tbuckley/cabot-search huggingface dataset:
Phosphatase and Tensin Homologue Deficiency in Glioblastoma Confers Resistance to Radiation and Temozolomide that Is Reversed by the Protease Inhibitor Nelfinavir
Authors: Zibin Jiang, Nabendu Pore, George J. Cerniglia, Rosemarie Mick, Maria-Magdelena Georgescu, Eric J. Bernhard, Stephen M. Hahn, Anjali K. Gupta, Amit Maity
Journal: Cancer Research (2007)

Abstract Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the nelfinavir acts along the Akt pathway to radiosensitize cells. However, nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm3 in the radiation + nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and nelfinavir. (P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas. [Cancer Res 2007;67(9):4467–72]
Cost-effectiveness of Screening BRCA1/2 Mutation Carriers With Breast Magnetic Resonance Imaging
Authors: Sylvia K. Plevritis, Allison W. Kurian, Bronislava M. Sigal, Bruce L. Daniel, Debra M. Ikeda, Frank E. Stockdale, Alan M. Garber
Journal: JAMA (2006)

eterious mutations in the BRCA1 or BRCA2 cancer susceptibility genes have a 45% to 65% lifetime risk of developing breast cancer. 1 The risk can be reduced by prophylactic mastectomy but many BRCA1/2 mutation carriers decline prophylactic mastectomy 2 and seek effective screening strategies that detect breast cancer early.5][6] Screening with contrastenhanced breast magnetic resonance imaging (MRI) has been shown to detect disease earlier than mammography in high-risk women; cancers detected by MRI are often axillary lymphnode negative and stage I. [6][7][8][9][10][11][12][13][14] Recently, the Blue Cross and Blue Shield Technology Evaluation Center reported that screening with breast MRI provides clinical benefit to high-risk women. 15lthough breast MRI screening is highly sensitive, it increases the rate of falsepositive test results, and it has not been shown to reduce breast cancer mortality. 16Furthermore, breast MRI screen-ing is at least 10 times more expensive than mammographic screening and generates higher diagnostic costs. 7,9,14ecause cost may be the greatest barrier to broader evaluation and dissemi-nation of breast MRI screening, its costeffectiveness is a critical consideration.We evaluated the cost-effectiveness of adding breast MRI screening in BRCA1/2 mutation carriers, incorporating the
Explanations of Socioeconomic Differences in Excess Risk of Type 2 Diabetes in Swedish Men and Women
Authors: Emilie E. Agardh, Anders Ahlbom, Tomas Andersson, Suad Efendic, Valdemar Grill, Johan Hallqvist, Claes-Göran Östenson
Journal: Diabetes Care (2004)

We investigated to what extent socioeconomic differences in type 2 diabetes risk could be explained by established risk factors (obesity, physical inactivity, smoking, and heredity) and psychosocial factors (low decision latitude at work and low sense of coherence).This cross-sectional study comprised 3,128 healthy Swedish men and 4,821 women, aged 35-56 years, living in the Stockholm area. An oral glucose tolerance test identified 55 men and 52 women with type 2 diabetes. The relative contribution of established and psychosocial factors to socioeconomic differences in diabetes risk was assessed by comparing analyses with adjustment for different sets of these factors.The relative risks (RRs) for type 2 diabetes in middle and low socioeconomic groups in men were 2.4 (95% CI 1.0-5.3) and 2.9 (1.5-5.7), respectively, and in women 3.2 (1.5-6.6) and 2.7 (1.3-5.9), respectively. In men, the RRs decreased to 1.9 (0.8-4.4) and 2.1 (1.0-4.2) after adjustment for established risk factors; no further change was found when psychosocial factors were included. In women, the RRs changed to 2.4 (1.1-5.2) and 1.6 (0.7-3.8) by including established risk factors and to 2.3 (1.0-5.1) and 1.9 (0.8-4.3) by inclusion of psychosocial factors. After adjustment for both established and psychosocial factors, the RRs were 1.4 (0.6-3.6) and 1.0 (0.4-2.5), respectively.In men, the excess risk of type 2 diabetes was partly explained by established risk factors (36-42%), whereas psychosocial factors had no effect. In women, most of the socioeconomic differences in type 2 diabetes were explained by simultaneous adjustment for established risk factors and psychosocial factors (81-100%).
Caveolin-1–Deficient Mice Have Increased Tumor Microvascular Permeability, Angiogenesis, and Growth
Authors: Michelle I. Lin, Jun Yu, Takahisa Murata, William C. Sessa
Journal: Cancer Research (2007)

Abstract Caveolin-1 (Cav-1) is a major structural protein that is essential to the formation of the organelle, caveolae. Cav-1 knockout (KO) mice were observed to be completely devoid of caveolae yet they exhibit a hyperpermeable vasculature. Given the nature of the hyperpermeable Cav-1 KO endothelium, we sought to investigate if tumors grown in Cav-1 KO mice would be leaky and grow faster. Indeed, Lewis lung carcinoma cells implanted into Cav-1 KO mice had increased tumor vascular permeability, measured by Evans blue extravasation and fibrinogen deposition compared with tumors implanted into wild-type (WT) mice. Cav-1 KO mice also had significantly higher tumor growth rates, attributable to increased tumor angiogenesis and decreased tumor cell death. Furthermore, administration of an antipermeability peptide, cavtratin, was able to correct the tumor hyperpermeability as well as attenuate the increased tumor growth. Mechanistically, endothelial cells isolated from Cav-1 KO mice exhibited increased tyrosine phosphorylation on vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and decreased association with the adherens junction protein, VE-cadherin. Thus, the loss of Cav-1 increases tumor permeability and growth and that may relate to enhanced VEGF signaling due to lack of Cav-1 inhibition of VEGFR-2 or decreased VE-cadherin mediated VEGFR-2 phosphorylation. [Cancer Res 2007;67(6):2849–56]
How do patients with either asthma or COPD perceive acute bronchodilation?
Authors: A Noseda, J Schmerber, T Prigogine, JC Yernault
Journal: European Respiratory Journal (1993)

The purpose of this study was to assess the perception of bronchodilation, as a change in shortness of breath on a bipolar visual analogue scale (VAS), in 16 asthmatics and 20 subjects with COPD. Bronchodilation was gradually induced by five consecutive terbutaline inhalations (cumulated dose 800 micrograms). The subjects were categorized into high and low perceivers, on the basis of a cut-off of 25% VAS line length (after the fifth inhalation). The quality of perception was studied on a within-subject basis by linear regression analysis of VAS ratings against changes in lung function, and was characterized in terms of strength of correlation (squared correlation coefficient, r2), slope, and VAS axis intercept. Fourteen out of 16 asthmatics, and 13 out of 20 COPD subjects, were high perceivers. In the COPD group, the high perceivers had a larger objective response--particularly in inspiratory vital capacity--than the low perceivers. The strongest correlation between subjective and objective response was obtained in asthmatics when the improvement in shortness of breath was evaluated against the decrease in specific inspiratory resistance (median r2 = 0.831). In COPD low perceivers, subjective and objective response were unrelated, while COPD high perceivers differed from the asthmatics by larger intercepts. The perceptual characteristics were unrelated to the degree of baseline obstruction, whilst a modest relationship (r = 0.51) was found between the increase in forced expiratory volume in one second (FEV1) and r2 of the VAS/delta FEV1 analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Surgical treatment of false aneurysm of the left ventricle after myocardial infarction.
Authors: F P Shabbo, D S Dymond, G M Rees, I M Hill
Journal: Thorax (1983)

Rupture of the left ventricle after myocardial infarction results either in sudden death from cardiac tamponade or, when pericardial adhesions are present, in bleeding that is confined to a limited space, which gradually expands as the blood flows through a small communicating orifice under high pressure, forming a false aneurysm. In three such patients a false aneurysm of the left ventricle after myocardial infarction was successfully treated by operation. The interval from the initiating event to the time of surgery averaged 10 months. Two of the patients had pericarditis and all presented at some stage of the illness with tachyarrhythmias and cardiac failure. All the patients survived operation and have improved functionally. Because of the propensity of false aneurysms to rupture, early diagnosis and aggressive surgical treatment are recommended.
HER2 Silences Tumor Suppression in Breast Cancer Cells by Switching Expression of C/EBPβ Isoforms
Authors: Anna Arnal-Estapé, Maria Tarragona, Mònica Morales, Marc Guiu, Cristina Nadal, Joan Massagué, Roger R. Gomis
Journal: Cancer Research (2010)

Abstract Tumor progression requires ablation of suppressor functions mediated by transforming growth factor β (TGFβ) signaling and by oncogene-induced senescence (OIS), but how these functions are canceled in specific subtypes of breast cancer remains unknown. In this study, we show that HER2-overexpressing breast cancer cells avert TGFβ- and OIS-mediated tumor suppression by switching expression of 2 functionally distinct isoforms of the transcription factor C/EBPβ, which has been implicated previously in breast cancer development. HER2 signaling activates the translational regulatory factor CUGBP1, which favors the production of the transcriptionally inhibitory isoform LIP over that of the active isoform LAP. LIP overexpression prevents the assembly of LAP/Smad transcriptional repressor complexes on the MYC promoter in response to TGFβ, and interferes with activation of OIS responses. Treatment of HER2-transformed mammary epithelial cells with the HER2 antibody trastuzumab reduces LIP levels, restoring these suppressor responses. Our findings reveal a novel mechanism through which HER2 silences tumor suppression in a concerted manner, contributing to the potency of this oncogene in breast cancer. Cancer Res; 70(23); 9927–36. ©2010 AACR.
Psychiatric comorbidity in COPD and its determinants
Authors: Mohamed Zidan, Rasha Daabis, Heba Essam
Journal: European Respiratory Journal (2012)

Background:  Depression and anxiety are prevalent in patients with chronic obstructive pulmonary disease (COPD); however, their etiology and relationship to the clinical features of COPD are not well understood.   OBJECTIVES:  To evaluate the prevalence of psychiatric comorbidity (depression and anxiety) in COPD patients and to examine possible associations with demographic and clinical characteristics as well as health-related quality of life of these patients.   DESIGN AND METHODS:  A total of 100 clinically stable COPD patients answered the St. George9s Respiratory Questionnaire (SGRQ) (assessing HRQoL), the Hospital Anxiety and Depression Scale (HADS), Modified Medical Research Council (MMRC) Dyspnea Scale. Socio-demographic information, lung function, and other clinical data were collected.   RESULTS:  The prevalence of depression was found to be 40 %, while that of anxiety was 29%. Patients living alone, having a longer duration of COPD diagnosis, lower BMI and more severe disease (as measured by FEV1% of predicted) had more depressive and anxious symptoms. The significant independent predictors of both anxiety and depression were higher MMRC score and worse quality of life.   Conclusion:  We found that patients with COPD had high prevalence of depressive and anxious symptoms. Clinical and physiologic measures were less important determinants of psychiatric comorbidities in COPD than dyspnea and quality-of-life. Therefore, screening and treatment of these psychiatric comorbidities in patients with COPD may lead to significant improvements in patients9 quality of life.
The Severe Acute Respiratory Syndrome
Authors: Joseph S M Peiris, Kwok Y Yuen, Albert D M E Osterhaus, Klaus Stöhr
Journal: New England Journal of Medicine (2003)

The severe acute respiratory syndrome (SARS) is responsible for the first pandemic of the 21st century. Within months after its emergence in Guangdong Province in mainland China, it had affected more than 8000 patients and caused 774 deaths in 26 countries on five continents. It illustrated dramatically the potential of air travel and globalization for the dissemination of an emerging infectious disease and highlighted the need for a coordinated global response to contain such disease threats. We review the cause, epidemiology, and clinical features of the disease.
Is weekly sclerotherapy really better than every three weeks?
Authors: John Terblanche, Kenneth E. F. Hobbs
Journal: Hepatology (1987)

To compare the efficacy and safety of one week versus three weeks interval treatment schedules of endoscopic sclerotherapy, injections were carried out in a prospective manner in 96 patients with variceal bleeding; 47 on a one week and 49 on a three week treatment schedule. Weekly endoscopic sclerotherapy eradicated oesophageal varices significantly (p &lt; 0.01) earlier (mean ± SD 7.1 ± 2.43 weeks) as compared with the three week regimen (mean ± SD 14.86 ± 4.86 weeks). The rebleeding rate was also significantly less (p &lt; 0.05) with weekly endoscopic sclerotherapy (8.5%) as compared with three week endoscopic sclerotherapy treatment (26.5%). The amount of alcohol and the number of endoscopic sclerotherapy courses required for complete variceal eradication did not differ significantly between the two groups. Patients undergoing weekly injections were seen to have significantly more oesophageal ulcers (p &lt; 0.01) as compared with the three week group, necessitating at times (23%) postponement of the procedure. There was, however, no difference between the two groups in the frequency of oesophageal structure formation, dysphagia, retrosternal pain, and fever. Mortality was also similar in the two groups. It can be concluded that a weekly schedule of endoscopic sclerotherapy appears superior to a three week schedule.
DNA fingerprinting of glioma cell lines and considerations on similarity measurements
Authors: P. Bady, A.-C. Diserens, V. Castella, S. Kalt, K. Heinimann, M.-F. Hamou, M. Delorenzi, M. E. Hegi
Journal: Neuro-Oncology (2012)

Glioma cell lines are an important tool for research in basic and translational neuro-oncology. Documentation of their genetic identity has become a requirement for scientific journals and grant applications to exclude cross-contamination and misidentification that lead to misinterpretation of results. Here, we report the standard 16 marker short tandem repeat (STR) DNA fingerprints for a panel of 39 widely used glioma cell lines as reference. Comparison of the fingerprints among themselves and with the large DSMZ database comprising 9 marker STRs for 2278 cell lines uncovered 3 misidentified cell lines and confirmed previously known cross-contaminations. Furthermore, 2 glioma cell lines exhibited identity scores of 0.8, which is proposed as the cutoff for detecting cross-contamination. Additional characteristics, comprising lack of a B-raf mutation in one line and a similarity score of 1 with the original tumor tissue in the other, excluded a cross-contamination. Subsequent simulation procedures suggested that, when using DNA fingerprints comprising only 9 STR markers, the commonly used similarity score of 0.8 is not sufficiently stringent to unambiguously differentiate the origin. DNA fingerprints are confounded by frequent genetic alterations in cancer cell lines, particularly loss of heterozygosity, that reduce the informativeness of STR markers and, thereby, the overall power for distinction. The similarity score depends on the number of markers measured; thus, more markers or additional cell line characteristics, such as information on specific mutations, may be necessary to clarify the origin.
ERJ peer reviewers: does this pillar of the Journal's quality need help?
Authors: G.B. Migliori, J.B. Soriano, V. Brusasco, A.T. Dinh-Xuan
Journal: European Respiratory Journal (2011)

The European Respiratory Journal ( ERJ ) has a long history of success [1]. This success, which has allowed the Journal to keep its impact factor (IF) above 5 for 5 consecutive years, has been paralleled by the impressive growth of the European Respiratory Society (ERS) and its membership [2]. No doubt, a strong society needs a strong journal.

In order to be effective, each individual manuscript should have an aim and a perspective. The aims of this Editorial are to explain to the ERJ readers why peer review is so important to the determination of Journal quality, and to present our needs in terms of reviewers’ services. This exercise will be conducted from a reader’s point of view first, then from an author's and the Journal's.

Any given reader is interested in having the best manuscripts published in their journal. So, what defines a good manuscript? The manuscript should contain true data and novel information, should be easy to read and, ideally, should provide useful support for the reader's clinical or scientific research activity. This means that a careful selection process needs to be performed at the Editorial level.

For the last 3 years, the ERJ has received an average of >2,000 manuscripts annually, covering all areas of respiratory medicine. Only 18% of these manuscripts have been published in the Journal. How is this process organised? Although largely imperfect, peer review is widely considered to be the best way of assessing scientific merit [3–5]. A difficult obstacle race with scrupulous scientific criteria has been designed to select the best manuscripts; the Chief Editors are responsible for this process, with the collaboration of the Editorial Board. After administrative checks performed by the Publications Office, the Chief Editors perform a first-screening, instantly rejecting 8% of …
Endocannabinoid overactivity and intestinal inflammation
Authors: V Di Marzo
Journal: Gut (2006)

Cannabinoid receptors of type 1 and 2 (CB<sub>1</sub> and CB<sub>2</sub>), endogenous ligands that activate them (endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB<sub>1 </sub>receptors by endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this "endocannabinoid overactivity" and its possible exploitation for therapeutic purposes are discussed here.
The Eukaryotic Ancestor Had a Complex Ubiquitin Signaling System of Archaeal Origin
Authors: Xavier Grau-Bové, Arnau Sebé-Pedrós, Iñaki Ruiz-Trillo
Journal: Molecular Biology and Evolution (2014)

The origin of the eukaryotic cell is one of the most important transitions in the history of life. However, the emergence and early evolution of eukaryotes remains poorly understood. Recent data have shown that the last eukaryotic common ancestor (LECA) was much more complex than previously thought. The LECA already had the genetic machinery encoding the endomembrane apparatus, spliceosome, nuclear pore, and myosin and kinesin cytoskeletal motors. It is unclear, however, when the functional regulation of these cellular components evolved. Here, we address this question by analyzing the origin and evolution of the ubiquitin (Ub) signaling system, one of the most important regulatory layers in eukaryotes. We delineated the evolution of the whole Ub, Small-Ub-related MOdifier (SUMO), and Ub-fold modifier 1 (Ufm1) signaling networks by analyzing representatives from all major eukaryotic, bacterial, and archaeal lineages. We found that the Ub toolkit had a pre-eukaryotic origin and is present in three extant archaeal groups. The pre-eukaryotic Ub toolkit greatly expanded during eukaryogenesis, through massive gene innovation and diversification of protein domain architectures. This resulted in a LECA with essentially all of the Ub-related genes, including the SUMO and Ufm1 Ub-like systems. Ub and SUMO signaling further expanded during eukaryotic evolution, especially labeling and delabeling enzymes responsible for substrate selection. Additionally, we analyzed protein domain architecture evolution and found that multicellular lineages have the most complex Ub systems in terms of domain architectures. Together, we demonstrate that the Ub system predates the origin of eukaryotes and that a burst of innovation during eukaryogenesis led to a LECA with complex posttranslational regulation.
Hepatic Clearance of Renin in Canine Experimental Models for Low- and High-Output Heart Failure
Authors: EDWARD G. SCHNEIDER, James O. Davis, Charles A. ROBB, John S. Baumber
Journal: Circulation Research (1969)

Hepatic blood flow, hepatic extraction of renin, and hepatic clearance of renin were compared in normal conscious dogs, in dogs with constriction of the thoracic inferior vena cava (as a model of low-output heart failure), and in dogs with an aortic-caval fistula (high-output heart failure). Both "failure" preparations showed marked sodium retention. Renin was measured by methods described previously and expressed as nanograms of angiotensin produced during incubation per milliliter of plasma. Hepatic plasma flow was determined by the sodium sulfobromophthalein method. The dogs with low-output heart failure had a marked reduction in hepatic plasma flow, while those with high-output failure showed no significant change in this flow. Plasma renin was significantly elevated in both models of heart failure. Dogs with low-output failure had an increase ( P &lt; .05) in hepatic renin extraction from a normal value of 19.8% to 33.4%, while those with high-output failure showed a decrease in hepatic renin extraction to 11.9% ( P &lt; .01). The hepatic clearance of renin in low-output failure (104 ml/ min) was the same as the average normal value of 104 ml/min, while clearance of renin by the liver in high-output failure was reduced to 51 ml/min ( P &lt; .001). The data provide evidence that the decreased metabolism of renin contributes substantially to the increased plasma level of renin in experimental high-output heart failure.