tbuckley/cabot-search huggingface dataset:
HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression
Authors: Jui-Ching Chen, Mei-Lin Wu, Kuo-Chin Huang, Wan-Wan Lin
Journal: Cardiovascular Research (2008)

Since apoptosis of macrophages induced by stress to the endoplasmic reticulum (ER) contributes to advanced atherosclerotic lesions, we sought to understand the effects of statins on the unfolded protein response (UPR).We used pharmacological, biochemical, and siRNA (small interfering ribonucleic acid) approaches to determine the signalling cascades of statin-induced 78 kDa glucose-regulated protein (GRP78) gene transcription and its role in cytoprotection. Exposure of RAW264.7 macrophages to statins increased the expression of GRP78, activating transcription factor 6, X box protein-1, and phosphorylated eukaryotic translation initiation factor 2alpha, while it had no effect on CCAAT/enhancer binding protein-homologous protein. GRP78 induction was abolished by co-treatment with mevalonate and 1,2-bis(o-aminophenoxy)ethane-N, N, N',N'-tetraacetic acid, indicating the involvement of both 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase-dependent and -independent mechanisms. Studies on promoter activity measurements indicated that phosphoinositide turnover, cellular homologue of v-src (c-Src), protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and p38 are involved in upregulating GRP78 gene transcription. We also observed that elevation of intracellular Ca(2+) and interruption of small G proteins are two bifurcated but cooperative signalling pathways for c-Src activation, leading to downstream activation of phospholipase C, PKC, ERK, and p38. Functionally we demonstrated that fluvastatin could protect macrophages from hypoxia-induced cell death through GRP78 induction.We demonstrate a novel action of statins of inducing a cytoprotective UPR, providing new insights into the clinical potential of statins for ameliorating ER stress-related diseases.
Surgical treatment of hydatid cyst of the lung: review of 30 cases
Authors: I Yalcinkaya, M Er, B Ozbay, S Ugras
Journal: European Respiratory Journal (1999)

Hydatid cyst disease is still a problem in Turkey, especially in the east Anatolian region, as well as in many other places in the world. A retrospective review was made of the surgical treatment of 30 patients with pulmonary hydatid cysts during the last 3 yrs. Nineteen patients were male and 11 female with an average age of 23.5 yrs (range 4-44 yrs). Cystotomy and capitonnage were performed in 28 of the 30 cases (93.4%). The transdiaphragmatic route or simultaneous laparotomy was preferred when the liver was involved. Albendazole was used in four patients with multiple hydatid cyst due to probable recurrence in the postoperative period. Cough and chest pain were the prominent symptoms in the majority of cases. A single lobe was affected in 22 patients. Unilateral multiple foci were present in four patients and bilateral multiple foci in four. Six patients had concomitant liver cysts. Morbidity was low and no mortality was seen. No recurrences were seen on control chest radiographs during the last 2-yr follow-up. In the treatment of hydatid cyst of the lung, conservative surgical methods such as cystotomy and capitonnage still remain the treatment of choice. Medical treatment could be used for prophylactic purposes and in some instances, but the percutaneous aspiration method should not be performed.
Novel Mechanisms of Resistance to Endocrine Therapy: Genomic and Nongenomic Considerations
Authors: Anupama E. Gururaj, Suresh K. Rayala, Ratna K. Vadlamudi, Rakesh Kumar
Journal: Clinical Cancer Research (2006)

Abstract Selective estrogen receptor (ER) modulators have been the most commonly used neoadjuvant therapy for hormone-dependent breast cancer. However, resistance to endocrine therapy, either inherent or acquired during treatment, presents a major challenge in disease management. The causes of resistance to hormone therapy are not well understood and are the subject of active investigation. It is increasingly clear that decreasing sensitivity of ER-positive breast cancer cells to antiestrogens is caused by several factors. Cross talk between ER and growth factor signaling has emerged as a critical factor in endocrine resistance. Here, we present evidence that receptor tyrosine kinase signaling also plays a role in resistance by controlling the subcellular localization of ER signaling components. Localization of ER in either the nuclear or cytoplasmic compartments has functional implications. Recent work suggests that dynein light chain 1, a recently identified substrate of p21-activated kinase 1, modulates ER transactivation functions through a novel ER coactivator function. Likewise, receptor tyrosine kinase signaling can also alter the expression of ER coregulators such as metastasis-associated antigen 1, leading to hormonal independence. Furthermore, proline-, glutamic acid-, leucine-rich protein 1, an ER coactivator involved in both genomic and nongenomic signaling pathways, is activated by epidermal growth factor receptor and plays a prominent role in resistance to tamoxifen. These recent advances suggest new targeted therapeutic approaches that may lead to either reversion or prevention of endocrine resistance in breast tumors.
Diffuse Large B-Cell Lymphoma with Overexpression of Cyclin E Substantiates Poor Standard Treatment Response and Inferior Outcome
Authors: Alexandar Tzankov, Andreas Gschwendtner, Florian Augustin, Michael Fiegl, Ellen C. Obermann, Stephan Dirnhofer, Philip Went
Journal: Clinical Cancer Research (2006)

Gold standard to predict survival and stratify patients for risk-adapted therapy in diffuse large B-cell lymphoma (DLBCL) is the international prognostic index, although it does not consider the molecular heterogeneity of DLBCL. Deregulation of cyclin E (CCNE) is a strong predictor of poor prognosis in some neoplastic diseases. In tumor cells, it induces chromosomal instability with an increased rate of aneuploidy/polyploidy.We analyzed in this retrospective study the prognostic value of immunohistochemical CCNE expression on a validated tissue microarray containing 101 de novo DLBCLs and, in 9 cases, the CCNE-induced chromosomal instability as assessed by cytometry.Forty-six of 98 evaluable DLBCLs expressed CCNE in a mean proportion of 20 +/- 29% of tumor cells; 38 cases expressed CCNE in >/=20% of tumor cells. CCNE-positive samples were aneuploid compared with near tetraploidy in CCNE-negative cases. Multivariate analysis showed CCNE expression in >/=20% of tumor cells to be an international prognostic index-independent, Adriamycin-based treatment-independent, and BCL2-independent prognostic factor for poor disease-specific survival. CCNE expression in >/=80% of tumor cells was associated with dismal short-term prognosis. CCNE expression in >/=50% of tumor cells emerged as an independent predictive factor for standard CHOP treatment resistance.CCNE expression assessment is easy on paraffin-embedded tissue. The high prognostic value of CCNE expression in DLBCL may be the basis for future prospective trials. In addition, a high CCNE expression hints at the presence of a possible target for individualized cancer therapy.
Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk
Authors: T. de Sablet, M. B. Piazuelo, C. L. Shaffer, B. G. Schneider, M. Asim, R. Chaturvedi, L. E. Bravo, L. A. Sicinschi, A. G. Delgado, R. M. Mera, D. A. Israel, J. Romero-Gallo, R. M. Peek, T. L. Cover, P. Correa, K. T. Wilson
Journal: Gut (2011)

<h3>Background and aims</h3> <i>Helicobacter pylori</i> colonises the stomach in half of all humans, and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. While gastric cancer rates correlate with <i>H pylori</i> prevalence in some areas, there are regions where infection is nearly universal, but rates of gastric cancer are low. In the case of Colombia, there is a 25-fold increase in gastric cancer rate in the Andean mountain (high risk) region compared to the coastal (low risk) region, despite similarly high (∼90%) prevalence of <i>H pylori</i> in the two locations. Our aim was to investigate the ancestral origin of <i>H pylori</i> strains isolated from subjects in these high- and low-risk regions and to determine whether this is a predictive determinant of precancerous lesions. <h3>Methods</h3> Multi-locus sequence typing was used to investigate phylogeographic origins of infecting <i>H pylori</i> strains isolated from subjects in the Pacific coast and Andes Mountains in the state of Nariño, Colombia. We analysed 64 subjects infected with <i>cagA<sup>+</sup> vacA</i> s1m1 strains. Gastric biopsy slides from each individual were scored for histological lesions and evaluated for DNA damage by immunohistochemistry. <h3>Results</h3> We show that strains from the high-risk region were all of European phylogeographic origin, whereas those from the low risk region were of either European (34%) or African origin (66%). European strain origin was strongly predictive of increased premalignant histological lesions and epithelial DNA damage, even in the low-risk region; African strain origin was associated with reduced severity of these parameters. <h3>Conclusion</h3> The phylogeographic origin of <i>H pylori</i> strains provides an explanation for geographic differences in cancer risk deriving from this infection.
Prolonged conservative care versus early surgery in patients with sciatica from lumbar disc herniation: cost utility analysis alongside a randomised controlled trial
Authors: Wilbert B van den Hout, Wilco C Peul, Bart W Koes, Ronald Brand, Job Kievit, Ralph T W M Thomeer
Journal: BMJ (2008)

<b>Objective</b> To determine whether the faster recovery after early surgery for sciatica compared with prolonged conservative care is attained at reasonable costs. <b>Design</b> Cost utility analysis alongside a randomised controlled trial. <b>Setting</b> Nine Dutch hospitals. <b>Participants</b> 283 patients with sciatica for 6-12 weeks, caused by lumbar disc herniation. <b>Interventions</b> Six months of prolonged conservative care compared with early surgery. <b>Main outcome measures</b> Quality adjusted life years (QALYs) at one year and societal costs, estimated from patient reported utilities (UK and US EuroQol, SF-6D, and visual analogue scale) and diaries on costs (healthcare, patient's costs, and productivity). <b>Results</b> Compared with prolonged conservative care, early surgery provided faster recovery, with a gain in QALYs according to the UK EuroQol of 0.044 (95% confidence interval 0.005 to 0.083), the US EuroQol of 0.032 (0.005 to 0.059), the SF-6D of 0.024 (0.003 to 0.046), and the visual analogue scale of 0.032 (−0.003 to 0.066). From the healthcare perspective, early surgery resulted in higher costs (difference €1819 (£1449; $2832), 95% confidence interval €842 to €2790), with a cost utility ratio per QALY of €41 000 (€14 000 to €430 000). From the societal perspective, savings on productivity costs led to a negligible total difference in cost (€−12, €−4029 to €4006). <b>Conclusions</b> Faster recovery from sciatica makes early surgery likely to be cost effective compared with prolonged conservative care. The estimated difference in healthcare costs was acceptable and was compensated for by the difference in absenteeism from work. For a willingness to pay of €40 000 or more per QALY, early surgery need not be withheld for economic reasons. <b>Trial registration</b> Current Controlled Trials ISRCTN 26872154.
The “is-ought fallacy” fallacy
Authors: Mike Oaksford, Nick Chater
Journal: Behavioral and Brain Sciences (2011)

Abstract Mere facts about how the world is cannot determine how we ought to think or behave. Elqayam &amp; Evans (E&amp;E) argue that this “is-ought fallacy” undercuts the use of rational analysis in explaining how people reason, by ourselves and with others. But this presumed application of the “is-ought” fallacy is itself fallacious. Rational analysis seeks to explain how people do reason, for example in laboratory experiments, not how they ought to reason. Thus, no ought is derived from an is ; and rational analysis is unchallenged by E&amp;E's arguments.
Treatment of hepatocellular carcinoma: too many options?
Authors: A P Venook
Journal: Journal of Clinical Oncology (1994)

PURPOSE This study attempts to review the therapeutic interventions being used to treat patients with hepatocellular carcinoma (HCC). DESIGN An English language literature search, including abstracts and original articles, and a review of the bibliographies of such articles, was conducted. RESULTS Surgery is possible in few patients and curative in only a small percentage. Conventional chemotherapy is ineffective in HCC. Modifications of chemotherapy, including intraarterial infusion, chemoembolization, lipiodol, styrene-maleic acid-neocarzinostatin (SMANCS), and isolated hepatic perfusion, have led to improved tumor responses, but have not materially affected patient outcome. Radioimmunotherapy and conformal radiotherapy have had no more than a marginal impact on patient outcome. Surgical innovations such as cryosurgery and percutaneous alcohol injection have not yet been shown to offer any advantage, and liver transplantation, while curative in some patients, requires an enormous expenditure of resources to achieve cure in few patients. CONCLUSION Prevention is the ideal approach to HCC. Surgical cure is rarely possible, and while numerous therapies may palliate symptoms, patient selection and the lack of randomized studies make their impact on median survival difficult to assess. Patients being treated for HCC should be enrolled on treatment protocols testing multimodality or new strategies.
COPD assessment: I, II, III, IV and/or A, B, C, D
Authors: Claus Vogelmeier, Jørgen Vestbo
Journal: European Respiratory Journal (2014)

In 2001 the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee published its first consensus report [1]. At that time the authors suggested that the assessment of chronic obstructive pulmonary disease (COPD) should be primarily based on the extent of airflow limitation. In the following years, evidence accumulated that COPD is a complex and heterogeneous disease and that airflow limitation is not closely correlated to a variety of patient-related outcomes [2]. These findings, and the intent to create a more comprehensive system to better reflect the situation of an individual patient, were the basis for a novel concept recently published by GOLD. Now, the assessment is no longer based on the extent of airflow limitation alone; in addition, the patient's exacerbation history and symptoms are taken into account [3]. Based on the severity of symptoms and the exacerbation risk, four categories (A, B, C and D) were defined.

Since then, this novel assessment scheme has been studied in several existing cohorts, ranging from more than 2000 clinically stable COPD patients in the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) [4], over a more broadly composed cohort of 4000 smokers from the COPDGene study [5], to population samples from Copenhagen [6] …
Allele-Specific Regulation of Matrix Metalloproteinase-12 Gene Activity Is Associated With Coronary Artery Luminal Dimensions in Diabetic Patients With Manifest Coronary Artery Disease
Authors: Sofia Jormsjö, Shu Ye, Joseffa Moritz, Dirk H. Walter, Stefanie Dimmeler, Andreas M. Zeiher, Adriano Henney, Anders Hamsten, Per Eriksson
Journal: Circulation Research (2000)

Abstract —Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from healthy individuals detected a common polymorphism within the MMP-12 gene promoter (an A-to-G substitution at position –82). The frequency of the G allele was 0.19. The polymorphism influences the binding of the transcription factor activator protein-1 (AP-1) in electromobility shift assay. A higher binding affinity of AP-1 to the A allele was associated with higher MMP-12 promoter activity in vitro in transient transfection studies in U937 and murine lung macrophage (MALU) cells. Phorbol 12-myristate 13-acetate (PMA) and insulin, 2 known activators of AP-1, increased the binding of AP-1 to the MMP-12 promoter, with higher affinity for the A allele. In transfection experiments, both the A and the G alleles responded to insulin and PMA, the A allele showing higher promoter activity than the G allele. Furthermore, Western blot analysis demonstrated that insulin increased MMP-12 protein production. To analyze whether the –82 A/G polymorphism is associated with coronary artery disease, 367 consecutive patients who underwent percutaneous transluminal coronary angiography with stent implantation were genotyped. In patients (n=71) with diabetes, the A allele was associated with a smaller luminal diameter. In conclusion, a common functional polymorphism within the MMP-12 promoter influences coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.
Early death in dialysis patients
Authors: J M Soucie, W M McClellan
Journal: Journal of the American Society of Nephrology (1996)

Patients who die within the first 90 days after beginning dialysis are not included in mortality rates and may be absent from incidence counts. To identify factors associated with mortality within 3 months of the initiation of dialysis for ESRD and to estimate the impact of early deaths on ESRD incidence and mortality rates, this study investigated 15,245 patients who began dialysis in Georgia, North Carolina, and South Carolina over a 5-yr period. Data were collected by dialysis facility staff and reported to an ESRD registry. Six percent of all new patients died within 90 days of dialysis initiation (32% of all deaths occurring in the first year of treatment). Characteristics independently associated with increased risk of early death included older age, white race, male gender, physical and nutritional impairment, smoking, and the presence of cancer, congestive heart failure, clinical depression, and history of myocardial infarction. Depending on race-gender group, age-adjusted mortality rates based on this cohort were underestimated by 3 to 12% when patients who died early were excluded. These results suggest that certain patient characteristics-some potentially modifiable-confer increased risk of early death, and that the systematic exclusion of patients who die early from the U.S. national registry substantially influences ESRD mortality rates.
GPCR-like signaling mediated by smoothened contributes to acquired chemoresistance through activating Gli
Authors: Xia Zhan, Juan Wang, Yuan Liu, Yuanqiu Peng, Wenfu Tan
Journal: Molecular Cancer (2014)

Smoothened (Smo), which possesses a structural similarity with classic G-protein coupled receptors (GPCR), is the most important molecular target in Hedgehog (Hh) signaling system for developing anticancer drugs; however, whether Smo may transmit GPCR-like signaling to activate the canonical transcriptional factor Gli of Hh signaling system and consequently to be involved in the Gli-dependent biological events remains controversial. In this study, using the acquired chemoresistant cancer cell lines and their respective parental cells, we found that Smo may activate Gli through Gαi, Gβγ-JNK signaling axis, thereby promoting the Gli-dependent acquired chemoresistance. These observations were further complementarily strengthened by data obtained from chemosensitive cancer cells with artificially elevated Hh pathway activity. Hence, our data demonstrate that GPCR-like signaling mediated by Smo contributes to the acquired chemoresistance through activating the canonical Hh transcriptional factor Gli; therefore improving our knowledge of the nature of the signal transduction of Smo and the molecular mechanisms responsible for the acquired chemoresistance maintained by Hh pathway. Moreover, our data that JNK after activated by Smo-Gβγ signaling axis may stimulate the Gli activity and consequently promotes acquired chemoresistance expose a promising and potential target for developing anti-cancer drugs aimed at Hh pathway and for combating the acquired resistance raised by using of anti-cancer drugs targeting Smo.
A British Medical Association Lecture on AURAL DISCHARGES: THEIR SIGNIFICANCE AND TREATMENT
Authors: J. F. O'Malley
Journal: BMJ (1934)

The subject of this lecture embraces a very large section of the common diseases of the ear, so that of netessity, in the time at my disposal, I can only deal with the salient points.This is probably not a matter for regret, as an attempt to crowd into it a great amount of detail would detract from its c'larity and usefulness.All discharges escaping from the external auditory meatus are pathological in origin, with the exception of cerumen, although this may possibly become so when it is excessive or impacted.They may have as their primary source the pinna, external meatus, middle ear, mastoid antrum or cells, or even the intracranial cavity.They generally have certain characteristics, which enable us to make a useful class:fication of them as set forth below.These characteristics, if carefully elicited in taking the history of the case, possess considerable value, in that they often indicate the nature of the disease and so form the first pointer towards a correct diagnosis. Classification of Aural DischargeJ Colourless or not 1.Middle-ear catarrh with Scanty perforated druim Copious 2. Cerebro-spinal fluid v Sticky, mucoid, 3. Meatal eczema or viscidIn the first the fluid is colourless, very scanty, odour- less, and sticky.It is similar.to the efflux in the early stage of a common cold, but it may later become purulent and yellow.
From anecdote to EBM
Authors: T. Treasure
Journal: Journal of the Royal Society of Medicine (2006)

Given an opportunity for an historical introduction cardiac surgeons like to quote Stephen Paget from his 1896 book The Surgery of the Chest:


`Surgery of the heart has probably reached the limits set by Nature to all surgery: no new method, and no new discovery, can overcome the natural difficulties that attend a wound of the heart.'1


This was in the context of suturing a stab wound of the heart. A century later virtually no structural abnormality of the heart—congenital, acquired or degenerative—was surgically irrepairable. Changed also is the nature of evidence required to justify practice. Paget's teaching, typical of its time, employs descriptions of clinical cases.1 The challenge now is to practice `evidence-based medicine',2 but there may be more in the rhetoric rather than the reality.
A risk profile for stroke or death in atrial fibrillation: the Framingham heart study
Authors: Thomas J. Wang, Joseph M. Massaro, Ralph B. D'Agostino, Daniel Levy, Philip A. Wolf, William B. Kannel, Martin G. Larson, Ramachandran S. Vasan, Emelia J. Benjamin
Journal: Journal of the American College of Cardiology (2002)