tbuckley/cabot-search huggingface dataset:
The Ras pathway in cancer.
Authors: Frank McCormick
Journal: Cancer Research (2006)

SY23-01  The Ras pathway is frequently activated in human cancer. Activated growth factor receptors signal through Ras, as well as other pathways, and Ras mutations account for half or more of colorectal cancers and lung cancers and significant fractions of other cancers. Proteins downstream of Ras, such as B-Raf and PI 3′ kinase, PTEN and others are also altered at high frequencies. These observations suggest that the Ras pathway may contain multiple opportunities for therapeutic interventions. Such therapies may also be useful in other indications, such as neurofibromatosis type 1 and Costello syndrome, which are caused by hyperactivation of Ras proteins indirectly or directly.  Ras proteins in their active states engage a large number of potential effector proteins. Of these, the Raf kinases, sub-types of PI 3′ kinases and the RalGDS proteins are best known, but others may also play an important role in Ras signal transduction and in cancer. In addition, a number of Ras-related proteins have been characterized, and many of these are likely to play roles in cancer, though their functions may be less direct than the classical Ras proteins that are activated directly by point mutation.  Analysis of mutations in Ras proteins and their effectors has revealed exclusive and non-exclusive relationships that point to the inter-dependence of these pathways in the development of cancer. For example, in melanoma, activating mutations in N-ras are mutually exclusive with either mutations in B-Raf or in PTEN, suggesting that a single activating mutation in Ras is sufficient to activate both downstream pathways. In other cancers, multiple hits have been observed in the same pathway, implying that in these cancers, full pathway activation requires several additive inputs. The implications of these relationships will be discussed in the context of drug targets in this pathway.
RETRACTED: Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells
Authors: Changhwan Yoon, Soo-Jeong Cho, Bülent Arman Aksoy, Do Joong Park, Nikolaus Schultz, Sandra W. Ryeom, Sam S. Yoon
Journal: Clinical Cancer Research (2015)

The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA.
US court upholds use of sedative in executions
Authors: Michael McCarthy
Journal: BMJ (2015)

In a 5-4 decision the US Supreme Court ruled on 29 June that the sedative midazolam can be used in the controversial three drug execution protocol adopted by the state of Oklahoma.1 Although the ruling was made largely on technical issues, several justices used the decision to argue for and against the constitutionality of capital punishment.

In 1997 Oklahoma adopted a lethal injection protocol that involved the intravenous administration of the barbiturate sodium thiopental to induce unconsciousness, followed by a paralytic agent to inhibit musculoskeletal movements and to paralyze the diaphragm, causing asphyxiation, as well as an infusion of potassium chloride to induce cardiac arrest.

Supporters of the protocol argued that, by rendering prisoners unconscious, the barbiturate shielded them from the terror of asphyxiation and the searing pain caused by the infusion of a high dose of potassium chloride.

However, under pressure from death penalty opponents, drug companies began refusing to provide firstly sodium thiopental and later another barbiturate, pentobarbital; and, in 2011, the European Commission expanded its ban on the export of products that could be used in executions or torture to include these barbiturates. Unable to obtain either drug, Oklahoma decided to use midazolam at 500 …
Mesenchymal stem cells prevent early inflammation in a rat model of ventilator induced lung injury
Authors: Laura Chimenti, Tomas Luque, Marisa Bonsignore, Daniel Navajas, Ramon Farrè
Journal: European Respiratory Journal (2011)

Background:  Recent studies have suggested that bone marrow-derived mesenchymal stem cells (MSC) might have potential therapeutic effects in acute lung injury (ALI), specifically in bleomycin-induced and bacterial LPS-induced lung injury models. However, whether MSC could induce an early anti-inflammatory response in lung injury induced by overventilation remains to be elucidated.   Aim:  To assess the potential role of MSC in preventing or modulating early inflammation in healthy rats subjected to ventilator induced lung injury (VILI).   Methods:  Adult male Sprague-Dawley rats (250-300 g) were anaesthetised, tracheotomised, intubated and paralysed by intravenous instillation of pancuronium bromide. Nine rats were ventilated with a high tidal volume of 25 ml/kg (VILI) for 3 h. Five millions of MSC were intravenously injected to 4 of these rats 30 min before starting ventilation. Spontaneously breathing anesthetised rats (N=4) served as controls. After 3 h of VILI/control the animals were sacrificed and broncoalveolar lavage inflammatory cells were assessed.   Results:  In VILI, MSC significantly (p   Conclusion:  This preliminary result suggests that infusion of bone marrow-derived MSC prevents early inflammation in VILI.  Funding: L. Chimenti was a recipient of a ERS/Marie Curie Postdoctoral Research Fellowships 2010
Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe Français d'Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer.
Authors: P Thiesse, L Ollivier, D Di Stefano-Louineau, S Négrier, J Savary, K Pignard, C Lasset, B Escudier
Journal: Journal of Clinical Oncology (1997)

PURPOSE We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC. MATERIALS AND METHODS The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC. RESULTS Major disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed. CONCLUSION We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.
Relation of asthma and body mass index in children
Authors: Akefeh Ahmadiafshar, Sara Tabbakhha, Zohreh Torabi, Behnaz Falakaflaki
Journal: European Respiratory Journal (2011)

Background: The prevalence of obesity and asthma has increased in past decades. Most prospective studies suggest that obesity increases the risk of asthma.but some did not find this association.

Aims and objectives: The purpose of this study was to determine the association between asthma and Body Mass Index

Method: This case-control study was conducted on 200 asthmatic children aged 6-15 years and 200 healthy controls. The criteria for asthma diagnosis and its classification were on the basis of National Asthma Education and Prevention Program (NAEPP). BMI of patients and controls were also measured and BMI grater than 85% and 95% were defined as overweight and obese respectively. The data was analyzed by SPSS software.

Results: The BMI among the asthmatic children (17.9 kg/m2) was higher than the BMI among the non-asthmatics (16.5kg/m2), p value =0/0001. This relationship was significant in both males and females.%18 of asthmatic children were classified as overweight and 13.5% of them were obese. The frequency of overweight and obesity in control group was7.5% and 6%, p value =0.0001. However, there was no significant relationship between severity, duration of asthma and kind of medication and BMI in asthmatic children, p value >0.05.

Conclusion: Result of this study showed that there is an association between asthma symptoms and obesity in children. Therefore, attention to weight control in asthmatic children might be effective.
Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes
Authors: Connie N. Hess, Stefan James, Renato D. Lopes, Daniel M. Wojdyla, Megan L. Neely, Danny Liaw, Emil Hagstrom, Deepak L. Bhatt, Steen Husted, Shaun G. Goodman, Basil S. Lewis, Freek W.A. Verheugt, Raffaele De Caterina, Hisao Ogawa, Lars Wallentin, John H. Alexander
Journal: Journal of the American College of Cardiology (2015)
Incidence of Major Cardiovascular Events in Immigrants to Ontario, Canada
Authors: Jack V. Tu, Anna Chu, Mohammad R. Rezai, Helen Guo, Laura C. Maclagan, Peter C. Austin, Gillian L. Booth, Douglas G. Manuel, Maria Chiu, Dennis T. Ko, Douglas S. Lee, Baiju R. Shah, Linda R. Donovan, Qazi Zain Sohail, David A. Alter
Journal: Circulation (2015)

Immigrants from ethnic minority groups represent an increasing proportion of the population in many high-income countries but little is known about the causes and amount of variation between various immigrant groups in the incidence of major cardiovascular events.We conducted the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) Immigrant study, a big data initiative, linking information from Citizenship and Immigration Canada's Permanent Resident database to nine population-based health databases. A cohort of 824 662 first-generation immigrants aged 30 to 74 as of January 2002 from eight major ethnic groups and 201 countries of birth who immigrated to Ontario, Canada between 1985 and 2000 were compared to a reference group of 5.2 million long-term residents. The overall 10-year age-standardized incidence of major cardiovascular events was 30% lower among immigrants compared with long-term residents. East Asian immigrants (predominantly ethnic Chinese) had the lowest incidence overall (2.4 in males, 1.1 in females per 1000 person-years) but this increased with greater duration of stay in Canada. South Asian immigrants, including those born in Guyana had the highest event rates (8.9 in males, 3.6 in females per 1000 person-years), along with immigrants born in Iraq and Afghanistan. Adjustment for traditional risk factors reduced but did not eliminate differences in cardiovascular risk between various ethnic groups and long-term residents.Striking differences in the incidence of cardiovascular events exist among immigrants to Canada from different ethnic backgrounds. Traditional risk factors explain part but not all of these differences.
Sunlight or diet: what is the answer for providing sufficient vitamin D in the U.K.?: reply from author
Authors: B.L. Diffey
Journal: British Journal of Dermatology (2010)

Conflicts of interest: none declared. Madam, Macdonald and colleagues make an important point about the poorly understood contribution of tissue stores of vitamin D to overall 25‐hydroxyvitamin D [25(OH)D] status, a view with which I agree and alluded to in my paper.1 As shown by Macdonald et al. in their Figure, and supported by the data in Table 3 of my paper,1 winter‐time levels of circulating 25(OH)D in the U.K. are typically around 40 nmol L−1, rising to 60 nmol L−1 in the summer. These summer values are the result of spending a few hours per day outside. For example, in the study reported by Hyppönen and Power,2 who measured serum 25(OH)D concentrations in over 7000 white British people aged 45 years and found a mean summer to winter difference of 19·2 nmol L−1, the authors reported that during the summer just 5·5% of respondents claimed to spend < 30 min per day outdoors, with 42·1% spending between 0·5 and 3 h and 52·4% spending 3 h or more outdoors per day. These times outdoors are similar to those observed in a Danish study3 where during a summer season a mean of 2·9 h (range 0·3–6·5) per day was spent outdoors. Clearly the vast majority of people spends much longer outdoors than the ubiquitous advice that 10–20 min of daily casual sun exposure during the summer months is adequate in maintaining a healthy vitamin D status.4
Pharmacokinetic effect of aprepitant on irinotecan in patients with colorectal cancer
Authors: J. J. Nieva, W. Webb, G. Siuzdak
Journal: Journal of Clinical Oncology (2007)

19622 Background: Alterations in the activity of cytochrome P450 enzymes can affect the clearance of chemotherapeutic drugs. Aprepitant, a moderate inhibitor and inducer of cytochrome P450 3A4, is now increasingly used for the prevention of chemotherapy induced nausea and vomiting as an adjuct to irinotecan-containing chemotherapy. There is little published data on the potential interaction between these agents. We sought to determine if aprepitant impacts the clinical pharmacokinetics of irinotecan. Methods: Patients with colorectal cancer receiving FOLFIRI chemotherapy were eligible for enrollment. Each patient received 2 cycles of FOLFIRI chemotherapy with, and 2 cycles without, aprepitant as part of the anti-emetic regimen. Plasma was obtained for each chemotherapy cycle at: 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 24 and 48 hours. Irinotecan and its active metabolite SN-38 plasma levels were measured in duplicate by LC-FLD. Differences between groups were evaluated using a paired students t-test. Results: We administered 8 cycles of FOLFIRI chemotherapy for treatment of colorectal cancer to 2 patients. Median Cmax of irinotecan and SN-38 was 1,628 ± 1,565 ng/mL and 18.8 ± 9.7 ng/mL for aprepitant treated chemotherapy cycles compared with 1376 ± 1536 ng/mL and 23.5 ± 8.5 ng/mL for conventionally pre-medicated cycles. Median area under the concentration versus time curve (AUC) for irinotecan was 583.9 ± 317.6 μg/ml·min in aprepitant treated cycles and 682.6 ±266.5 μg/ml·min during conventionally treated cycles. Median AUC for SN-38 was 15.0 ± 7.5 μg/ml·min and 18.0 ± 9.0 μg/ml·min in aprepitant and conventionally premedicated chemotherapy cycles respectively. Conclusions: In this pilot study, aprepitant, as it is typically administered, did not have any significant effect on irinotecan pharmacokinetics in patients with colorectal cancer. No significant financial relationships to disclose.
The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection
Authors: Lifan Xu, Yi Cao, Zhunyi Xie, Qizhao Huang, Qiang Bai, Xia Yang, Ran He, Yaxing Hao, Haoqiang Wang, Tingting Zhao, Zhonglei Fan, Aijian Qin, Jianqiang Ye, Xinyuan Zhou, Lilin Ye, Yuzhang Wu
Journal: Nature Immunology (2015)
Late-breaking abstract: The coagulant factor Xa induces PAR-1 and annexin A2-dependent airway smooth muscle cytokine production and cell proliferation
Authors: Michael Schuliga, Trudy Harris, Simon Royce, Alastair Stewart
Journal: European Respiratory Journal (2014)

Introduction During asthma exacerbation, plasma circulating coagulant factor X (FX) enters the inflamed airways and is activated (FXa). Like thrombin, FXa activates the protease activated receptor-1 (PAR-1), and may have an important role in asthma. Extracellular annexin A2 is also implicated in PAR-1 signalling.

Aim To investigate the PAR-1-mediated effects of FXa on airway smooth muscle (ASM) cell function.

Methods Human ASM cells were incubated with FX, FXa (0.5-50 nM) and thrombin (300 mU/mL). PAR-1 and annexin A2 were targeted by siRNA or functional blocking antibodies. Thrombin and PAR-1 were inhibited using hirudin and SCH79797, respectively. Levels of interleukin-6 (IL-6) and cell proliferation were assessed by ELISA (24 h) and cell enumeration (48 h) respectively. Immunohistochemistry was used to evaluate the distribution and levels of annexin A2 and S100A10 in airway biopsies of asthmatics and controls. S100A10 is a binding partner of annexin A2 required for its extracellular trafficking.

Results FXa, but not FX, stimulated SCH79797-sensitive ASM IL-6 production and cell proliferation. FXa effects were partially attenuated by hirudin, suggesting FXa converts ASM pro-thrombin to thrombin. Targeting annexin A2 attenuated FXa-, but not thrombin-stimulated ASM function. In airway biopsies, annexin A2 was detected in the periphery of the ASM bundle. Although annexin A2 levels appeared to be similar in the airways of asthmatics and controls, S100A10 levels were increased in severe asthma.

Conclusion These findings establish FXa as a potentially important asthma mediator, stimulating ASM function, through actions requiring PAR-1 and annexin A2.
Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota
Authors: Jia Sun, Laetitia Furio, Ramine Mecheri, Anne M. van der Does, Erik Lundeberg, Loredana Saveanu, Yongquan Chen, Peter van Endert, Birgitta Agerberth, Julien Diana
Journal: Immunity (2015)
Pulse oximetry during saline challenge in vocal cord dysfunction and airway hyper-responsiveness
Authors: Allyson Upward, Jeffrey Pretto, Michael Hensley
Journal: European Respiratory Journal (2011)

The hypertonic saline challenge (HSC) is a commonly used diagnostic tool to assess airway hyper-responsiveness (AHR) and vocal cord dysfunction (VCD). Dyspnoea during testing is not uncommon and we postulated that oxygen desaturation may be a causative factor.   Aim:  To document the degree of arterial desaturation during saline challenge and compare SpO2 changes in AHR, VCD and negative responses.   Method:  SpO2 (Nellcor N595) was continuously recorded during 78 consecutive HSCs. SpO2 data was averaged over 32 seconds and minimum values used for analysis. Change in dyspnoea score (Borg) during the challenge was also recorded. Results were classified as AHR (change in FEV1 ≥15%), as VCD (change in MIF ≥20%) or negative otherwise.   Results:  Mean (SD) FEV1 was 86 (15)% predicted for AHR (n=20), 92 (18)% for VCD (n=18) and 94 (18)% for negative results (n=40). There was a consistent trend in SpO2 for all subject groups with significant desaturation during the final doses of saline and during bronchodilatation (ANOVA p   Conclusion:  Hypertonic saline challenge causes a significant and reproducible pattern of arterial desaturation irrespective of the test response. These data would be consistent with progressive hypoventilation during HSC rather than indicating desaturation due to worsening ventilation-perfusion mismatching. Hypoxaemia does not appear to be the primary cause of dyspnoea during HSC.
RETRACTED: Grizzly Bears Exhibit Augmented Insulin Sensitivity while Obese Prior to a Reversible Insulin Resistance during Hibernation
Authors: O. Lynne Nelson, Heiko T. Jansen, Elizabeth Galbreath, Kurt Morgenstern, Jamie Lauren Gehring, Kimberly Scott Rigano, Jae Lee, Jianhua Gong, Adam J. Shaywitz, Chantal A. Vella, Charles T. Robbins, Kevin C. Corbit
Journal: Cell Metabolism (2014)
The safety of treating the right middle lobe with bronchial thermoplasty
Authors: Tanya Wiese, Murali Kondapaneni
Journal: European Respiratory Journal (2013)

Background : Bronchial thermoplasty (BT) is an FDA approved procedure to treat severe asthma in adults. Studies have shown improved quality of life, decreased exacerbations, and decrease medication in many of the patients who receive this therapy. The original studies on BT did not include treatment of the right middle lobe. There were initial concerns that BT may cause inflammation, edema, or stenosis of the airway. Thus, the right middle lobe was not treated as it is the most vulnerable to damage due to its unique anatomical features. However, the AIR2 trial showed by computed tomography of the chest that BT does not cause any immediate or long term damage to the airways. At our institution we perform BT on the right middle lobe and are the first to report on this.

Design: Retrospective review of one institutions experience with bronchial thermoplasty of the right middle lobe.

Results : We reviewed the data of our first 10 BT patients treated over an 8 month time period. The right middle lobe was treated with the right lower lobe at the time of the first procedure. Direct examination or the right middle lobe 6 weeks later showed no airway narrowing by stenosis or bronchomalacia in any of the 10 patients. Six months later, no patient has experienced problems with stenosis or malacia of the right middle lobe. As in previous studies, there was no significant change in FEV1 and patients had similar improvements in quality of life scores as compared to previous studies (1.39 vs 1.35).

Conclusion : The right middle lobe can safely be treated with BT. Longer term follow-up is needed to determine if there may be any additional benefit to including the right middle lobe.
Albinism and schizophreniform psychosis: a pedigree study
Authors: M Baron
Journal: American Journal of Psychiatry (1976)

The author presents a pedigree study of albinism associated with schizophreniform psychosis and concludes that the evidence of an association between the two traits is strong; the evidence for genetic linkage is suggestive. The pineal hormone melatonin and the melanocyte-stimulating hormone inhibitory factor may be etiologic determinants of psychosis associated with albinism.
An evolutionary comparison of Acinetobacter calcoaceticus trpF with trpF genes of several organisms.
Authors: C M Ross, J B Kaplan, M E Winkler, B P Nichols
Journal: Molecular Biology and Evolution (1990)

The deduced amino acid sequence of Acinetobacter calcoaceticus N-(5'-phosphoribosyl) anthranilate isomerase (PRAI), which is coded by trpF, was compared with TrpF of Caulobacter crescentus, Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, Neurospora crassa, and Aspergillus nidulans. Sixty percent of identical or similar amino acids were located in alpha/beta TIM (triose-phosphate isomerase) barrels and in residues important in substrate binding and catalysis. In addition, the analysis of trpF genes presented here supports a model by which fusion between separate trpC and trpF genes arose in some cases by in-frame deletions.
Differences in pulmonary rehabilitation outcomes in patients after single or double lung transplantation
Authors: Tessa Schneeberger, Rainer Gloeckl, Bernd Sczepanski, Sandra Winterkamp, Klaus Kenn
Journal: European Respiratory Journal (2014)

Introduction:  PR following LTx can almost be seen as an established therapeutic modality. However, differences concerning the efficiency of pulmonary rehabilitation (PR) in patients with single (SLTx) or double (DLTx) lung transplantation have barely been studied yet.  Methods:  In a retrospective analysis (period: 1997-2013) 550 patients with COPD or interstitial lung diseases after LTx (SLTx: n=212, FEV 1  55±18% pred., age: 58±6 ys; DLTx: n=338, FEV 1  70±19% pred., age: 53±8 ys) were included. All patients underwent a standardized inpatient PR program of 41±18 days in average. Data of 6-minute walking distance (6MWD), health related quality of life (physical [PCS] and mental [MCS] component summary of the SF 36 questionnaire) and adverse events during PR have been registered and analyzed.  Results:  In SLTx patients, 6MWD increased from 267±134 to 381±120 (p  Conclusion:  These results show that patients benefit significantly and clinically relevant from a comprehensive PR program performed immediately after surgery to a similar extend with regard to HRQL. However exercise capacity improved significantly more in patients after DLTx.