tbuckley/cabot-search huggingface dataset:
In vivo study of indomethacin in bronchiectasis: effect on neutrophil function and lung secretion
Authors: CG Llewellyn-Jones, MM Johnson, JL Mitchell, A Pye, VC Okafor, SL Hill, RA Stockley
Journal: European Respiratory Journal (1995)

Bronchiectasis is associated with sputum containing high levels of the proteolytic enzyme elastase, which is thought to be involved in the pathogenesis of the disease. Agents which inhibit neutrophil function and interfere with neutrophil elastase release may have a beneficial effect on the development and progression of such diseases. We have studied the effects of the nonsteroidal anti-inflammatory agent indomethacin on neutrophil function in nine patients with clinically stable bronchiectasis. All patients remained clinically stable during the study. We observed a significant reduction in peripheral neutrophil chemotaxis to 10 nmol.L-1 N-formyl-methionyl-leucyl-phenylalanine (FMLP) from a mean of 19.86 (SEM 1.35) to 8.46 (0.68) cells.field-1 after 4 weeks of therapy. There was also a significant reduction in fibronectin degradation both by resting and FMLP-stimulated neutrophils, from a mean of 1.90 (0.19) micrograms x 3 x 10(5) cells at the start of therapy to 0.87 (0.08) micrograms after 4 weeks, and from 3.17 (0.35) micrograms to 1.48 (0.05) micrograms, respectively. There was no effect on spontaneous or stimulated superoxide anion generation by neutrophils. Despite the marked changes in peripheral neutrophil function, no adverse effect was observed on viable bacterial load in the bronchial secretions. In addition, there was no difference in sputum albumin, elastase or myeloperoxidase levels, and only minor changes in the chemotactic activity of the sputum. These results suggest that nonsteroidal anti-inflammatory agents have a major effect on peripheral neutrophil function but do not appear to have an adverse effect on bacterial colonization of the airways.
Human papillomavirus mediated inhibition of DNA damage sensing and repair drives skin carcinogenesis
Authors: Martin Hufbauer, James Cooke, Gijsbertus T. J. van der Horst, Herbert Pfister, Alan Storey, Baki Akgül
Journal: Molecular Cancer (2015)

The failure to mount an effective DNA damage response to repair UV induced cyclobutane pyrimidine dimers (CPDs) results in an increased propensity to develop cutaneous squamous cell carcinoma (cSCC). High-risk patient groups, such as organ transplant recipients (OTRs) frequently exhibit field cancerization at UV exposed body sites from which multiple human papillomavirus (HPV)-associated cSCCs develop rapidly, leading to profound morbidity and increased mortality. In vitro molecular evidence indicates that HPV of genus beta-papillomavirus (β-PV) play an important role in accelerating the early stages of skin tumorigenesis. We investigated the effects of UV induced DNA damage in murine models of β-PV E6 oncoprotein driven skin tumorigenesis by crossing K14-HPV8-E6wt mice (developing skin tumors after UV treatment) with K14-CPD-photolyase animals and by generating the K14-HPV8-E6-K136N mutant mouse strain. Thymine dimers (marker for CPDs) and γH2AX (a marker for DNA double strand breaks) levels were determined in the murine skin and organotypic skin cultures of E6 expressing primary human keratinocytes after UV-irradiation by immunohistochemistry and in cell lines by In Cell Western blotting. Phosphorylation of ATR/Chk1 and ATM were assessed in cell lines and organotypic skin cultures by Western blots and immunohistochemistry. Skin tumor development after UV-irradiation in K14-HPV8-E6wt mice could completely be blocked through expression of CPD-photolyase. Through quantification of thymine dimers after UV irradiation in cells expressing E6 proteins with point mutations at conserved residues we identified a critical lysine in the C-terminal part of the protein for prevention of DNA damage repair and p300 binding. Whereas all K14-HPV8-E6wt animals develop skin tumors after UV expression of the HPV8-E6-K136N mutant significantly blocked skin tumor development after UV treatment. The persistence of CPDs in hyperproliferative epidermis K14-HPV8-E6wt skin resulted in the accumulation of γH2AX foci. DNA damage sensing was impaired in E6 positive cells grown as monolayer culture and in organotypic cultures, due to lack of phosphorylation of ATM, ATR and Chk1. We showed that cells expressing E6 fail to sense and mount an effective response to repair UV-induced DNA lesions and demonstrated a physiological relevance of E6-mediated inhibition of DNA damage repair for tumor initiation. These are the first mechanistical in vivo data on the tumorigenicity of HPV8 and demonstrate that the impairment of DNA damage repair pathways by the viral E6 protein is a critical factor in HPV-driven skin carcinogenesis.
A novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) gene mutation, presenting with neonatal cholestasis
Authors: Aleida G.M. de Vries, Willie M. Bakker-van Waarde, Anne C.M. Dassel, Monique Losekoot, Evelien W. Duiker, Annette S.H. Gouw, Frank A.J.A. Bodewes
Journal: Journal of Hepatology (2015)
Obstructive findings in sarcoidosis, diagnosis and therapies modalities
Authors: Jelica Videnovic-Ivanov, Snezana Filipovic, Violeta Vucinic, Vlada Zugic
Journal: European Respiratory Journal (2012)

Introduction: Symptoms of respiratory disturbances are common during the course of sarcoidosis. The aim of analysis is to notifie obstructive findings in sarcoidosis. Method: The analyses is restrospective in all incominig patients to the Clinic for lung diseases and tuberculosis CC of Serbia in Belgrade. Results: 127 (8,7%) patients with dry cough and occasionaly dyspnea had the impairent of lung function. The main findings were: FEVl / VC 63,1% in 57- 44,8% patients; in 27-21,1% patients – FEVl / FVC were 55,7% ,  in 3-2,3% patients FEVl / FVC were 68.7 %. Gender distribution were as followed: 264 (66,2%)Female- Male 135 (33,8%); average ages were 43,32 years. Extrathoracis sarcoidosis involvement were find out in 3 (2.3%) patients (skin, lymph nodes,).Lung and nonpulmonary sarcoidosis is notify in 27 pts and in 97 pts lung were the only sarcoidosis manifestation. Radiographic stadium of lung involvement: I-87(68.5%), II-31(24,4%), III-7%(5,%), IV-1 (0,78%). Acute onset of sarcoidosis is predominatly with average level of ACE: 75.3 U / L. After obtaining the diagnosis of sarcoidosis, inhaled corticosteroides were administered, 160 mcg-daily through 3 months with controls which meansa :ACE and UCa/24h levels, lung function, chest X ray. Regression of symptoms such as dry cough were obtained in 55% patients after the period of 2 months; 45% patients were excluded due to persistence of symptoms seeking prednisone. Conclusion – inhaled corticosteroid have the role in sarcoidosis treatment resolving symptoms such as cough, improvement of FEV1, but the main therapy in most of the patients is still orally administired prednisone.
Cardiac structure and function at baseline in the DEFLATA study: The impact of lung hyperinflation and its relationship with the GOLD classification
Authors: Ian S. Stone, Wai-Yee James, Redha Boubertakh, Neil C. Barnes, Steffen E. Petersen
Journal: European Respiratory Journal (2014)

INTRODUCTION The mechanisms underlying cardiac dysfunction and its impact on symptoms in COPD are poorly understood.

AIMS 1) To compare cardiac structure and function in COPD of varying severities; 2) To establish the impact of lung hyperinflation on cardiac structure and function; 3) To identify determinants of respiratory symptoms in this cohort

METHODS Between December 2012-2013, 30 hyperinflated COPD patients were randomized into the DEFLATA study and underwent cardiac magnetic resonance, spirometry, body plethysmography, arterial stiffness and baseline bloods.

RESULTS Smaller ventricular volumes were found in GOLD stage 4 vs GOLD 1-3 (right ventricle end diastolic volume Index 61±18 vs 85±15 ml (p=0.003), left ventricle end diastolic volume index 52±16 vs 70±8 ml p=0.001). No differences in cardiac structure were found when separated according to the ABCD classification. Although no relationship was found between lung hyperinflation and ventricular size, residual volume percent predicted (Rvol) was related to reduced left atrial size independent of gender, oxygen saturations (SO2), central systolic pressure, LV ejection and fibrinogen (β=-0.13, p=0.028). Fibrinogen related to COPD Assessment Test (CAT) scores independent of age, spirometry, Rvol, SO2, exacerbations, and cardiac function (β=7.9, p=0.03).

CONCLUSION Air flow limitation and lung hyperinflation are associated with reduced cardiac chamber size, although this has no independent impact on respiratory symptoms, where it appears systemic inflammation may have a role. Further studies are warranted to establish whether these cardiac morphological changes are reversible.
Reply to K.I. Pritchard
Authors: Duveken B.Y. Fontein, Cornelis J.H. van de Velde
Journal: Journal of Clinical Oncology (2013)

women at high risk treated with tamoxifen compared with placebo. 11 Understanding the mechanism underlying development of symptoms due to any type of endocrine therapy is important for determining why their presence might lead to improved breast cancer outcomes.For example, studies have suggested that prior chemotherapy is associated with development of arthralgias during AI therapy. [12][3][14][15] It is unclear whether the arthralgias and the improved disease-free survival are due to an interaction between the chemotherapy and the AI therapy rather than specifically to the AI therapy.In addition, knowledge about the underlying etiology could yield important insights into how best to manage these bothersome toxicities that can compromise quality of life for breast cancer survivors.The anticipated adverse effects of a therapy can be as important to patients as the anticancer effect of the treatment.This can be particularly relevant for long-term oral medications such as adjuvant endocrine therapy for breast cancer.However, the clinical trial designs currently utilized during development of oncologic medications frequently focus only on the latter.Inclusion of patient-reported outcomes during drug development is likely to yield important information about the impact of a therapy on daily functioning and quality of life. 16 In addition, as suggested above, analysis of patient-reported outcomes could potentially yield insights into the mechanism of action of the therapy and prediction of benefit from the treatment, and could be used to inform personalized treatment decision making.
Allogeneic Bone Marrow Transplantation Versus Chemotherapy for the Treatment of Childhood Acute Lymphoblastic Leukemia in Second Remission: A Single-Institution Study
Authors: Farid Boulad, Peter Steinherz, Bernadette Reyes, Glenn Heller, Alfred P. Gillio, Trudy N. Small, Joel A. Brochstein, Nancy A. Kernan, Richard J. O'Reilly
Journal: Journal of Clinical Oncology (1999)

PURPOSE: A retrospective analysis of the treatment of childhood acute lymphoblastic leukemia (ALL) in second remission (CR2) was undertaken at our institution to compare the outcome and prognostic factors of patients treated with chemotherapy or allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Seventy-five children who suffered a medullary relapse and achieved a second remission were treated with either an unmodified allogeneic HLA-matched sibling BMT after hyperfractionated total body irradiation (TBI) and cyclophosphamide (n = 38) or chemotherapy according to institutional chemotherapy protocols (n = 37). To avoid the bias of survival from the attainment of second remission in favor of BMT, the final comparative statistical analysis used the landmark approach and comprised 37 and 29 patients from the BMT and chemotherapy groups, respectively RESULTS: The disease-free survival (DFS) rate was 62% and 26% at 5 years, respectively, for the BMT and the chemotherapy groups (P = .03), with relapse rates of 19% and 67%, respectively, for these two groups (P = .01). There was an overall advantage for the BMT therapeutic approach, as compared with chemotherapy, for patients with ALL in CR2 (1) for patients with a WBC count (at diagnosis) of 20 × 10 9 /L or higher (DFS, 40% v 0%) and those with a WBC count of less than 20 × 10 9 /L (DFS, 73% v 35%), (2) for patients whose duration of CR1 was less than 24 months (DFS 48% v 9%) and for patients whose duration of CR1 was 24 months or longer (DFS, 81% v 37%) and (3) for patients who were initially treated with intensive regimens incorporating more than five chemotherapy agents (DFS, 57% v 20%) and for patients treated with five agents or fewer (DFS, 72% v 32%). CONCLUSION: In our single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with those for patients treated with chemotherapy, regardless of the duration of first remission, the disease characteristics at diagnosis, or the intensity of prior treatment during first remission.
Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: Fact or fiction?
Authors: Sarah E. Jones, Stuart A. Green, Amy L. Clark, Samantha S.C. Kon, Mandy J. Dickson, Ann-Marie Nolan, Clare Moloney, Faisal Kamal, Brigitte M. Haselden, Sharon Fleming, William D.-C. Man
Journal: European Respiratory Journal (2013)

Background Early pulmonary rehabilitation (PR), following hospitalisation for acute exacerbation of COPD (AECOPD), improves exercise capacity and health related quality of life (Man et al. 2004) and reduces hospital readmissions and mortality (Puhan et al. 2011). Despite the evidence, there is poor referral, uptake and completion rates for post-hospitalisation early PR. Aim To prospectively document referral, uptake, and completion rates for post-hospitalisation early PR in a Northwest London borough. Methods Data was collected between November 2011 and October 2012. Data was corroborated by medical notes, hospital coding data, and data collected by the COPD team and the local PR provider. Results Of 448 patients, 286 met the referral criteria for PR. Only 90 of the eligible patients (32%) were referred. Reasons for non-referral could not be ascertained reliably from medical records. 22 referred patients declined assessment; the remaining 68 patients were all assessed within 2 weeks of discharge. 59 patients started outpatient PR, with 44 completing (completion rate 75%).

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Conclusion Despite the strong evidence base, only a small proportion of eligible COPD patients receive early post-hospitalisation PR. Completion rates are in line with those seen with PR in stable patients. Further work is required to explore referrer and patient attitudes to post-hospitalisation PR.

 [1]: pending:yes
P50 Synthetic lethality in liver cancer cell lines treated with inhibitors of DNA double-strand break repair
Authors: H Reeves, L Cornell, J Munck, F Budhisetiawan, D Newell, J Bardos, D Manas, C Nicola
Journal: Gut (2010)

Introduction  DNA double-strand breaks (DSBs) are the most cytotoxic lesions induced by ionising radiation (IR) and anticancer drugs, such as topoisomerase II poisons (eg, doxorubicin). The major DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR), in which DNA-Dependent Protein Kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) are key components. DNA-PK in particular is up-regulated in hepatocellular carcinoma, (GEO profiles) possibly contributing to resistance to cytotoxic therapies.  Aim  To assess DNA-PK and ATM as therapeutic targets for chemo- and radio-sensitisation in hepatoma.  Method  Basal protein levels and activities were determined by Western blot analysis in hepatoma cell lines. DNA-PK and ATM activity following doxorubicin stimulation was measured using antibodies specific to phosphorylated Ser-2056 DNA-PKcs and phosphorylated Ser-1981 ATM. DSB repair was measured by immunofluorescence detection of γ-H2AX foci. Cell survival was determined by clonogenic assay.  Results  We demonstrated high basal levels of DNA-PK in three hepatoma cell lines (Huh7, Hep3B and HepG2), with DNA-PK activation induced by 0.25 μM doxorubicin. Despite similar DNA-PK activation, we observed differential sensitivity to doxorubicin (7%, 49% and 75% survival at 10 nM doxorubicin in Huh7, Hep3B and HepG2, respectively). HepG2 cells with the greatest resistance to doxorubicin displayed a 10-fold activation of ATM relative to the other cell lines. The DNA-PK inhibitor NU7441, increased doxorubicin and ionising radiation (IR) induced cytotoxicity in all cell lines (1.3 up to fourfold), correlating with a reduction in DSB repair measured by γ-H2AX foci. Importantly, in doxorubicin resistant HepG2 cells, while incubation with NU7441 or the ATM inhibitor (KU55933) alone, had minimal effects on cell survival (91% and 86%, respectively), their combination in the absence of a cytotoxic agent markedly inhibited cell survival (21%; p  Conclusion  These findings support the clinical application of DNA-PK and ATM inhibitors as chemo- and radio-sensitisors in hepatoma patients. Furthermore, these data suggest that hepatoma cell survival is dependent on up-regulation of DSB repair, effected by either DNA-PK or ATM, and that inhibition of both induces synthetic lethality—preventing DSB repair by both NHEJ and HR. The therapeutic implication is that in combination, these agents could be used to specifically induce cancer cell death, with minimal toxicity to surrounding liver tissues.
Awareness and knowledge of pediatricians in Cebu City of the national tuberculosis control program in the management of tuberculosis in children
Authors: Erving Noel Merlin
Journal: European Respiratory Journal (2013)

BACKGROUND: Tuberculosis (TB) in children is a daunting phenomenon to pediatricians because of the absence of a gold standard in diagnosing TB in children. Thus, WHO released the National Tuberculosis Control Program (NTP) guidelines as a standard method in diagnosing and treating TB in children.  OBJECTIVES: To determine and correlate the awareness and knowledge of pediatricians in Cebu City regarding the existence and implementation of the NTP guidelines.  METHODOLOGY: Validated questionnaires were distributed. Results were tallied in each category and level of knowledge was determined according to the scores with equivalent ratings. Knowledgeable pediatricians had excellent ratings(15/15), those who were not knowledgeable rated very good(14/15), good(13/15), fair(12/15), poor(11/15) and failed(  RESULTS: There were 92(61.3%) out of 150 pediatricians who responded. The 95% were aware of the NTP guidelines but only 4.5% are knowledgeable of its content. There was no significant correlation between pediatricians’ awareness and their knowledge of the guidelines with a p-value of 0.425817, which means that the high level of awareness among pediatricians regarding NTP guidelines did not reflect their knowledge in treating TB disease. They also had poor rate (10%) of reporting of TB cases to TB-DOTS center instead did self evaluation and monitoring.  CONCLUSION: The negative (r-value -0.08) correlation between the awareness and level of knowledge in treating TB in children is an important concern. Failure to adhere to the guidelines is a hindrance to decreasing TB in children.
Accelerated-Intensified Cyclophosphamide, Epirubicin, and Fluorouracil (CEF) Compared With Standard CEF in Metastatic Breast Cancer Patients: Results of a Multicenter, Randomized Phase III Study of the Italian Gruppo Oncologico Nord-Ouest–Mammella Inter Gruppo Group
Authors: Lucia Del Mastro, Marco Venturini, Rita Lionetto, Flavio Carnino, Domenico Guarneri, Luigi Gallo, Antonio Contu, Paolo Pronzato, Lorella Vesentini, Marina Bergaglio, Silvia Comis, Riccardo Rosso
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients. PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m 2 , epirubicin 60 mg/m 2 , and fluorouracil 600 mg/m 2 ) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m 2 , epirubicin 80 mg/m 2 , and fluorouracil 600 mg/m 2 ) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles. RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14–treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P = .94). A slightly non–statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P = .69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P = .16). CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.
Screening study for chronic obstructive pulmonary disease among adults in Pleven
Authors: Plamen Pavlov, Yavor Ivanov, Pavlina Glogovska, Tsanya Popova, Elena Borissova, Ventsislav Nozharov
Journal: European Respiratory Journal (2011)

Aim:  To carry out a screening study for chronic obstructive pulmonary disease (COPD) among the population in Pleven.   Material:  We studied 2047 people, 764 (37.3%) men and 1283 (62.7%) women, aged ≥ 40 years. Exposure to different risk factors was found in 1837 (90%) of them. All studied patients filled in a specially designed questionnaire and did spirometry (with bronchodilatation for the ones with forced expiratory value – FEV 1 , less than 80% predicted value).   Results:  We found COPD (both symptoms and spiromety data) in 14,9% of the studied population. The analysis of the data showed: sex - 21.7% of males and 10.8% of females (p=0.0001); age - 11.9% - 40-55 years and 19.3% above 55 years (p=0.0001); place of living - 13.9% urban and 18.8% country (p=0.01). The presence of risk factors was as follows: smoking (both current and former) - 23.2% (OR=12.2); occupation - 7.3% (OR=3.5); coal heating - 3.6% (OR=1.9); frequent respiratory infections - 15.5% (OR=8.28); family history - 13.2% (OR=6.94); air pollution - 2.3% (OR= 1.1); with multiple risk factors - 28.1% (OR= 14.8). Chronic respiratory symptoms were present in 84.9% of the COPD patients and in 43.6% of the people without airway obstruction (r=0.36, p=0.0001).   Conclusion:  The study found COPD in 14.9% of the studied population. There was prevalence in males, age above 55 years and in people living in the country. Among the risk factors most important were smoking, frequent respiratory infections and genetic predisposition.