ning Yang, Anne L. Rosenberg, Jeffrey A. Hooke, Albert J. Kovatich, Marja T. Nevalainen, Craig D. Shriver, Terry Hyslop, Guido Sauter, David L. Rimm, Anthony M. Magliocco, Hallgeir Rui
Journal: Journal of Clinical Oncology (2011)

Purpose To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. Patients and Methods Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. Results Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P &lt; .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). Conclusion Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.
Programmed cell death of keratinocytes in infliximab-treated plaque-type psoriasis
Authors: S. Krüger-Krasagakis, V.K. Galanopoulos, L. Giannikaki, M. Stefanidou, A.D. Tosca
Journal: British Journal of Dermatology (2006)

Tumour necrosis factor (TNF)-alpha blockade using infliximab, a chimeric anti-TNF-alpha antibody, is an effective treatment for plaque-type psoriasis, inducing remission in about 80% of patients.To examine infliximab-induced programmed cell death (PCD) of keratinocytes in psoriatic plaques on serial skin biopsy samples.Five patients with moderate to severe plaque-type psoriasis received infliximab infusions intravenously (5 mg kg(-1)) at weeks 0, 2 and 6. Biopsies of nonlesional and lesional skin (days 0, 5, 14 and 21) were obtained. Conventional microscopy was used to examine the morphology of the psoriatic keratinocytes. In situ detection of apoptosis was performed by electron microscopy and by immunohistochemical staining with anti-p53 and anti-caspase-3 antibodies. Results Infusion of infliximab induced a clinical response in all five patients with psoriasis, with a mean Psoriasis Area and Severity Index improvement of 24.8% already at day 5. This was accompanied by significant histopathological changes in the skin biopsy samples after infliximab treatment. Light and electron microscopic evaluation revealed apoptosis-like morphological changes in lesional keratinocytes, i.e. nuclear condensation, chromatin fragmentation and cytoplasmic vesiculation, visible already after the first infusion. These damaged keratinocytes stained positively for p53, but not for active caspase-3.The effects of infliximab in psoriasis extend beyond merely anti-inflammatory actions, and may include caspase-independent PCD of lesional keratinocytes. The PCD of keratinocytes may be an important mechanism that could explain at least in part the rapid and sustained therapeutic effect of infliximab in psoriasis.
Treatment of Skin Papillomas with Topical α-Lactalbumin–Oleic Acid
Authors: Lotta Gustafsson, Irene Leijonhufvud, Annika Aronsson, Ann-Kristin Mossberg, Catharina Svanborg
Journal: New England Journal of Medicine (2004)

We studied the effect on skin papillomas of topical application of a complex of alpha-lactalbumin and oleic acid (often referred to as human alpha-lactalbumin made lethal to tumor cells [HAMLET]) to establish proof of the principle that alpha-lactalbumin-oleic acid kills transformed cells but not healthy, differentiated cells.Forty patients with cutaneous papillomas that were resistant to conventional treatment were enrolled in a randomized, placebo-controlled, double-blind study, in which alpha-lactalbumin-oleic acid or saline placebo was applied daily for three weeks and the change in the volume of each lesion was recorded. After this first phase of the study, 34 patients participated in the second phase, an open-label trial of a three-week course of alpha-lactalbumin-oleic acid. Approximately two years after the end of the open-label phase of the study, 38 of the original 40 patients were examined, and long-term follow-up data were obtained.In the first phase of the study, the lesion volume was reduced by 75 percent or more in all 20 patients in the alpha-lactalbumin-oleic acid group, and in 88 of 92 papillomas; in the placebo group, a similar effect was evident in only 3 of 20 patients (15 of 74 papillomas) (P<0.001). After the patients in the initial placebo group had been treated with alpha-lactalbumin-oleic acid in the second phase of the study, a median reduction of 82 percent in lesion volume was observed. At follow-up two years after the end of the second phase, all lesions had completely resolved in 83 percent of the patients treated with alpha-lactalbumin-oleic acid, and the time to resolution was shorter in the group originally assigned to receive alpha-lactalbumin-oleic acid than among patients originally in the placebo group (2.4 vs. 9.9 months; P<0.01). No adverse reactions were reported, and there was no difference in the outcomes of treatment between immunocompetent and immunosuppressed patients.Treatment with topical alpha-lactalbumin-oleic acid has a beneficial and lasting effect on skin papillomas.
Progenitor-like Traits Contribute to Patient Survival and Prognosis in Oligodendroglial Tumors
Authors: Felicia Soo-Lee Ng, Tan Boon Toh, Esther Hui-Ling Ting, Geraldene Rong-Hui Koh, Edwin Sandanaraj, Mark Phong, Swee Seong Wong, Siew Hong Leong, Oi Lian Kon, Greg Tucker-Kellogg, Wai Hoe Ng, Ivan Ng, Carol Tang, Beng Ti Ang
Journal: Clinical Cancer Research (2012)

Patient-derived glioma-propagating cells (GPC) contain karyotypic and gene expression profiles that are found in the primary tumor. However, their clinical relevance is unclear. We ask whether GPCs contribute to disease progression and survival outcome in patients with glioma by analyzing gene expression profiles.We tapped into public sources of GPC gene expression data and derived a gene signature distinguishing oligodendroglial from glioblastoma multiforme (GBM) GPCs. By adapting a method in glioma biology, the Connectivity Map, we interrogated its strength of association in public clinical databases. We validated the top-ranking signaling pathways Wnt, Notch, and TGFβ, in GPCs and primary tumor specimens.We observed that patients with better prognosis correlated with oligodendroglial GPC features and lower tumor grade, and this was independent of the current clinical indicator, 1p/19q status. Patients with better prognosis had proneural tumors whereas the poorly surviving cohort had mesenchymal tumors. In addition, oligodendroglial GPCs were more sensitive to Wnt and Notch inhibition whereas GBM GPCs responded to TGFβR1 inhibition.We provide evidence that GPCs are clinically relevant. In addition, the more favorable prognosis of oligodendroglial tumors over GBM could be recapitulated transcriptomically at the GPC level, underscoring the relevance of this cellular model. Our gene signature detects molecular heterogeneity in oligodendroglial tumors that cannot be accounted for by the 1p/19q status alone, indicating that stem-like traits contribute to clinical status. Collectively, these data highlight the limitation of morphology-based histologic analyses in tumor classification, consequently impacting on treatment decisions.
A Phase II Study of SGN-30 in Cutaneous Anaplastic Large Cell Lymphoma and Related Lymphoproliferative Disorders
Authors: Madeleine Duvic, Sunil A. Reddy, Lauren Pinter-Brown, Neil J. Korman, John Zic, Dana A. Kennedy, Jennie Lorenz, Eric L. Sievers, Youn H. Kim
Journal: Clinical Cancer Research (2009)

Abstract Purpose: An open-label, multicenter, phase II study was conducted to define the safety and antitumor activity of the monoclonal antibody SGN-30 in patients with CD30+ primary cutaneous anaplastic large cell lymphoma (pc-ALCL), lymphomatoid papulosis (LyP), or transformed mycosis fungoides (T-MF). Experimental Design: In the initial course (six doses), patients received i.v. SGN-30 every 3 weeks; eligible patients could receive two additional courses. The initial dose level of 4 mg/kg was increased to 12 mg/kg by protocol amendment. Results: The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days). Fifteen of 23 patients (65%) experienced at least one adverse event during the study, most of which were mild or moderate. Conclusions: SGN-30 was clinically active in 16 of 23 patients with heavily pretreated pc-ALCL, LyP, and T-MF and was well tolerated in this study. (Clin Cancer Res 2009;15(19):6217–24)
Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy
Authors: Jenifer G Crilley, Ernest A Boehm, Edward Blair, Bheeshma Rajagopalan, Andrew M Blamire, Peter Styles, William J McKenna, Ingegerd Östman-Smith, Kieran Clarke, Hugh Watkins
Journal: Journal of the American College of Cardiology (2003)
The pre-clinical pharmacology of the inhaled muscarinic antagonist GSK573719 predicts once-daily clinical dosing
Authors: Dramane I. Lainé, Mark A. Luttmann, James J. Foley, Chris J. Dehaas, Charles J. Kotzer, Michael Salmon, William L. Rumsey
Journal: European Respiratory Journal (2011)

Introduction:  GSK573719 is a new, long-acting muscarinic antagonist offering sustained 24-h bronchodilation currently in phase III clinical trials for COPD.   Objectives:  To assess the pharmacology of GSK573719 in pre-clinical studies.   Methods/Results:  In CHO cells transfected with recombinant human M 3  receptors, GSK573719 demonstrated pM potency (–log pA 2 =23.9pM) in an acetylcholine (ACh)-mediated Ca 2+  mobilisation assay. Concentration-response curves indicated competitive antagonism with partial reversibility after drug wash out. Using isolated human bronchial strips in static tissue baths, GSK573719 was a potent, competitive antagonist (–log pA 2 =316pM) vs carbachol. Superfusion of bronchial strips with carbachol containing buffer showed that GSK573719 was slowly reversible in a concentration-dependent manner (1–100nM). Time to 50% restoration of contraction at 10nM was >600 min (vs 413 min with tiotropium bromide, 10nM). In conscious guinea pigs, GSK573719 dose-dependently blocked ACh-induced bronchoconstriction with long duration of action; a 2.5μg intratracheal dose elicited >50% bronchoprotection for >24h.   Conclusions:  GSK573719 is a potent muscarinic antagonist that demonstrates slow functional reversibility at cloned human M 3  receptors and at endogenous mAChR in isolated human bronchus. This profile translates into 24h duration of bronchodilation in the clinic, suitable as a once-daily treatment for COPD.  Funded by GSK.  *Formerly at GSK.
Chromosome abnormalities in human embryos
Authors: S Munne
Journal: Human Reproduction Update (1998)

The presence of numerical chromosome abnormalities in human embryos was studied using fluorescence in-situ hybridization with four or more chromosome-specific probes. When most cells of an embryo are analysed, this technique allows differentiation to be made between aneuploidy, mosaicism, haploidy and polyploidy. Abnormal types of fertilization, such as unipronucleated, tripronucleated zygotes and zygotes with uneven pronuclei, were studied using this technique. We have found a strong correlation between some types of dysmorphism with chromosomal abnormalities. In addition, the more impaired the development of an embryo, the more chromosomal abnormalities were detected in those embryos. Maternal age and other factors were linked to an increase in chromosome abnormalities (hormonal regimes, temperature changes), but not to intracytoplasmic sperm injection.
Diagnostic criteria for erosive lichen planus affecting the vulva: an international electronic-Delphi consensus exercise
Authors: R.C. Simpson, K.S. Thomas, P. Leighton, R. Murphy
Journal: British Journal of Dermatology (2013)

There is no defined set of criteria for diagnosing erosive lichen planus affecting the vulva (ELPV) and there is geographical variation in management.To reach consensus on clinicopathological diagnostic criteria for ELPV.This was a three-stage international electronic-Delphi exercise with a subsequent formal feedback process. In the first two rounds participants were asked to rate the importance of a list of clinicopathological criteria. Responses from round 1 were summarized and presented in round 2, along with additional criteria suggested by participants. In round 3, participants were asked to rate the items that had reached consensus as 'essential' or 'supportive' features in diagnosing ELPV. Consensus was defined as being reached if 75% of participants agreed on the importance of an item.A total of 73 experts representing dermatology, gynaecology, histopathology and genitourinary medicine participated; 69 (95%) completed all three rounds. Consensus was achieved for the following 'supportive' diagnostic criteria: (i) well-demarcated erosions/erythematous areas at the vaginal introitus; (ii) presence of a hyperkeratotic border to lesions and/or Wickham striae in surrounding skin; (iii) symptoms of pain/burning; (iv) scarring/loss of normal architecture; (v) presence of vaginal inflammation; (vi) involvement of other mucosal surfaces; (vii) presence of a well-defined inflammatory band involving the dermoepidermo junction; (viii) presence of an inflammatory band consisting predominantly of lymphocytes; and (ix) signs of basal layer degeneration. It was suggested that at least three supportive features should be present to make a diagnosis of ELPV, although this number is subject to further discussion.This study has identified a diagnostic dataset for ELPV that can be adopted into clinical practice and clinical trials.
HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis
Authors: I. Auger, C. Roudier, S. Guis, N. Balandraud, J. Roudier
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To test whether HLA-DR alleles influence the production of particular autoantibodies in rheumatoid arthritis (RA) patients, we screened synovial proteins with sera of RA patients homozygous for different HLA-DR alleles by using 2D blots. We found that sera of RA patients homozygous for HLA-DRB1*0404 recognised a 100-kDa synovial protein identified as calpastatin. We studied B and T cell epitopes on calpastatin and their association with HLA-DRB1*0404. <h3>Methods:</h3> The frequency of positive sera in patients expressing different RA-associated HLA-DR allele combinations was calculated by inhouse ELISA using purified synovial calpastatin or calpastatin peptides encompassing the entire calpastatin protein as immunosorbent. Interaction between calpastatin peptides and HLA-DR alleles was tested by a direct binding assay. T cell responses to calpastatin were measured in RA patients and controls. <h3>Results:</h3> We found that RA-associated HLA-DR alleles are associated with presence of autoantibodies to synovial calpastatin in RA patients' sera. HLA-DRB1*0404 is strongly associated with antisynovial calpastatin in RA sera. One linear B cell epitope is preferentially associated with HLA-DRB1*0404. Multiple peptides from calpastatin bind every tested HLA-DR allele associated or not with RA. Peptides from domain 1 and 4 of calpastatin are the best HLA-DR allele binders. The T cell response to calpastatin is frequent in RA patients and independent of the HLA-DR background. <h3>Conclusions:</h3> HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis.
Patient package inserts.
Authors: J D Collinge
Journal: BMJ (1978)

the limits of their own recognised competence in both diagnosis and treatment, but I think that Dr Waxman's use of the term "lay" is ambiguous.While "lay" originally meant "non-clerical," it is now sometimes understood to mean "non-medical," and hence his reference to "lay therapists'' in the first paragraph of his letter is perhaps misleading.The fact that his own society is helping to give training in hypnosis to professionals who are neither medically nor dentally qualified should make clear the recognised status of hypnosis in therapy today.