tbuckley/cabot-search huggingface dataset:
A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform
Authors: Anne-Joy M. de Graan, Laure Elens, Marcel Smid, John W. Martens, Alex Sparreboom, Annemieke J.M. Nieuweboer, Lena E. Friberg, Samira Elbouazzaoui, Erik A.C. Wiemer, Bronno van der Holt, Jaap Verweij, Ron H.N. van Schaik, Ron H.J. Mathijssen
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. Experimental Design: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training- and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. Results: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). Conclusions: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance. Clin Cancer Res; 19(18); 5210–7. ©2013 AACR.
Endobronchial biopsies in children with protracted bacterial bronchitis
Authors: Konstantinos Douros, Panagiota Kitsanta, Despina Mermiri, Vasilis Grammeniatis, Nicolaos Kavantzas, Mark Everard, Andrew Fretzayias, Kostas Priftis
Journal: European Respiratory Journal (2013)

Background – Aim: Despite several studies having investigated the inflammation in Protracted Bacterial Bronchitis (PBB), with the use of bronchoalveolar lavage (BAL), there is a scarcity of information about disease pathogenesis in the airway walls. The aim of this study was to identify the inflammatory cell populations that infiltrate the airways in PBB.  Methods: Study population was consisted of 35 patients with long-term wet cough (>8 weeks) and a temporal or partial response after one or more courses of antibiotics. All patients underwent Flexible Bronchoscopy with BAL and endobronchial biopsy with tissue sampling from carina. Children were antibiotic-free for at least 1 week. Quantitative cultures of BAL were considered positive if they rendered growth of ≥105 cfu/mL, or growth of ≥104 cfu/mL if only one pathogen was isolated. Biopsy samples were stained for morphology and findings were described semi-quantitatively. Cell counts 1-5, 6-10, and >10 for eosinophils, and 1-100, 101-300, and >300 for all other cells, were defined as grades 1, 2, and 3, respectively.  Results: All patients had positive BAL cultures. Median grades in biopsy samples were 0 for eosinophils and 1 for all other cells (histiocytes, plasmacytes, and lymphocytes). We were unable to detect any neutrophils on endobronchial tissues whereas on BAL the mean (sd) percentage of neutrophils was 15.7 (1.9).  Conclusion: The lack of neutrophilic infiltration in bronchial mucosa implies a quite distinct pattern of inflammation from the one present in airway lumen whereas the rarity of eosinophils denotes that the underlying pathology differs from asthma.
What's the Connection?
Authors: Aharon E. Sareli, William J. Janssen, Daniel Sterman, Sanjay Saint, Reed E. Pyeritz
Journal: New England Journal of Medicine (2008)

A 26-year-old man presented with a 1-month history of persistent cough productive of white sputum, which was occasionally tinged with blood. He reported mild pleuritic chest pain but had no dyspnea, fever, chills, night sweats, or weight loss. The patient had had no epistaxis or episodes of sinusitis. One week before presentation, he received an empirical course of azithromycin, with no resolution of his symptoms.
Early Activation of the Multicomponent Signaling Complex Associated With Focal Adhesion Kinase Induced by Pressure Overload in the Rat Heart
Authors: Kleber G. Franchini, Adriana S. Torsoni, Paulo H. A. Soares, Mario J. A. Saad
Journal: Circulation Research (2000)

Mechanical overload elicits functional and structural adaptive mechanisms in cardiac muscle. Signaling pathways linked to integrin/cytoskeleton complexes may have a function in mediation of the effects of mechanical stimulus in myocardial cells. We investigated the tyrosine phosphorylation and the assembly of the multicomponent signaling complex associated with focal adhesion kinase (Fak) and the actin cytoskeleton in the overloaded myocardium of rats. Pressure overload induced a 3-fold increase in Fak tyrosine phosphorylation within 3 minutes after a 60-mm Hg rise in aortic pressure. A pressure stimulus that lasted for 60 minutes was accompanied by a 5-fold increase in the amount of tyrosine-phosphorylated Fak, and a stimulus as low as 10 mm Hg doubled the amount of tyrosine-phosphorylated Fak in the myocardium within 10 minutes. Pressure overload also induced a time-dependent association of actin with Fak and an increase in the amount of Fak detected in the cytoskeletal fraction of the myocardium. These events were paralleled by c-Src activation and binding to Fak and by an association of Grb2 and p85 subunit of phosphatidylinositol 3-kinase with Fak. Erk1/2 and Akt, two possible downstream effectors of Fak via Grb2 and phosphatidylinositol 3-kinase, were also shown to be activated in parallel with Fak. These findings show that pressure overload induced a rapid activation of the Fak multiple signaling complex in the myocardium of rats, which suggests that this mechanism may have a role in mechanotransduction in the myocardium.
Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model
Authors: Jinwei Hu, Xiangpeng Yuan, MinHee K Ko, Dali Yin, Manuel R Sacapano, Xiao Wang, Bindu M Konda, Andres Espinoza, Ksenia Prosolovich, John M Ong, Dwain Irvin, Keith L Black
Journal: Molecular Cancer (2007)

Abstract Background The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. Results In this study, we examined the function and regulation of calcium-activated potassium (K Ca ) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a K Ca channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a K Ca channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found K Ca channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of K Ca channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of K Ca channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of K Ca channels, which may contribute to the overexpression of K Ca channels in tumor microvessels and selectivity of BTB opening. Conclusion These findings suggest that K Ca channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.
Rupture of the Oesophagus
Authors: B. V. Slesser
Journal: Thorax (1951)

Perforation of the oesophagus still carries a high mortality, despite chemotherapy and antibiotics; and whether the rupture be in the cervical or the thoracic oesophagus, conservative management seems to be unsuccessful in most cases.Conservative measures have included the administration of chemotherapeutic drugs, intravenous fluid, gastrostomy, and in some cases drainage of the pleural cavity and of the cervical and mediastinal tissues.Barrett (1946) has pointed out that in patients suffering from spontaneous rup- ture the slit in the wall of the oesophagus may be of a considerable size, whereas the communication into the pleura may be relatively small.In consequence there is inadequate drainage into the pleural cavity and severe mediastinitis results.Fluid in the pleural cavity may be secondary, a consequence of the irritation of the gastric juices, so that simple drainage of the pleura is insufficient to relieve the toxaemia of the mediastinitis.This fact may explain the generally poor results following simple drainage of the pleura.Nevertheless, this method has on occasion been successful, as shown by cases recorded by Churchill (1935), Benson and Penberthy (1938), White (1941), Graham (1944), Adams (1946), and Dorsey (1948).Moore and Murphy (1948) treated their patient at first on conservative lines by thoracotomy and drain- age, and repaired the perforation three weeks later.Collis, Humphreys, and Bond (1944) recorded the first case of direct suture of a spontaneous oesophageal rupture.Unfortunately the outcome was not successful.Barrett (1946) reviewed the literature on spontaneous rupture of the normal oesophagus, and stressed the fact that its possible occurrence must always be kept in-mind in the differential diagnosis of any upper abdominal emergency, and that some success might attend prompt thoracotomy and suture when clinical signs sup- ported by radiology had led to early diagnosis.In 1947 he was able to record the first successful suture of a spontaneous rupture of the oesophagus.This was followed by another success reported by Olsen and Clagett (1947), their repair being carried out only three hours after the onset of symptoms.Cliffton (1949) has reported a successful closure, and in Scholefield's (1949) case successful suture and recovery ensued despite perforation into both pleural cavities.Lynch (1949) has three successful cases to his credit, two treated by suture and one by drainage of the pleura, the patient recovering after a stormy convalescence.The most recently recorded success is that of Dunavant and Skinner (1951).Nevertheless, perforation due to instrumentation or by impaction of foreign bodies is commoner than spontaneous rupture, and there is a reluctance to report cases of this type.Mosher (1935) reported 19 perforations in a series of 938 oesophagectomies.Goligher (1948) recorded two cases of rupture in the post- cricoid region after the passage of a gastroscope, and urged that prompt surgical on July 17,
Getting at MYC through RAS
Authors: Pavan Bachireddy, Pavan K. Bendapudi, Dean W. Felsher
Journal: Clinical Cancer Research (2005)

The discovery of oncogenes provided insight into the molecular underpinnings of cancer and suggested the promise of novel molecular strategies for cancer treatment as highlighted in this issue by Yaari et al. and by Bishop previously ([1][1], [2][2]). However, only recently have effective drugs that
Anti-DLL4 Inhibits Growth and Reduces Tumor-Initiating Cell Frequency in Colorectal Tumors with Oncogenic <i>KRAS</i> Mutations
Authors: Marcus Fischer, Wan-Ching Yen, Ann M. Kapoun, Min Wang, Gilbert O'Young, John Lewicki, Austin Gurney, Timothy Hoey
Journal: Cancer Research (2010)

KRAS mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating KRAS mutations.
Tacrolimus ointment-associated alcohol intolerance in infants receiving ethanol-containing medication
Authors: A-M. Calza, J. Lubbe
Journal: British Journal of Dermatology (2005)

Journal Article Tacrolimus ointment‐associated alcohol intolerance in infants receiving ethanol‐containing medication Get access A‐M. Calza, A‐M. Calza Dermatology Clinic, Geneva University Hospital, Switzerland Search for other works by this author on: Oxford Academic Google Scholar J. Lübbe J. Lübbe Dermatology Clinic, Geneva University Hospital, Switzerland J. Lübbe, E‐mail: jann.lubbe@hcuge.ch Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 3, 1 March 2005, Page 569, https://doi.org/10.1111/j.1365-2133.2005.06398.x Published: 01 March 2005
Association of PHF11 polymorphisms with asthma and allergy
Authors: G. Jones, G. Stewart
Journal: Thorax (2010)

Neutrophils are considered to be mature and terminally differentiated. They are short-lived, lack proliferation capacity and are impossible to transfect <i>in vitro</i> to express exogenous genes or proteins. These properties have made their <i>ex vivo</i> experimental manipulation and biochemical studies of their signal activation mechanisms and genetic makeup, challenging. Establishment of cell line models capable of differentiating along the myeloid lineage into mature neutrophil-like granulocytes, with similar morphological and functional properties to blood neutrophils would, therefore, be an important tool to enable transfection of key genes and determine the effects of such manipulations on neutrophil functions. PLB-985 is a recently established cell line that has been demonstrated to show greater levels of differentiation into granulocyte in the presence of appropriate differentiation-inducing agents, but the efficiency of differentiation reported so far was very low, and the differentiated cells only partly resembled mature blood neutrophils. This study developed a modified differentiation protocol and an optimised culture conditions that induced the PLB-985 cell line to differentiate into mature, neutrophil-like granulocytes, Terminally-differentiated, neutrophil-like phenotypes of PLB-985 cells that resembled mature blood neutrophil morphology, and which had an appreciably delayed apoptosis have been consistently cultured. This was evident by the acquisition of multi-lobed nucleus, granulated cytoplasm and delayed apoptosis. The differentiated PLB-985 cells may, therefore, provide an excellent neutrophil-model system for <i>in vitro</i> study of neutrophil differentiation, signalling and functions.
Nonimmediate Hypersensitivity Reaction After Trastuzumab Infusion: A Suspected Drug-Virus Interaction
Authors: Denisa E. Ferastraoaru, Maura N. Dickler, Sima Patel, Erica A. Fischer, Melissa P. Pulitzer, Patricia L. Myskowski, Elina Jerschow
Journal: Journal of Clinical Oncology (2013)
Diagnostic tools in tuberculous pleurisy: a direct comparative study: 1
Authors: A.H. Diacon, B.W. Van de Wal, C. Wyser, J.P. Smedema, J. Bezuidenhout, C.T. Bolliger, G. Walzl
Journal: European Respiratory Journal (2003)

Thoracoscopy is the most accurate yet most expensive tool for establishing the diagnosis of tuberculous (TB) pleurisy. However, most high TB‐incidence regions have limited financial resources, lack the infrastructure needed for routine thoracoscopy and require an alternative, cost­effective diagnostic approach for pleural effusions. Altogether, 51 patients with undiagnosed exudative pleural effusions were recruited for a prospective, direct comparison between bronchial wash, pleural fluid microbiology and biochemistry (adenosine deaminase (ADA) and cell count), closed needle biopsy, and medical thoracoscopy. The final diagnosis was TB in 42 patients (82%), malignancy in five (10%) and idiopathic in four patients (8%). Sensitivity of histology, culture and combined histology/culture was 66, 48 and 79%, respectively for closed needle biopsy and 100, 76 and 100%, respectively for thoracoscopy. Both were 100% specific. Pleural fluid ADA of ≥50 U·L<sup>−1</sup> was 95% sensitive and 89% specific. Combined ADA, lymphocyte/neutrophil ratio ≥0.75 plus closed needle biopsy reached 93% sensitivity and 100% specificity. A combination of pleural fluid adenosine deaminase, differential cell count and closed needle biopsy has a high diagnostic accuracy in undiagnosed exudative pleural effusions in areas with high incidences of tuberculosis and might substitute medical thoracoscopy at considerably lower expense in resource­poor countries.
Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer
Authors: Liang Cao, Yunkai Yu, Sven Bilke, Robert L. Walker, Linnia H. Mayeenuddin, David O. Azorsa, Fan Yang, Marbin Pineda, Lee J. Helman, Paul S. Meltzer
Journal: Cancer Research (2010)

The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHR-positive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma.
Melanoma Vaccines: Possible Progress After Years of Frustration?
Authors: C. Schmidt
Journal: JNCI Journal of the National Cancer Institute (2009)

Scientists are developing several additional immunotherapeutic methods, each with similar goals: to focus the immune response against tumors with greater specifi city and to block the natural suppressor mechanisms that tumors use to protect themselves from immune reactions. According to Paul Chapman , M.D., an attending physician at Memorial Sloan – Kettering Cancer Center, these approaches offer new hope for immunotherapy in the fi ght against melanoma and other cancers. “At some point, we might be able to use vaccines to prevent metastatic disease among melanoma patients whose lymph nodes have been surgically removed,” he said. “Or perhaps we could immunize people at high risk of the illness while they’re still teenagers, but that’s a dream scenario that won’t happen anytime soon.” Treatment Versus Prevention
Increased binding of SP1 to the γ‐globin gene promoter upon site‐specific cytosine methylation
Authors: Pritam K. Sengupta, Donald Lavelle, Joseph Desimone
Journal: American Journal of Hematology (1994)

Abstract We have studied the effect of site‐specific cytosine methylation on the binding of nuclear proteins to the γ‐globin promoter region from −71 to −34. This sequence was recently shown to contain a stage selector element responsible for increased transcription from the γ compared to the β promoter when both are linked to Locus Control Region enhancer sequences. We observed that Sp1 binding to this sequence is increased upon site‐specific cytosine methylation, such that only methylation of the cytosine in the −50 CpG dinucleotide effects Sp1 binding. Methylation of the distal C of the Hpall site has no effect. The possible functional role of Sp1 as a repressor of γ‐globin synthesis is discussed. © 1994 Wiley‐Liss, Inc.
Differential stimulation of murine lymphoma growth in vitro by normal and BCG-activated macrophages.
Authors: C F Nathan, W D Terry
Journal: The Journal of Experimental Medicine (1975)

Peritoneal macrophages from mice infected with Bacille Calmette-Guérin (BCG) and from normal mice were examined for their effects in vitro on thymidine uptake by 10 murine lymphomas, a murine fibroblast line, and a guinea pig hepatoma. Only the murine fibroblast line showed growth inhibition in the presence of BCG macrophages. For the majority of tumors, normal macrophages were profoundly stimulatory to tumor cell DNA synthesis, while BCG macrophages were much less stimulatory, without being frankly inhibitory. The effect of 2-mercaptoethanol on tumor cell growth was also studied. All lymphomas stimulated to grow more rapidly in vitro by normal macrophages were stimulated to a similar degree by 2-mercaptoethanol.