tbuckley/cabot-search huggingface dataset:
Epidermal Growth Factor Receptor Mutations in Small Cell Lung Cancer
Authors: Akiko Tatematsu, Junichi Shimizu, Yoshiko Murakami, Yoshitsugu Horio, Shigeo Nakamura, Toyoaki Hida, Tetsuya Mitsudomi, Yasushi Yatabe
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The vast majority of epidermal growth factor receptor (EGFR) mutations occur in lung adenocarcinoma, and even rare cases of other subtypes with this mutation, such as adenosquamous cell carcinoma, are associated with adenocarcinoma histology. According to this adenocarcinoma-specific nature of EGFR mutation, analysis of EGFR mutations with small cell lung cancers (SCLC) may provide a clue to its histogenesis. Experimental Design: The mutational status of the EGFR gene was accessed in a cohort of 122 patients with SCLC; all patients were from a single institute. When the EGFR mutated, its gene copy number was also examined. Results: EGFR mutations were detected in five SCLCs (4%). The patients were mainly in the light smoker and histologic combined subtype. All but one of the tumors harbored gene amplifications. Notably, in three tumors of the combined SCLC subtype, both components of adenocarcinoma and SCLC harbored an EGFR mutation, whereas gene amplification was detected only in the adenocarcinoma component. A partial response was achieved in a patient (with an EGFR mutation) who was treated with gefitinib. Conclusions: Although EGFR mutations are rare in SCLC, a combined subtype of SCLC with adenocarcinoma in light smokers may have a chance of harboring EGFR mutations. For patients with an EGFR mutation, EGFR tyrosine kinase inhibitor can be a treatment option. In terms of molecular pathogenesis, it is suggested that some SCLCs may have developed from pre-existing adenocarcinomas with EGFR mutations, but the development may not be simply linear, taking into consideration the discordant distribution of EGFR amplification.
Studies on the Pathogenesis of Type I (Distal) Renal Tubular Acidosis as Revealed by the Urinary Pco2 Tensions
Authors: M. L. Halperin, M. B. Goldstein, A. Haig, M. D. Johnson, B. J. Stinebaugh
Journal: Journal of Clinical Investigation (1974)

This study was designed to investigate the pathogenesis of type I (distal) renal tubular acidosis. Urinary and blood Pco(2) tensions were determined when the pH of the urine was equal to or exceeded the corresponding blood pH. This provided an indication of net hydrogen ion secretion in the distal nephron. In 16 normal subjects, the Pco(2) of the urine exceeded blood values (U-B Pco(2)) by 32.7+/-3.1 mm Hg. In contrast, the urinary Pco(2) tensions in 10 patients with type I (distal) renal tubular acidosis were not significantly greater than blood values (U-B Pco(2) = 2.0+/-2.2 mm Hg). These results indicate that type I (distal) renal tubular acidosis is caused by failure of the cells of the distal nephron to secrete hydrogen ions rather than to gradient-limited hydrogen ion addition to the urine. This is suggested by the fact that urinary Pco(2) levels should be higher than blood Pco(2) levels when hydrogen ions are secreted into urine containing bicarbonate in the distal nephron and they were not in this study despite the presence of a favorable hydrogen ion gradient (tubular fluid pH exceeded blood pH).
Evaluation of alveolar surfactant aggregates<i>in vitro</i>and<i>in vivo</i>
Authors: A.M. Brackenbury, J.L. Malloy, L.A. McCaig, L-J. Yao, R.A.W. Veldhuizen, J.F. Lewis
Journal: European Respiratory Journal (2002)

In acute lung injury, a decrease in surface-active large aggregates and an increase in the less surface-active small surfactant aggregates are observed. The objective of the current study was to determine if the increase in small aggregates interfered with the function of large aggregates, thereby independently contributing to lung dysfunction. Isolated large aggregates, small aggregates, and large aggregate+small aggregate combinations were analysed for in vitro surface activity utilizing a pulsating bubble surfactometer. Subsequently, large aggregates, small aggregates, and large aggregate+small aggregate combinations were administered to surfactant-deficient, adult Sprague-Dawley rats. Physiological parameters were measured during 1 h of ventilation. After sacrifice, the whole lung lavage was analysed for protein concentration, and surface activity of the recovered large aggregates. The minimum surface tension of the large aggregate+small aggregate preparations (10 mN·m −1 ) was significantly higher than large aggregates alone (1 mN·m −1 ), but lower than small aggregates alone (21 mN·m −1 ) after 100 pulsations. In vivo , rats receiving large aggregates+small aggregates showed immediate increases in oxygenation, similar to animals given large aggregates, whereas animals given small aggregates and control animals maintained low oxygenation values. In conclusion, small aggregates interfered with large aggregates function in vitro , but this was not observed in vivo in this experimental model.
Electrostatic Contributions of Aromatic Residues in the Local Anesthetic Receptor of Voltage-Gated Sodium Channels
Authors: Christopher A. Ahern, Amy L. Eastwood, Dennis A. Dougherty, Richard Horn
Journal: Circulation Research (2007)

Antiarrhythmics, anticonvulsants, and local anesthetics target voltage-gated sodium channels, decreasing excitability of nerve and muscle cells. Channel inhibition by members of this family of cationic, hydrophobic drugs relies on the presence of highly conserved aromatic residues in the pore-lining S6 segment of the fourth homologous domain of the channel. We tested whether channel inhibition was facilitated by an electrostatic attraction between lidocaine and π electrons of the aromatic rings of these residues, namely a cation-π interaction. To this end, we used the in vivo nonsense suppression method to incorporate a series of unnatural phenylalanine derivatives designed to systematically reduce the negative electrostatic potential on the face of the aromatic ring. In contrast to standard point mutations at the same sites, these subtly altered amino acids preserve the wild-type voltage dependence of channel activation and inactivation. Although these phenylalanine derivatives have no effect on low-affinity tonic inhibition by lidocaine or its permanently charged derivative QX-314 at any of the substituted sites, high-affinity use-dependent inhibition displays substantial cation-π energetics for 1 residue only: Phe1579 in rNa V 1.4. Replacement of the aromatic ring of Phe1579 by cyclohexane, for example, strongly reduces use-dependent inhibition and speeds recovery of lidocaine-engaged channels. Channel block by the neutral local anesthetic benzocaine is unaffected by the distribution of π electrons at Phe1579, indicating that our aromatic manipulations expose electrostatic contributions to channel inhibition. These results fine tune our understanding of local anesthetic inhibition of voltage-gated sodium channels and will help the design of safer and more salutary therapeutic agents.
Segmental Hyperperfusion in Lobar Pneumonia Visualized with Respiratory-gated Four-Dimensional Pulmonary Perfusion Positron Emission Tomography–Computed Tomography
Authors: Michael S. Hofman, Jason Callahan, Peter Eu, Rodney J. Hicks
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

A 64-year-oldman underwent a respiratory-gated four-dimensional pulmonary perfusion positron emission tomography (PET)/computed tomography (CT) for preoperative regional lung function quantification. This was performed after intravenous administration of Gamacroaggregated albumin (1–3). At the time of imaging, he had a productive cough, fever, and subsequent clinical diagnosis of bronchopneumonia. Images demonstrated an area of hyperperfusion localized to an area of dense collapse/consolidative change in the lateral segment of the right middle lobe (Figure 1 and supplemental video E1). The abnormality was also clearly apparent on the nonattenuation correction images, excluding an attenuation artifact. Studies have typically documented matched ventilation–perfusion or reverse mismatch phenomenon in pneumonia (4). Although occlusive obstruction of lobar airways is usually accompanied by reflex hypoxic vasoconstriction, the local release of inflammatory mediators with vasodilatory properties with infection results in failure of this mechanism and shunting leading to hypoxia (5). The histopathologic correlate is the red hepatization phase of lobar pneumonia. Tc-macroaggregated albumin single-photon emission computed tomography/CT had also been performed in this patient, but no corresponding perfusion abnormality was found. Although this was performed 72 hours earlier, the CT abnormality was similar; we contend that in addition to the superior imaging characteristics of PET, the absence of respiratory gating and attenuation correction contributed to lack of abnormality on single-photon emission computed tomography. The higher spatial and temporal resolution of PET combined with four-dimensional acquisition (6) provides a major advance in image quality and may improve our understanding of pulmonary physiology in a spectrum of diseases. n
Donaldson defends decision not to resign over recruitment chaos
Authors: Adrian O'Dowd
Journal: BMJ (2007)

England's chief medical officer, Liam Donaldson, has told MPs that he was right not to resign over the chaotic recruitment system for junior doctors.

Professor Donaldson, giving evidence to the parliamentary health select committee, said he would not take personal and sole responsibility for the problems faced by junior doctors this year when they applied for posts under the new Modernising Medical Careers (MMC) programme.

The committee, in the first evidence session of its inquiry into the MMC programme, asked why Professor Donaldson had not felt it appropriate to leave his job, considering the scale of the problems. Thousands of junior …
A9.5 Identification and Validation of a Protein Combination Including S100A9 able to Predict the Response to the MTX/Etanercept Association in Rheumatoid Arthritis Patients
Authors: A Obry, T Lequerré, J Hardouin, O Boyer, O Vittecoq, P Cosette
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The number of biologic agents in Rheumatoid Arthritis (RA) is continuously increasing. However, clinicians observe that around 30 to 40% of treated patients fail to respond to TNFα blocking agents. One way to optimise the drug prescription is to identify predictive markers of drug responsiveness. <h3>Objectives</h3> To identify a combination of serum proteins whose expression profile would predict the RA patients responses to the association of methotrexate (MTX) and etanercept (ETA) by mass spectrometry-based quantification methods and ELISA. <h3>Methods</h3> A “cohort discovery phase” of 23 patients with active RA was treated by a subcutaneous injection of. The clinical efficacy of these drugs was evaluated with the DAS28 score after 6 months of treatment according to the EULAR response criteria. For proteomic analysis, a serum sample was collected in patients prior to treatment exposure. A “label free” approach on the whole proteome was performed by mass spectrometry on the 25 sera. Accordingly, the proteome of each sample was extracted and in-gel digested. The resulting peptides were analysed by LTQ Orbitrap® (ThermoFisher). Differential analysis between responder and non responder samples was performed with LCMS ProGenesis® (Nonlinear Dynamics). To validate these results a relative quantification of selected protein was performed on the second “cohort validation phase” by ELISA. The proteome of peripheral blood mononuclear cells (PBMC) from a second cohort of seven patients with similar characteristics has also been studied by the same label free approach. <h3>Results</h3> The label free approach revealed 12 differentially expressed serum proteins according to patient response. This combination of proteins was used to build a Random Forest statistical model to predict the patient’s status. This model was validated by a blind test on a panel of seven patients. Moreover, these results have shown the protein S100A9 overexpression in both the serum and the PBMCs from responder’s patients and this expression was confirmed by ELISA. <h3>Conclusions</h3> The label free approach has identified a combination of predictive markers of response to MTX treatment/ETA. Thus, using sera samples collected in patients prior to treatment exposure, it is possible to predict response to treatment with a small error. These proteins represent interesting candidate biomarkers of response that must be validated in a larger population. Already identified as a diagnostic and prognostic biomarker of RA, the S100A9 protein has been identified as a predictive biomarker of response both in serum and in PBMCs.
Low genic variation in male-reproductive-tract proteins of Drosophila melanogaster and D. simulans.
Authors: M B Coulthart, R S Singh
Journal: Molecular Biology and Evolution (1988)

We report results, using two-dimensional gel electrophoresis (2DE), of natural population surveys of allelic variation in approximately 300 male-reproductive-tract polypeptides in both Drosophila melanogaster and its sibling species, D. simulans. Despite our efforts to maximize operational sensitivity of our 2DE gels to polymorphism, variation estimates in both species were low (proportion of polymorphic loci [P] = 9%, and average heterozygosity [H] = 1%-3%), compared with those by one-dimensional gel electrophoresis (1DE) (P = 29%-55%; H = 8%-19%) in the same populations. However, H of polymorphic loci was very similar for 2DE and 1DE proteins; and for 17 of a total of 54 polymorphic proteins, 2DE detected three or four distinct alleles. The results suggest that the differing levels of variability widely seen with 1DE and 2DE are real and reflect differing intensities of functional constraint between different classes of structural loci. However, the alternative possibility remains that 2DE has a greater between-locus unevenness of variant detection sensitivity than does 1DE.
The Positive Correlation between dN/dS and dS in Mammals Is Due to Runs of Adjacent Substitutions
Authors: Nina Stoletzki, Adam Eyre-Walker
Journal: Molecular Biology and Evolution (2010)

A positive correlation between ω, the ratio of the nonsynonymous and synonymous substitution rates, and dS, the synonymous substitution rate has recently been reported. This correlation is unexpected under simple evolutionary models. Here, we investigate two explanations for this correlation: first, whether it is a consequence of a statistical bias in the estimation of ω and second, whether it is due to substitutions at adjacent sites. Using simulations, we show that estimates of ω are biased when levels of divergence are low. This is true using the methods of Yang and Nielsen, Nei and Gojobori, and Muse and Gaut. Although the bias could generate a positive correlation between ω and dS, we show that it is unlikely to be the main determinant. Instead we show that the correlation is reduced when genes that are high quality in sequence, annotation, and alignment are used. The remaining—likely genuine—positive correlation appears to be due to adjacent tandem substitutions; single substitutions, though far more numerous, do not contribute to the correlation. Genuine adjacent substitutions may be due to mutation or selection.
Costimulation as a Platform for the Development of Vaccines: A Peptide-Based Vaccine Containing a Novel Form of 4-1BB Ligand Eradicates Established Tumors
Authors: Rajesh K. Sharma, Kutlu G. Elpek, Esma S. Yolcu, Rich-Henry Schabowsky, Hong Zhao, Laura Bandura-Morgan, Haval Shirwan
Journal: Cancer Research (2009)

Abstract Vaccines represent an attractive treatment modality for the management of cancer primarily because of their specificity and generation of immunologic memory important for controlling recurrences. However, the efficacy of therapeutic vaccines may require formulations that not only generate effective immune responses but also overcome immune evasion mechanisms employed by progressing tumor. Costimulatory molecules play critical roles in modulating innate, adaptive, and regulatory immunity and have potential to serve as effective immunomodulatory components of therapeutic vaccines. In this study, we tested the function of a novel soluble form of 4-1BB ligand (4-1BBL) costimulatory molecule in modulating innate, adaptive, and regulatory immunity and assessed its therapeutic efficacy in the HPV-16 E7-expressing TC-1 cervical cancer and survivin-expressing 3LL lung carcinoma mouse models. Vaccination with 4-1BBL activated dendritic cells and enhanced antigen uptake, generated CD8+ T-cell effector/memory responses, and endowed T effector cells refractory to suppression by CD4+CD25+FoxP3+ T regulatory cells. Immunization with 4-1BBL in combination with an E7 peptide or survivin protein resulted in eradication of TC-1 and 3LL tumors, respectively. 4-1BBL was more effective than TLR agonists LPS, MPL, and CpG and an agonistic 4-1BB antibody as a component of E7 peptide-based therapeutic vaccine for the generation of immune responses and eradication of TC-1 established tumors in the absence of detectable toxicity. Therapeutic efficacy was associated with reversal of tumor-mediated nonresponsiveness/anergy as well as establishment of long-term CD8+ T-cell memory. Potent pleiotropic immunomodulatory activities combined with lack of toxicity highlight the potential of 4-1BBL molecule as an effective component of therapeutic cancer vaccines. [Cancer Res 2009;69(10):4319–26]
Palliative Cancer Care: An Epidemiologic Study
Authors: Gerhild Becker, Isaak Hatami, Carola Xander, Bettina Dworschak-Flach, Manfred Olschewski, Felix Momm, Peter Deibert, Irene J. Higginson, Hubert E. Blum
Journal: Journal of Clinical Oncology (2011)

To analyze the need for palliative care in hospital patients who have cancer. Palliative care is an essential component of comprehensive cancer care and identification of palliative care needs (PCNs) of patients with cancer is a topic that has not been thoroughly studied.Data were collected prospectively from inpatients of University Medical Center Freiburg in Freiburg, Germany, with 982 hospital beds included in the study. During the observation period of 17 months, each patient discharged from a hospital ward was screened by surveying the treating physician who was responsible for dismissal about patients' PCNs based on the WHO 1990 definition of palliative care. To complete obligatory electronic discharge management, a modified dismissal form asking to classify the patient as having PCN "yes/no" had to be filled out for each patient discharged.The response rate was 96% with data for 39,849 patients that could be analyzed. A total of 6.9% of all hospital patients and 9.1% of patients older than age 65 years were considered to have PCNs. Of the 2,757 patients with PCNs, 67% (n = 1,836) had cancer. Among the 11,584 patients with cancer, 15.8% were classified as having PCNs. PCNs were particularly high in patients with head and neck cancer (28.3%), malignant melanoma (26.0%), and brain tumors (18.2%). Suffering from cancer increases the probability of developing PCNs by a factor of 3.63 (95% CI, 3.27 to 4.04). For patients with metastatic cancer, the risk of developing PCNs is increased 12-fold (odds ratio, 12.27; 95% CI, 11.07 to 13.60).Structures to provide palliative care for patients with cancer are needed.
Significance of the occurrence of transparent skin. A study of histological characteristics and biosynthesis of dermal collagen.
Authors: B McConkey, K W Walton, S A Carney, J C Lawrence, C R Ricketts
Journal: Annals of the Rheumatic Diseases (1967)

Transparent skin has been observed in a proportion of elderly people and its association with senile osteoporosis has already been noted (McConkey, Fraser, Bligh, and Whiteley, 1963).In patients with rheumatoid disease, whether treated with steroids or not, it was found to be com- moner than in elderly people unaffected by rheuma- toid disease (McConkey, Fraser, and Bligh, 1965).Clinical studies led to the hypothesis that trans- parent skin is the consequence of a change in the connective tissues of the skin and that a similar change might be taking place in the connective tissues of the bones.This is an account of the histological changes characteristic of transparent skin and of some ex- periments undertaken to investigate its pathogenesis. Methods Selection of Patients49 patients were studied in all, including one case of scleroderma studied for comparative purposes (see below).Whether for histology, or for estimation of skin collagen or of water content, the procedure adopted was to select a number of patients with unequivocally abnormal skin and to compare the results obtained in these with those obtained in matched controls.The thickness of a fold of skin on the dorsum of the hand was measured with Harpenden calipers.For each patient with transparent skin (as previously defined, McConkey and others, 1963), a control patient was selected who corresponded in age, sex, and skin thickness but whose skin was opaque.No patient was receiving treatment with corticosteroids or had other evidence of skin disease.Skin biopsies were taken from the dorsum of the hand over the 3rd-4th metacarpal.
Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma
Authors: J. Garcia-Donas, L.J. Leandro-García, A. González del Alba, M. Morente, I. Alemany, E. Esteban, J.A. Arranz, M.A. Climent, E. Gallardo, D.E. Castellano, J. Bellmunt, B. Mellado, J. Puente, F. Moreno, A. Font, S. Hernando, M. Robledo, C. Rodríguez-Antona
Journal: Annals of Oncology (2013)

BackgroundPrevious studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC).Patients and methodsThe expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib.ResultsHigh expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023).ConclusionsWe found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.