tbuckley/cabot-search huggingface dataset:
Phase II and Pharmacodynamic Study of the Farnesyltransferase Inhibitor R115777 as Initial Therapy in Patients With Metastatic Pancreatic Adenocarcinoma
Authors: Steven J. Cohen, Linus Ho, Sulabha Ranganathan, James L. Abbruzzese, R. Katherine Alpaugh, Mary Beard, Nancy L. Lewis, Susan McLaughlin, André Rogatko, Juan J. Perez-Ruixo, Amanda M. Thistle, Tom Verhaeghe, Hao Wang, Louis M. Weiner, John J. Wright, Gary R. Hudes, Neal J. Meropol
Journal: Journal of Clinical Oncology (2003)

R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma.Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2.No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15.Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.
Asthma and the Hygiene Hypothesis. Does Cleanliness Matter?
Authors: Juliane Weber, Sabina Illi, Dennis Nowak, Rudolf Schierl, Otto Holst, Erika von Mutius, Markus J. Ege
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: The early hygiene hypothesis explained the development of allergies by a lack of infections; nowadays, the aspect of excessive cleanliness in affluent populations seems to have replaced this concept. Yet, no investigation has shown that home or personal cleanliness relate to allergic diseases.Objectives: To relate personal and home cleanliness to risk of asthma and allergies.Methods: Comprehensive questionnaire information on home or personal cleanliness and allergic health conditions at school age was collected in 399 participants of the urban Perinatale Asthma Umwelt Langzeit Allergie Studie (PAULA) birth cohort. Bacterial markers were assessed in floor and mattress dust and were related to cleanliness and allergic diseases.Measurements and Main Results: Personal cleanliness was inversely related to bacterial compounds on floors and mattresses, whereas home cleanliness effectively reduced dust amount but not microbial markers. Exposure to muramic acid related to a lower prevalence of school-age asthma (adjusted odds ratio, 0.59 [95% confidence interval, 0.39; 0.90]). Mattress endotoxin in the first year of life was inversely associated with atopic sensitization (0.73 [0.56–0.96]) and asthma at school age (0.72 [0.55–0.95]). Despite the associations of dust parameters both with cleanliness and allergic health conditions, the development of allergies was not related to home and personal cleanliness.Conclusions: Bacterial exposure in house dust determined childhood asthma and allergies. Personal cleanliness, such as washing hands, and home cleanliness were objectively reflected by dust parameters in homes. However, neither personal nor home cleanliness was associated with a risk for asthma and allergies. Other microbial components in house dust not affected by personal hygiene are likely to play a role.
Relationship of Breast Magnetic Resonance Imaging to Outcome After Breast-Conservation Treatment With Radiation for Women With Early-Stage Invasive Breast Carcinoma or Ductal Carcinoma in Situ
Authors: Lawrence J. Solin, Susan G. Orel, Wei-Ting Hwang, Eleanor E. Harris, Mitchell D. Schnall
Journal: Journal of Clinical Oncology (2008)

To determine the relationship of breast magnetic resonance imaging (MRI) to outcome after breast-conservation treatment (BCT) with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ.A total of 756 women with early stage invasive breast carcinoma or ductal carcinoma in situ underwent BCT including definitive breast irradiation during 1992 to 2001. At the time of initial diagnosis and evaluation, routine breast imaging included conventional mammography. Of the 756 women, 215 women (28%) had also undergone a breast MRI study, and 541 women (72%) had not undergone a breast MRI study. The median follow-up after treatment was 4.6 years (range, 0.1 to 13.5 years).For the women with a breast MRI study compared with the women without a breast MRI study, there were no differences in the 8-year rates of any local failure (3% v 4%, respectively; P = .51) or local-only first failure (3% v 4%, respectively; P = .32). There were also no differences between the two groups for the 8-year rates of overall survival (86% v 87%, respectively; P = .51), cause-specific survival (94% v 95%, respectively; P = .63), freedom from distant metastases (89% v 92%, respectively; P = .16), or contralateral breast cancer (6% v 6%, respectively; P = .39).The use of a breast MRI study at the time of initial diagnosis and evaluation was not associated with an improvement in outcome after BCT with radiation.
Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases
Authors: P-R. Burgel, J. A. Nadel
Journal: European Respiratory Journal (2008)

Inhaled air is contaminated with pathogens and particulates that may deposit in the airways and damage the host. In response to these invaders, the airway epithelium has developed innate immune responses that provide a defence against the invaders and protect the airway structure and function. Thus, the epithelium of conducting airways becomes the “battleground” between the invaders and the host. Recent evidence suggests that airway epithelial surface signalling through the epidermal growth factor receptor (EGFR) is a convergent pathway producing innate immune responses to a variety of infectious and noninfectious noxious stimuli. In the present review, the EGFR signalling pathways leading to airway mucin production, neutrophil recruitment ( via interleukin-8 production) and airway epithelial repair were examined. The importance of these findings in human airway diseases was also investigated. The current authors suggest that the exaggerated innate immune responses found in chronic inflammatory airway diseases ( e.g. chronic obstructive pulmonary disease, cystic fibrosis and severe asthma) contribute to the pathogenesis or the aggravation of these diseases. Potential therapies include inhibition of the various elements of the described epidermal growth factor receptor cascade. In considering each therapeutic intervention, the potential benefits must be considered in relation to potential deleterious effects.
Sport medicine and the ethics of boxing
Authors: S Leclerc, C D Herrera
Journal: British Journal of Sports Medicine (1999)

In the light of medical evidence of the health risks associated with boxing, a watchful agnostic position among sport physicians is no longer justifiable. The normal activity in a boxing match places the athletes at risk of head injury, some of which may be difficult to detect and impossible to repair. This suggests that sport physicians and others expert in the prevention and diagnosis of such injuries should take a public stand against boxing, as other medical associations have. Although there is a need for continuing research into the health risks, doctors can in the interim take steps to increase public awareness of these risks. Sport physicians in particular can make a strong public statement by also ending their professional involvement with boxing. This need not be interpreted as paternalism; doctors are qualified neither to make laws nor to restrict private behaviour. Sport physicians are, however, well equipped to advise those who do make laws and those who choose to engage in boxing. In the end, because this stance against boxing will probably reduce the number of brain injuries in certain athletes, autonomy will be preserved, rather than restricted.
Four cases, one family: A cluster of resistant tuberculosis
Authors: Tulin Sevim, Oguz Aktas, Emine Aksoy, Meltem Agca, Fatma Tokgöz, Turan Karagöz
Journal: European Respiratory Journal (2013)

Multidrug-(MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is an emerging health issue attracting attention worldwide. We report a family with both parents and 3 children. The father was diagnosed as chronic TB, 2 children were diagnosed as MDR-TB and the other child was diagnosed as XDR-TB whereas mother was healthy.  CASE 1 (father): He used first and second line TB drugs irregularly for 32 years, his smears had remained positive and died from TB.  CASE 2 (son): He was diagnosed as tuberculosis at the age of 16, died aged-31 from TB.  CASE 3 (daughter): She was diagnosed as TB at the age of 8, admitted to our clinic aged-34. Drug susceptibility testing (DST) showed XDR-TB. The treatment regimen of moxifloxacin, amikacin, capreomycin, cycloserine, clofazimine, linezolid, klaritromisin was administered. At the end of 22 months she was successfully cured.  CASE 4 (daughter): She was diagnosed as TB at the age of 10, admitted to our clinic when aged-29. DST showed MDR-TB. Moxifloxacin, linezolid, cycloserine, pyrazinamide, amoxicillin clavulanic acid, amikacin, capreomycin were started. She was successfully cured.  In conclusion, MDR and XDR TB treatment is very challenging. Still, in order to prevent the spread of resistant bacillus infection throughout the community, those patients need to be treated on a national tuberculosis programme-scale.
Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies.
Authors: C Czerkinsky, W J Koopman, S Jackson, J E Collins, S S Crago, R E Schrohenloher, B A Julian, J H Galla, J Mestecky
Journal: Journal of Clinical Investigation (1986)

Circulating immune complexes (CIC) containing IgA and C3 were elevated in 48% of IgA nephropathy patients; IgA1 was the predominant subclass. IgA1-IgG CIC were detected in 44%, IgA2-IgG CIC in 7%, and IgM-IgA1 CIC in 16% of the patients. No IgM-IgA2 CIC were detectable. Sucrose gradient ultracentrifugation indicated that IgG-IgA1 CIC were predominantly of intermediate (13-19S) size whereas IgA1-C3 CIC sedimented from 11S to 19S. At acid pH, isolated CIC revealed the presence of substantial amounts of 7S IgA. One third of the patients had elevated serum IgA rheumatoid factor (RF) of both polymeric and monomeric forms despite normal levels of IgM-RF; 87% of patients with elevated IgA-RF had IgA1-IgG CIC. These results indicate that the IgA1 component of CIC in patients with IgA nephropathy is not necessarily of mucosal origin and suggest that a portion of these CIC consists of IgA RF immunologically complexed with autologous IgG.
Early proximal lung cancer diagnosis and treatment
Authors: A. McWilliams, B. Lam, T. Sutedja
Journal: European Respiratory Journal (2009)

Lung cancer remains the largest cause of cancer deaths worldwide and the overall 5-yr survival rate is only 15%. This is because the majority of the lung cancers are diagnosed at late stages and the treatment outcome is suboptimal. However, the survival of patients with early stage proximal lung cancer is excellent and with advancements in technology we are currently well equipped to diagnose and stage these lung cancers. Together with the application of local bronchoscopic therapeutic modalities that may potentially cure early stage intraluminal lesions, there is expanding interest in the further exploration of new avenues for early detection, localisation, staging, treatment and close surveillance of these high-risk patients who are suffering from chronic field carcinogenesis. The present article will deal with various issues regarding early detection, staging and treatment of centrally located early stage, mostly squamous type, lung cancer.
Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma
Authors: Ying Zheng, Braden C. McFarland, Denis Drygin, Hao Yu, Susan L. Bellis, Hyunsoo Kim, Markus Bredel, Etty N. Benveniste
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α′) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neoangiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt, and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT, and JAK/STAT-3 pathways is implicated in glioblastoma progression. As CK2 is involved in their activation, the expression and function of CK2 in glioblastoma was evaluated. Experimental Design and Results: Analysis of 537 glioblastomas from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in glioblastoma (33.7%), and is significantly associated with the classical glioblastoma subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB, and AKT pathways and downstream gene expression in human glioblastoma xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of glioblastoma cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65, and AKT, and promotes survival of mice with intracranial human glioblastoma xenografts. Conclusions: CK2 inhibitors may be considered for treatment of patients with glioblastoma. Clin Cancer Res; 19(23); 6484–94. ©2013 AACR.
697 HEPATOBILIARY EXCRETION MEASURED BY PET/CT USING THE CONJUGATED BILE ACID TRACER 11C-CSAR: FIRST EXPERIENCES IN PATIENTS WITH INTRAHEPATIC CHOLESTASIS
Authors: M. Sorensen, N.W. Orntoft, K. Frisch, P. Ott, S. Keiding
Journal: Journal of Hepatology (2013)
NKX3.1 Activates Expression of Insulin-like Growth Factor Binding Protein-3 to Mediate Insulin-like Growth Factor-I Signaling and Cell Proliferation
Authors: Erin Muhlbradt, Ekaterina Asatiani, Elizabeth Ortner, Antai Wang, Edward P. Gelmann
Journal: Cancer Research (2009)

Abstract NKX3.1 is a homeobox gene that codes for a haploinsufficient prostate cancer tumor suppressor. NKX3.1 protein levels are down-regulated in the majority of primary prostate cancer tissues. NKX3.1 expression in PC-3 cells increased insulin-like growth factor binding protein-3 (IGFBP-3) mRNA expression 10-fold as determined by expression microarray analysis. In both stably and transiently transfected PC-3 cells and in LNCaP cells, NKX3.1 expression increased IGFBP-3 mRNA and protein expression. In prostates of Nkx3.1 gene-targeted mice Igfbp-3 mRNA levels correlated with Nkx3.1 copy number. NKX3.1 expression in PC-3 cells attenuated the ability of insulin-like growth factor-I (IGF-I) to induce phosphorylation of type I IGF receptor (IGF-IR), insulin receptor substrate 1, phosphatidylinositol 3-kinase, and AKT. The effect of NKX3.1 on IGF-I signaling was not seen when cells were exposed to long-R3-IGF-I, an IGF-I variant peptide that does not bind to IGFBP-3. Additionally, small interfering RNA–induced knockdown of IGFBP-3 expression partially reversed the attenuation of IGF-IR signaling by NKX3.1 and abrogated NKX3.1 suppression of PC-3 cell proliferation. Thus, there is a close relationship in vitro and in vivo between NKX3.1 and IGFBP-3. The growth-suppressive effects of NKX3.1 in prostate cells are mediated, in part, by activation of IGFBP-3 expression. [Cancer Res 2009;69(6):2615–22]
Aerosolized surfactant inhibits acetylcholine-induced airway obstruction in rats
Authors: J Hohlfeld, HG Hoymann, J Molthan, H Fabel, U Heinrich
Journal: European Respiratory Journal (1997)

Exogenous surfactant treatment inhibits antigen-induced airway obstruction in sensitized guinea-pigs. Aerosolized surfactant also improves respiratory function in asthmatic patients. The aim of the present study was to determine whether aerosolized surfactant inhibits nonallergic airway obstruction induced by acetylcholine. Anaesthetized Wistar rats were treated by aerosol with the beta2-adrenoceptor agonist terbutaline, surfactant (Alveofact), a surfactant-terbutaline combination, or vehicle (control). Animals were then challenged by aerosolized acetylcholine to elicit receptor-mediated airway obstruction. A second group of animals was challenged with intravenous acetylcholine. Respiratory function variables were measured by body plethysmography before and after treatment, and after the acetylcholine challenge. Baseline lung function values before and after treatment were similar in all groups. Acetylcholine challenge by aerosol increased lung resistance by 64% in control animals. Pretreatment with terbutaline and surfactant significantly limited the increase of lung resistance to +36 and +34%, respectively. Simultaneous aerosolization of surfactant and terbutaline also inhibited airway obstruction but their effects were not additive. By contrast, terbutaline treatment inhibited the effects of intravenous acetylcholine, but surfactant did not. In conclusion, we suggest that surfactant aerosol may prevent acetylcholine and other pharmacological agents from reaching the airway smooth muscle from the airway lumen but not via the bloodstream.
Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2
Authors: T. S. Plantinga, T. O. Crisan, M. Oosting, F. L. van de Veerdonk, D. J. de Jong, D. J. Philpott, J. W. M. van der Meer, S. E. Girardin, L. A. B. Joosten, M. G. Netea
Journal: Gut (2011)

<h3>Objective</h3> Autophagy has recently been shown to modulate the production of pro-inflammatory cytokine production and to contribute to antigen processing and presentation through the major histocompatibility complex. Genetic variation in the autophagy gene <i>ATG16L1</i> has been recently implicated in Crohn9s disease pathogenesis. The mechanisms underlying this association are not yet known, although experimental models suggest an inhibitory effect of autophagy on interleukin 1β (IL-1β) responses. Here, the effect of <i>ATG16L1</i> genetic variation on cytokine responses has been assessed in humans. <h3>Design and setting</h3> Peripheral blood mononuclear cells from healthy individuals and patients with Crohn9s disease with different <i>ATG16L1</i> genotypes were stimulated with ligands for Toll-like receptor 2 (TLR2), TLR4 and nucleotide-binding oligomerisation domain 2 (NOD2), with or without the autophagy inhibitor 3-methyladenine. Induction of cytokine production and related factors were measured at the mRNA and protein level. Furthermore, protein levels of ATG16L1 were assessed by western blot. <h3>Results</h3> The present study demonstrates that cells isolated from individuals bearing the <i>ATG16L1</i> Thr300Ala risk variant, which is shown to affect ATG16L1 protein expression upon NOD2 stimulation, display increased production of the pro-inflammatory cytokines IL-1β and IL-6, specifically after stimulation with NOD2 ligands. In contrast, no differences were found when cells were stimulated with TLR2 or TLR4 agonists. These findings were confirmed in two independent cohorts of volunteers and in a group of patients with Crohn9s disease. The increased production could be ascribed to increased mRNA expression, while processing of pro-IL-1β by caspase-1 activation was not affected. The effect of the <i>ATG16L1</i> polymorphism was abrogated when autophagy was blocked. <h3>Conclusions</h3> The present study is the first to link the <i>ATG16L1</i> polymorphism with an excessive production of IL-1β and IL-6 in humans, which may explain the effects of this polymorphism on the inflammatory process in Crohn9s disease.
Evaluation of coal tar fractions for use in psoriasiform diseases using the mouse tail test.
Authors: ROSANNE WRENCH, ADAM Z. BRITTEN
Journal: British Journal of Dermatology (1975)

Twelve phenolic fractions of creosote and anthracene oils derived from a high temperature tar were applied in an ointment base to mouse tail skin. After treatment with the higher boiling acids, formerly parakeratotic scale areas underwent granular layer induction and ‘basket-weave’ keratin was produced. Changes in distribution of acid phosphatase and in horny layer fluorescence were consistent with the conversion to an orthokeratotic state. It is suggested that some of these phenols may be of value in the treatment of chronic psoriasis.
A Cluster of Cases of Severe Acute Respiratory Syndrome in Hong Kong
Authors: Kenneth W Tsang, Pak L Ho, Gaik C Ooi, Wilson K Yee, Teresa Wang, Moira Chan-Yeung, Wah K Lam, Wing H Seto, Loretta Y Yam, Thomas M Cheung, Poon C Wong, Bing Lam, Mary S Ip, Jane Chan, Kwok Y Yuen, Kar N Lai
Journal: New England Journal of Medicine (2003)

Information on the clinical features of the severe acute respiratory syndrome (SARS) will be of value to physicians caring for patients suspected of having this disorder. We abstracted data on the clinical presentation and course of disease in 10 epidemiologically linked Chinese patients (5 men and 5 women 38 to 72 years old) in whom SARS was diagnosed between February 22, 2003, and March 22, 2003, at our hospitals in Hong Kong, China. Exposure between the source patient and subsequent patients ranged from minimal to that between patient and health care provider. The incubation period ranged from 2 to 11 days. All patients presented with fever (temperature, >38 degrees C for over 24 hours), and most presented with rigor, dry cough, dyspnea, malaise, headache, and hypoxemia. Physical examination of the chest revealed crackles and percussion dullness. Lymphopenia was observed in nine patients, and most patients had mildly elevated aminotransferase levels but normal serum creatinine levels. Serial chest radiographs showed progressive air-space disease. Two patients died of progressive respiratory failure; histologic analysis of their lungs showed diffuse alveolar damage. There was no evidence of infection by Mycoplasma pneumoniae, Chlamydia pneumoniae, or Legionella pneumophila. All patients received corticosteroid and ribavirin therapy a mean (+/-SD) of 9.6+/-5.42 days after the onset of symptoms, and eight were treated earlier with a combination of beta-lactams and macrolide for 4+/-1.9 days, with no clinical or radiologic efficacy. SARS appears to be infectious in origin. Fever followed by rapidly progressive respiratory compromise is the key complex of signs and symptoms from which the syndrome derives its name. The microbiologic origins of SARS remain unclear.
Judge suggests steps to prevent employers unfairly referring whistleblowers to GMC
Authors: C. Dyer
Journal: BMJ (2015)

The General Medical Council has welcomed a package of recommendations from a senior retired judge aimed at preventing employers using the regulator as a tool to get back at whistleblowing doctors.1

Anthony Hooper, a former Court of Appeal judge, has recommended that employers be asked, when referring a doctor to the GMC for investigation, whether the doctor has raised any concerns about the safety of patients or “the integrity of the system.”

Hooper was asked by the UK regulator to suggest steps that could be taken to improve the experience of whistleblowing …