tbuckley/cabot-search huggingface dataset:
Clinical significance of genetic aberrations in secondary acute myeloid leukemia
Authors: Jelena D. Milosevic, Ana Puda, Luca Malcovati, Tiina Berg, Michael Hofbauer, Alexey Stukalov, Thorsten Klampfl, Ashot S. Harutyunyan, Heinz Gisslinger, Bettina Gisslinger, Tatiana Burjanivova, Elisa Rumi, Daniela Pietra, Chiara Elena, Alessandro M. Vannucchi, Michael Doubek, Dana Dvorakova, Blanka Robesova, Rotraud Wieser, Elisabeth Koller, Nada Suvajdzic, Dragica Tomin, Natasa Tosic, Jacques Colinge, Zdenek Racil, Michael Steurer, Sonja Pavlovic, Mario Cazzola, Robert Kralovics
Journal: American Journal of Hematology (2012)

The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% ± 9.4% vs. 35.4% ± 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.33-5.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms.
Skin testing for immediate hypersensitivity to betalactams: comparison between two commercial kits
Authors: J. L. Rodríguez‐Bada, M. I. Montañez, M. J. Torres, C. Mayorga, G. Canto, E. Perez‐Inestrosa, R. Suau, M. Blanca
Journal: Allergy (2006)

Introduction: Skin testing with major and minor determinants of benzylpenicillin is the recommended standard practice to evaluate subjects with immediate hypersensitivity to betalactams. The withdrawal of these products from the market has set us back to the early days, before the introduction of reagents for in vivo testing. Objectives: To compare a recently released kit of benzylpenicillin conjugated to poly‐ l ‐lysine (PPL) and minor determinants mixture (MDM) with the previously existing kit in a positive control group of subjects sensitized to major and/or minor determinants of benzylpenicillin. Methods: Skin tests with both kits were made in a group of positive subjects previously diagnosed with immediate hypersensitivity to penicillins and with positive results to PPL and/or MDM and in a negative control group. Radioallergosorbent test (RAST) inhibition assays with a pool of sera and individual samples were carried out to compare the inhibition capacity of PPL and MDM of both kits. Results: Of 22 cases selected from our historical group, 14 were positive: eight to PPL, three to MDM and three to both. These results were equivalent for both kits. RAST inhibition studies showed similar potencies in the inhibition of PPL and MDM. Conclusions: Both tests show similar results in terms of RAST inhibition assays and skin tests sensitivity and specificity in the groups selected. The new assay can be used for the same purpose and indications as the previous test.
A Study of Carboplatin-Coated Tube for the Unresectable Cholangiocarcinoma
Authors: Shinichi Mezawa, Hisato Homma, Tsutomu Sato, Tadashi Doi, Koji Miyanishi, Koichi Takada, Takehiro Kukitsu, Kazuyuki Murase, Naoto Yoshizaki, Minoru Takahashi, Sumio Sakamaki, Yoshiro Niitsu
Journal: Hepatology (2000)

Most cases of cholangiocarcinoma have reached an unresectable stage by the time they are discovered despite significant progress of diagnostic modalities. Many of these patients with obstructive jaundice are often treated by biliary drainage using stents to relieve the jaundice. However, the stent patency period is as short as 3 to 9 months because of tumor ingrowth or overgrowth, and mean survival is at most 12 months. Therefore, both continuous relief of obstructive jaundice and local control of the tumor are required in the treatment for advanced cholangiocarcinoma. In this investigation, we developed a new percutaneous transhepatic biliary drainage tube coated with carboplatin (carboplatin-coated tube; CCT). CCT continuously released a fixed amount of carboplatin for 4 weeks and showed an antitumor effect on human cholangiocarcinoma cell line HuCC-T1 in vitro. When CCT was embedded in subcutaneous tumor inoculated in nude mice, a significant reduction of tumor size with no apparent damage to normal adjacent tissue was observed. On the basis of these studies, 5 patients with inoperable cholangiocarcinoma were treated with CCT for 4 weeks. Overall efficacy rate of 5 patients with cholangiocarcinoma was 60% (partial response in 3 and no change in 2). No apparent side effect was observed in these patients. Thus, CCT may provide a new treatment modality for this disease. Randomized controlled trials comparing CCT therapy with palliative stenting are required to confirm these results.
Objective Response to Chemotherapy As a Potential Surrogate End Point of Survival in Metastatic Breast Cancer Patients
Authors: Paolo Bruzzi, Lucia Del Mastro, Maria P. Sormani, Lars Bastholt, Marco Danova, Christian Focan, George Fountzilas, James Paul, Riccardo Rosso, Marco Venturini
Journal: Journal of Clinical Oncology (2005)

To assess the validity of objective response to chemotherapy as a surrogate end point for survival in metastatic breast cancer.We carried out a meta-analysis on individual data from 2,126 metastatic breast cancer patients who were enrolled onto 10 randomized trials comparing standard versus intensified epirubicin-containing chemotherapy.The intensified chemotherapy was associated with a significantly higher tumor response rate compared with standard chemotherapy (pooled odds ratio for nonresponse, 0.60; 95% CI, 0.51 to 0.72). The intensified regimens also led to better (although not significant) survival (pooled odds ratio, 0.94; 95% CI, 0.86 to 1.04; P = .22). Tumor response was a highly significant predictor of survival (P < .0001). When tumor response was introduced in the Cox model, the hazard ratio in favor of experimental treatment changed from 0.94 to 1.005 (95% CI, 0.91 to 1.11; P = .92), indicating that no residual effect of the experimental treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of intensified epirubicin was a result of the increase in response rate. The median survival time of patients with complete response and partial response was 28.8 months (95% CI, 25.4 to 45.3 months) and 21.3 months (95% CI, 19.2 to 22.4 months), respectively; whereas, the median survival time of patients with no response was 14.6 months (95% CI, 13.9 to 15.4 months).These results support the hypothesis that the achievement of an objective response to chemotherapy in metastatic breast cancer is associated with a true survival benefit. The potential role of objective response as a surrogate end point for survival in chemotherapy trials of metastatic breast cancer warrants further investigation.
Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea: a prospective cohort study
Authors: Oriol Mitjà, Sheila A Lukehart, Gideon Pokowas, Penias Moses, August Kapa, Charmie Godornes, Jennifer Robson, Sarah Cherian, Wendy Houinei, Walter Kazadi, Peter Siba, Elisa de Lazzari, Quique Bassat
Journal: The Lancet Global Health (2014)

Skin infections with ulceration are a major health problem in countries of the south Pacific region. Yaws, caused by Treponema pallidum subspecies pertenue and diagnosed by the presence of skin ulcers and a reactive syphilis serology, is one major cause, but this infection can be confused clinically with ulcers due to other causative agents. We investigated T pallidum pertenue and another bacterium known to cause skin infections in the Pacific islands-Haemophilus ducreyi-as causes of skin ulceration in a yaws-endemic region. Additionally, we identified specific signs and symptoms associated with these causative agents of cutaneous ulcers and compared these findings with laboratory-based diagnoses.We did a prospective cohort study of five yaws-endemic villages (total population 3117 people) during a yaws elimination campaign in Papua New Guinea in April, 2013. We enrolled all consenting patients with chronic moist or exudative skin ulcers. We undertook a detailed dermatological assessment, syphilis serology, and PCR on lesional swabs to detect the presence of T pallidum pertenue and H ducreyi. Patients with PCR-confirmed bacterial infections were included in a comparative analysis of demographics and clinical features.Full outcome data were available for 90 people with skin ulcers. Of these patients, 17 (19%) had negative results in all molecular tests and were therefore excluded from the comparative analyses. A bacterial cause was identified in 73 (81%) participants-either H ducreyi (n=42), T pallidum pertenue (yaws; n=19), or coinfection with both organisms (dual infection; n=12). The demographic characteristics of the patients infected with yaws and with H ducreyi were similar. Skin lesions in patients with yaws and in those with dual infection were larger than those in patients infected with H ducreyi (p=0·071). The lesions in patients with yaws and dual infection were more circular in shape (79% and 67%) than in those infected with H ducreyi (21%; p<0·0001); more likely to have central granulating tissue (90% and 67% vs 14%; p<0·0001); and more likely to have indurated edges (74% and 83% vs 31%; p=0·0003). The prevalence of reactive combined serology (positive T pallidum haemagglutination test and rapid plasmin reagin titre of ≥1:8) was higher in cases of yaws (63%) and dual infections (92%) than in H ducreyi infections (29%; p<0·0001).In this yaws-endemic community, H ducreyi is an important and previously unrecognised cause of chronic skin ulceration. Reactive syphilis serology caused by latent yaws can occur in ulcers with the presence of H ducreyi alone. The introduction of PCR for ulcer surveillance could improve the accuracy of diagnosis in countries with yaws eradication campaigns.Newcrest Mining Company.
Randomized Phase II Study of Carboplatin and Etoposide With or Without the<i>bcl-2</i>Antisense Oligonucleotide Oblimersen for Extensive-Stage Small-Cell Lung Cancer: CALGB 30103
Authors: Charles M. Rudin, Ravi Salgia, Xiaofei Wang, Lydia D. Hodgson, Gregory A. Masters, Mark Green, Everett E. Vokes
Journal: Journal of Clinical Oncology (2008)

To assess the efficacy and toxicity of carboplatin, etoposide, and the bcl-2 antisense oligonucleotide oblimersen as initial therapy for extensive-stage small-cell lung cancer (ES-SCLC). bcl-2 has been implicated as a key factor in SCLC oncogenesis and chemotherapeutic resistance.A 3:1 randomized phase II study was performed to evaluate carboplatin and etoposide with (arm A) or without oblimersen (arm B) in 56 assessable patients with chemotherapy-naïve ES-SCLC. Outcome measures including toxicity, objective response rate, complete response rate, failure-free survival, overall survival, and 1-year survival rate.Oblimersen was associated with slightly more grade 3 to 4 hematologic toxicity (88% v 60%; P = .05). Response rates were 61% (95% CI, 45% to 76%) for arm A and 60% (95% CI, 32% to 84%) for arm B. The percentage of patients alive at 1 year was 24% (95% CI, 12% to 40%) with oblimersen, and 47% (95% CI, 21% to 73%) without oblimersen. Hazard ratios for failure-free survival (1.79; P = .07) and overall survival (2.13; P = .02) suggested worse outcome for patients receiving oblimersen. These results hold when adjusted for other prognostic factors, such as weight loss, in multivariate regression analysis.Despite extensive data supporting a critical role for Bcl-2 in chemoresistance in SCLC, addition of oblimersen to a standard regimen for this disease did not improve any clinical outcome measure. Emerging data from several groups suggest that this lack of efficacy may be due to insufficient suppression of Bcl-2 in vivo. Additional evaluation of this agent in SCLC is not warranted.
Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue
Authors: Gunisha Sagar, Raghuwansh P Sah, Naureen Javeed, Shamit K Dutta, Thomas C Smyrk, Julie S Lau, Nino Giorgadze, Tamar Tchkonia, James L Kirkland, Suresh T Chari, Debabrata Mukhopadhyay
Journal: Gut (2015)

<h3>Background and objectives</h3> New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis. <h3>Design</h3> Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes. <h3>Results</h3> In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen-activated protein kinases and promoted lipolysis by phosphorylating hormone-sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. <h3>Conclusions</h3> PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.
P11 Reduction in Healthcare Resource Utilisation with 2 Years Treatment with Omalizumab in Severe Atopic Asthmatics: A Single Centre Observation: Abstract P11 Table 1
Authors: H Cummings, J Thompson, A Bell, J Morjaria
Journal: Thorax (2012)

<h3>Background</h3> While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Omalizumab is licenced as add-on therapy for patients with uncontrolled severe persistent atopic (IgE-mediated) asthma. <h3>Aim</h3> Retrospective review of healthcare utilisation and clinical outcomes of the efficacy of Omalizumab administered as per NICE approval on a 2- or 4-weekly basis in adults with severe allergic asthma in our tertiary centre in Hull. <h3>Methods</h3> We compared data in our cohort of patients on Omalizumab therapy at 2-years pre-Omalizumab, 16-weeks, 1- and 2-years post-Omalizumab. Our primary outcome was healthcare utilisation (asthma-related hospital admissions, bed and critical care bed days, oral corticosteroid courses (OCS) and reduction in overall OCS dose). Secondary parameters assessed included subjective (asthma control test (ACT), and quality-of-life (AQLQ) and its domain scores) and objective parameters (spirometry and morning peak flows) outcomes. <h3>Results</h3> Our 9 patients (2 M, 7 F) on Omalizumab therapy had an average (±SD) age of 52 (±11.9) Overall in-hospital admissions reduced from 28 days in the 2 years pre-Omalizumab to 0, 4 and 3 days at 16-weeks, 1- and 2-years respectively. Correspondingly, medical bed days diminished from 163 pre-treatment to 0, 17 and 10 at 16-weeks, 1- and 2-years respectively. Astonishingly, critical care bed day’s utility declined from 36 pre-Omalizumab, to 0 at all post-Omalizumab time points. Furthermore, total OCS courses usage reduced noticeably from 39 pre-treatment to 5, 9 and 10 at 16-weeks, 1- and 2-years respectively. There were marked improvements in AQLQ and its domains, and ACT scores, however changes in objective measures assessed were minimal (see Table 1). <h3>Conclusion</h3> Results from our single centre, in a small cohort of severe atopic asthmatics treated with Omalizumab, have shown striking reductions in healthcare resource utilisation, OCS use and subjective assessments compared to the two years prior to its initiation. This real-life effectiveness of Omalizumab supports its utility in this group of severely allergic asthmatics refractory to standard treatment.
Contractile effect of the chemotactic factors f-Met-Leu-Phe and C5a on the human isolated umbilical artery. Role of cyclooxygenase products and tissue macrophages.
Authors: F Marceau, D deBlois, C Laplante, E Petitclerc, G Pelletier, J H Grose, T E Hugli
Journal: Circulation Research (1990)

Factors that are chemotactic for phagocytic leukocytes are known to elicit important acute circulatory changes, and the role of circulating leukocytes in these models is controversial. To evaluate the role of the blood vessel wall in the absence of circulating cells, spiral strips of human umbilical artery were exposed in vitro to the chemotactic peptides f-Met-Leu-Phe (1-100 nM) or C5a (2.5-25 nM). Contractile responses were observed for both peptides. Certain agonist analogues and a selective antagonist of the chemotactic action of f-Met-Leu-Phe behaved correspondingly as agonists and antagonist of the contractile effect on umbilical artery. The anaphylatoxin C3a also exerted a contractile effect on the tissue (25 nM and above), but this effect was highly tachyphylactic. Inhibitory drugs were used to examine the contributions of secondary mediators in eliciting the effects of C5a and f-Met-Leu-Phe. The contractile effect of both peptides was massively inhibited either by indomethacin or the thromboxane A2/prostaglandin H2 antagonist SQ 29548. Dazmegrel, a thromboxane A2 synthetase inhibitor, had partial inhibitory effects on contractions induced by either peptide. The contractile effect of C3a was prevented by indomethacin pretreatment. Vascular strips did not release measurable histamine in the bathing fluid after challenge with C5a or f-Met-Leu-Phe. The tissue apparently contains neither histamine nor mast cells. Autoradiography of 125I-labeled C5a or f-Met-Leu-Phe analogue showed specific binding of the peptides to cells dispersed in the vessel wall, but more frequently at the periphery. Cells stained positively for alpha-naphthyl acetate esterase showed a similar distribution. Pure cultures of smooth muscle cells derived from the umbilical artery failed to release prostanoids when exposed to f-Met-Leu-Phe or C5a, whereas fresh strips of this artery released more thromboxane B2 than the baseline in response to these peptides. We conclude that macrophagelike cells, present in the vessel wall, are the likely target cells for the chemotactic peptides. These cells trigger a contractile effect of the smooth muscle by generating cyclooxygenase products.
Digital Ischaemia and Malignant Disease
Authors: E. N. Wardle
Journal: BMJ (1967)

MMICJOURIt is, of course, much too early to assess the long-term success rate of such treatment, but so far the resuks have been quite impres- sive and a number of significant facts have emerged from the trial:Proper selection of cases is essntial.Recognition of the end point of treatment is difficult and comes only with appreciable clinical experience of the technique.Adequately treated lesions heal completely with an absolute minimum of scarring.The apparent absence of deep scarring and endarteritis permits the safe use of superficial irradiation at a later date should there be a residue or recurrence within the treated area.Superficial recurrences within previously
Treatment of Herniating Subdural Hematoma
Authors: Charles L. Wiseman
Journal: JAMA (1980)

To the Editor.—  Two letters (242:2844, 1979;241:2783,1979) appearing inThe Journaldiscussed successful neurosurgical intervention for acute subdural hematoma associated with transtentorial herniation. We describe a case in which noninvasive medical measures alone were successfully employed.  Report of a Case.—  A 33-year-old woman under treatment for metastatic breast cancer had been hospitalized for evaluation of frontal headache and thrombocytopenia (
Schizophrenia is a disease of general connectivity more than a specifically “social brain” network
Authors: Conrado Bosman, Enzo Brunetti, Francisco Aboitiz
Journal: Behavioral and Brain Sciences (2004)

Dysfunctions of the neural circuits that implement social behavior are necessary but not a sufficient condition to develop schizophrenia. We propose that schizophrenia represents a disease of general connectivity that impairs not only the “social brain” networks, but also different neural circuits related with higher cognitive and perceptual functions. We discuss possible mechanisms and evolutionary considerations.
Role of thrombin in pulmonary fibrosis
Authors: N.A. Hernández-Rodríguez, A.D. Cambrey, R.C. Chambers, A.J. Gray, R.J. McAnulty, G.J. Laurent, N.K. Harrison, A.M. Southcott, R.M. duBois, C.M. Black, M.F. Scully
Journal: The Lancet (1995)
Unmet needs in asthma: Global Asthma Physician and Patient (GAPP) Survey: global adult findings
Authors: G. W. Canonica, C. E. Baena‐Cagnani, M. S. Blaiss, R. Dahl, M. A. Kaliner, E. J. Valovirta
Journal: Allergy (2007)

Background: The Global Asthma Physician and Patient (GAPP) Survey is the first global quantitative survey designed to uncover asthma attitudes and treatment practices among separate groups of physicians and patients, with the goal of identifying barriers to optimal management. Method: A total of 5582 physician and patient interviews were conducted globally online, by telephone and face‐to‐face. This paper highlights key global findings from the adult arm (3559 interviews) conducted in 16 countries. Results: Physician and patient responses were found to differ when respondents were asked the same set of questions. Perceptions of time spent on asthma education, the quality of physician–patient communications, awareness and experience of side effects and understanding and knowledge of treatment noncompliance were found to differ between these two sets of respondents. Conclusions: The GAPP Survey not only defines an unmet need in asthma treatment, but also reveals that there is a direct relationship between the quality of physician–patient communication, the level of treatment side effects and the extent of patient compliance. These survey findings highlight a clear need for improved patient‐focused care in asthma.