tbuckley/cabot-search huggingface dataset:
Can generalism help revive the primary healthcare vision?
Authors: Joanne Reeve, Greg Irving, Chris F Dowrick
Journal: Journal of the Royal Society of Medicine (2011)

It is more than 30 years since the World Health Organization (WHO) called for a paradigm-shift to a model of primary healthcare: a vision of creating ‘Health for All’ through ‘putting people at the centre of health care’.1 Since then, we have seen significant advances in health and healthcare. People are ‘healthier, wealthier and liver longer today than 30 years ago’.2 Economic growth, increased resources, and rapid expansion of scientific knowledge and technological advancement have all contributed.2 But we see growing concerns that the primary healthcare vision is being lost, with a worrying impact on our current systems of healthcare.2 The burden of care on individual patients is increasing.3 An excessive focus on disease, fragmentation of care and unregulated commercialization2 has been linked to inefficiency, ineffectiveness and inequity.4 All against a background of changing health needs, notably a rise in the burden of chronic, complex illness.2,5 WHO calls for a revival and strengthening of the primary healthcare vision to meet modern needs, refocusing health services around people.2 Generalism describes an approach to care which is person-, not disease-focused; continuous, not episodic; integrates biotechnical and biographical understanding of illness; and promotes health as a resource for living, and not an end in itself.6 So can generalism help revive the primary healthcare vision?
Randomized Trial of Procarbazine, Lomustine, and Vincristine in the Adjuvant Treatment of High-Grade Astrocytoma: A Medical Research Council Trial
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Meta-analyses of the published literature suggest a survival benefit to adjuvant chemotherapy for high-grade astrocytoma, which individual small trials have been unable to demonstrate reliably. The Medical Research Council Brain Tumour Working Party initiated the largest randomized trial of adjuvant chemotherapy for glioma in an attempt to provide a definitive answer. PATIENTS AND METHODS: After surgery, patients aged ≤ 70 years, with World Health Organization grade 3 or 4 astrocytoma, were randomized to radiotherapy alone (RT) or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) given at 6-week intervals to a maximum of 12 courses (procarbazine 100 mg/m 2 days 1 to 10, lomustine 100 mg/m 2 day 1, and vincristine 1.5 mg/m 2 (max 2 mg) day 1). A neuropathology panel independently reviewed all cases. To reliably detect a 10% increase in 2-year survival (from 15% to 25%), 600 patients were required. RESULTS: Between September 1988 and May 1997, 15 United Kingdom centers randomized 674 patients (RT = 339 patients; RT-PCV = 335 patients). With a median follow-up for survivors of 3 years, 617 patients have died, (RT = 310 patients; RT-PCV = 307 patients). Median survival was 9.5 months for RT and 10 months for RT-PCV (hazard ratio = 0.95; 95% confidence interval, 0.81 to 1.11; log-rank P = .50). Tests for interaction revealed no significant differences in treatment effect according to tumor grade, age, performance status, or extent of neurosurgery. CONCLUSION: This trial shows no benefit to PCV chemotherapy, and current data exclude an increase in median survival of more than 10 weeks and in a 1- or 2-year survival rate of more than 7% to 8%. This suggests that no-chemotherapy control arms remain ethical in randomized trials in high-grade astrocytoma.
Phase II Randomized Study of Trastuzumab Emtansine Versus Trastuzumab Plus Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Authors: Sara A. Hurvitz, Luc Dirix, Judit Kocsis, Giulia V. Bianchi, Janice Lu, Jeferson Vinholes, Ellie Guardino, Chunyan Song, Barbara Tong, Vivian Ng, Yu-Waye Chu, Edith A. Perez
Journal: Journal of Clinical Oncology (2013)

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting.Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life.Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), [corrected] and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approximately 23 months in both arms.In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.
How evidence based is the management of two common sports injuries in a sports injury clinic?
Authors: I R Murray, S A Murray, K MacKenzie, S Coleman
Journal: British Journal of Sports Medicine (2005)

To examine the diagnosis and management of adults attending a sports injury clinic, to establish to what extent the management of the two most common injuries treated at this clinic is evidence based, and to explore factors that affect management.A retrospective examination of 100 random case notes extracted age, sex, sport, type and site of injury, treatment, and outcome. Systematic literature reviews examined the extent and quality of scientific evidence for the management of the two most commonly presenting injuries. A clinical attachment period and practitioner interviews allowed recognition of factors impinging on management decisions.Patellofemoral pain syndrome (PFPS; 10% of all injuries) and Achilles tendinopathy (6% of all injuries) were the most commonly presenting injuries. The mean (SD) number of treatments used for PFPS was 2.8 (0.9). The mean number of treatments used for Achilles tendinopathy was 3.7 (1.0). Clinicians reported that personal experience formed the basis of management plans in 44% of PFPS cases and 59% of Achilles tendinopathy cases, and that primary research evidence only accounted for 24% of management plans in PFPS and 14% in Achilles tendinopathy. Practitioners were unaware of literature supporting over 50% of the treatment modalities they used. However, clinicians were often using evidence based treatments, unaware of the supporting research data.This study highlights a lack of evidence base, a lack of knowledge of the research evidence, and a lack of management based on the current evidence that is available for these conditions. Practitioners practised evidence based medicine in under 50% of cases.
Low Serum Vitamin D Levels Are Associated With Inferior Survival in Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies
Authors: Jennifer L. Kelly, Gilles Salles, Bryan Goldman, Richard I. Fisher, Pauline Brice, Oliver Press, Olivier Casasnovas, David G. Maloney, Pierre Soubeyran, Lisa Rimsza, Corinne Haioun, Luc Xerri, Michael LeBlanc, Hervé Tilly, Jonathan W. Friedberg
Journal: Journal of Clinical Oncology (2015)

Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome.SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography-tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS).After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort).Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting.
Cannabinoid Receptor Agonists Inhibit Sensory Nerve Activation in Guinea Pig Airways
Authors: Shigemi Yoshihara, Hiroshi Morimoto, Yumi Yamada, Toshio Abe, Osamu Arisaka
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

We examined the effects of cannabinoid receptor agonists on various respiratory reactions induced by the activation of capsaicin-sensitive afferent sensory nerves (C-fibers). (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone (WIN 55212–2) dose-dependently inhibited electrical field stimulation– and capsaicin-induced guinea pig bronchial smooth muscle contraction, but not the neurokinin A–induced contraction. A cannabinoid CB2 receptor antagonist, {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide} (SR 144528), reduced the inhibitory effect of WIN 55212–2, but not a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A). A cannabinoid CB2 agonist, JWH 133, also inhibited electrical field stimulation–induced guinea pig bronchial smooth muscle contraction and its inhibitory effect was blocked by SR 144528. The inhibitory effect of WIN 55212–2 on electrical field stimulation-induced bronchial contraction was reduced by the pretreatment of large conductance Ca2+-activated K+ channel (Maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not other K+ channel blockers, dendrotoxin or glibenclamide. A Maxi-K+ channel opener, 1-(2′-hydroxy-5′-trifluoromethylphenyl)-5-trifluoromethyl-2(3H)benzimidazolone (NS1619), inhibited bronchial contraction induced by electrical field stimulation. WIN 55212–2 and JWH 133 blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. These findings suggest that WIN 55212–2 inhibit the activation of C-fibers via cannabinoid CB2 receptors and Maxi-K+ channels in guinea pig airways.
Clinical significance of the evaluation of hepatic reticuloendothelial removal capacity in patients with cirrhosis
Authors: Massimo Bolognesi, Carlo Merkel, Simone Bianco, Paolo Angeli, David Sacerdoti, Piero Amodio, Angelo Gatta
Journal: Hepatology (1994)

The reticuloendothelial system plays an important role in the prevention of bacterial infection in patients with cirrhosis. Few data are available, however, on its activity in such patients. The aim of this study was to evaluate the maximum removal capacity of hepatic reticuloendothelial system in patients with cirrhosis on the basis of study of the removal kinetics of increasing amounts of 99mTc millimicrospheres and to verify its value as a prognostic factor for death and development of spontaneous bacterial peritonitis. Common clinical and biochemical parameters, Pugh score, maximum removal capacity, aminopyrine metabolic capacity and galactose elimination capacity were measured in 43 patients with cirrhosis (33 with alcoholic cirrhosis, 8 with posthepatitic cirrhosis and 2 with cryptogenic cirrhosis). Hepatic plasma flow and indocyanine green plasma clearance were also measured in 16 of these patients. Reference range of maximum removal capacity was determined in seven normal subjects. Maximal removal capacity below the normal range was found in 24 patients (56%). In the whole series maximum removal capacity averaged 16 +/- 12 micrograms/kg body wt/min (mean +/- S.D.). Maximal removal capacity was significantly correlated with serum albumin, prothrombin index, Pugh score, aminopyrine breath test, galactose elimination capacity and indocyanine green plasma clearance but not with hepatic plasma flow. During follow-up of up to 48 mo, spontaneous bacterial peritonitis developed in six patients, all with impaired maximum uptake capacity, and 11 patients died. Survival was significantly shorter in patients with impaired maximum removal capacity than in those with normal maximum removal capacity (log-rank test: p = 0.024).(ABSTRACT TRUNCATED AT 250 WORDS)
miR-205 Targets PTEN and PHLPP2 to Augment AKT Signaling and Drive Malignant Phenotypes in Non–Small Cell Lung Cancer
Authors: Junchao Cai, Lishan Fang, Yongbo Huang, Rong Li, Jie Yuan, Yi Yang, Xun Zhu, Baixue Chen, Jueheng Wu, Mengfeng Li
Journal: Cancer Research (2013)

Abstract AKT signaling is constitutively activated in various cancers, due in large part to loss-of-function in the PTEN and PHLPP phosphatases that act as tumor suppressor genes. However, AKT signaling is activated widely in non–small cell lung cancers (NSCLC) where genetic alterations in PTEN or PHLPP genes are rare, suggesting an undefined mechanism(s) for their suppression. In this study, we report upregulation of the oncomir microRNA (miR)-205 in multiple subtypes of NSCLC, which directly represses PTEN and PHLPP2 expression and activates both the AKT/FOXO3a and AKT/mTOR signaling pathways. miR-205 overexpression in NSCLC cells accelerated tumor cell proliferation and promoted blood vessel formation in vitro and in vivo. Conversely, RNA interference–mediated silencing of endogenous miR-205 abrogated these effects. The malignant properties induced by miR-205 in NSCLC cells were reversed by AKT inhibitors, FOXO3a overexpression, rapamycin treatment, or restoring PHLPP2 or PTEN expression. Mechanistic investigations revealed that miR-205 overexpression was a result of NF-κB–mediated transactivation of the miR-205 gene. Taken together, our results define a major epigenetic mechanism for suppression of PTEN and PHLPP2 in NSCLC, identifying a pivotal role for miR-205 in development and progression of this widespread disease. Cancer Res; 73(17); 5402–15. ©2013 AACR.
MiR-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP-mediated suppression of NF-κB activity
Authors: Hongping Xia, Yukui Yan, Minghua Hu, Yaxian Wang, Yongsheng Wang, Yi Dai, Jianming Chen, Guangfu Di, Xiaobing Chen, Xiaochun Jiang
Journal: Neuro-Oncology (2012)

Malignant gliomas are the most common and deadly primary brain tumors in adults. Increasing evidence has indicated that microRNAs (miRNAs) have an influence on the regulation of apoptotic cell signaling. Downregulation of miRNA 218 (miR-218) has been indicated in human glioma specimens. Here, we investigate the function of miR-218 in apoptosis and tumor growth of glioma cells. The expression of miR-218 was detected by real-time quantitative reverse transcriptase PCR. The effects of miR-218 on glioma cell proliferation and tumorigenicity were investigated by in vitro clonogenicity and in vivo xenograft assay. Apoptosis was evaluated by flow cytometric analysis and assay by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling. The downstream targets of miR-218 were identified by bioinformatics analysis and further validated by Western blot and luciferase reporter assay. Overexpression of miR-218 induces glioma cell apoptosis and inhibits glioma cell viability, proliferation, and tumorigenicity. Epidermal growth factor receptor–coamplified and overexpressed protein (ECOP) was identified as a functional downstream target of miR-218, which can regulate transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and associated with apoptotic response. Ectopic expression of ECOP rescued the glioma cells from miR-218–induced apoptosis and increased NF-κB activity. These results suggest that miR-218 sensitizes glioma cells to apoptosis by regulating ECOP-mediated suppression of NF-κB activity, which may provide novel opportunities for glioma therapy.
Fragile Histidine Triad Gene Inactivation in Lung Cancer
Authors: Carla Verri, Luca Roz, Davide Conte, Triantafillos Liloglou, Anna Livio, Aurelien Vesin, Alessandra Fabbri, Francesca Andriani, Christian Brambilla, Luca Tavecchio, Giuseppe Calarco, Elisa Calabrò, Andrea Mancini, Diego Tosi, Paolo Bossi, John K. Field, Elisabeth Brambilla, Gabriella Sozzi
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer.Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors.Methods: FHIT immunostaining was performed on 305 tumor samples. The methylation status of FHIT promoter was assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples of which a subset of 187 patients had available normal/tumor DNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers.Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7% of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was present when methylation and LOH were analyzed together (P = 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P < 0.0001) and in smokers (P = 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P = 0.0415).Conclusions: Our results indicate that different molecular mechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.
Cell-Mediated Immunity in Mice Against Papain-Solubilized Histocompatibility and Tumor-Specific Antigens by a Macrophage Migration Inhibition Microassay
Authors: B. A. Maurer, J. H. Dean, J. L. McCoy, E. Appella, L W. Law
Journal: JNCI Journal of the National Cancer Institute (1976)

The cell-mediated immune status of B10.D2 (H-2d) mice immunized with spleen cells from a congenic strain, B10.A (H-2a), differing at the H-2 locus and of BALB/c mice immunized with a syngeneic simian virus 40 (SV40)-induced sarcoma (mKSA-TU5) was evaluated by an agarose microassay for migration inhibition factor. The inducing antigens in this experiment were papain-solubilized and partially purified chromatographic preparations of spleen cells from A/J mice (H-2a) and a papain-solubilized antigen extract prepared from a tissue culture-adapted cell line (TU-5), derived from the SV40-induced mKSA tumor. The assay used microliters of normal or immune peritoneal exudate cells (PEC) resuspended in a 2-mul droplet of agarose and cultured in the presence or absence of antigen. Specific migration inhibition of PEC from immunized mice was observed with concentrations of solubilized antigen preparations as low as 2.0 mug/ml (3.67 mug/chamber).
G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes
Authors: Mutsuo Harada, Yingjie Qin, Hiroyuki Takano, Tohru Minamino, Yunzeng Zou, Haruhiro Toko, Masashi Ohtsuka, Katsuhisa Matsuura, Masanori Sano, Jun-ichiro Nishi, Koji Iwanaga, Hiroshi Akazawa, Takeshige Kunieda, Weidong Zhu, Hiroshi Hasegawa, Keita Kunisada, Toshio Nagai, Haruaki Nakaya, Keiko Yamauchi-Takihara, Issei Komuro
Journal: Nature Medicine (2005)
Smoking and the gastrointestinal tract.
Authors: J R Bennett
Journal: Gut (1972)

Progress reportSmoking and the gastrointestinal tract 'Tobacco, divine, rare, super-excellent tobacco, which goes far beyond all their panaceas, potable gold, and philosopher's stones, a sovereign remedy to all diseases.But, as it is commonly abused by most men, which take it as tinkers do ale, 'tis a plague, a mischief, a violent purger ofgoods, lands, health, hellish, devilish, and damned tobacco, the ruin and overthrow of bodv and soul.' (Anatomy of Melancholy, Robert Burton.)The ravages of smoking on the respiratory tract are well documented and equally well publicized.Unassailable facts about the response of the gut to smoking are scarcer.Smoking has long been equated with sin, and on this basis clinicians have recommended its cessation to alleviate a multitude of disorders, frequently without a firm scientific basis.Because of the direct contact of inhaled smoke with the respiratory tract, its likely contribution to the cause of pulmonary disorders justifies such empirical prohibition.The necessity to assume that smoking contributes to gastrointestinal disorders is less obvious, though of course some smoke is dissolved and swallowed.The well known tendency of habitual smokers to be regular drinkers of alcohol also' must lead to reservations about finding smoking 'guilty by statistical association' in surveys of disease.Experimental work on the effects of smoking is not easy.Smoking is an intermittent, but repetitive process, and its pharmacological effects may be immediate or delayed; demonstrating that a change in some physiological process is caused by smoking poses formidable problems.The dosage required to produce a significant and measurable change is difficult to determine, not least because nicotine has a double effect: it first stimulates and then depresses autonomic ganglia.Disparities between different studies of smoking's effects on the same physiological process may sometimes be explained by dose- variation alone.Further, although the possibility that smokers may have characteristics which predispose them both to acquire the smoking habit and to the risk of certain diseases2 (perhaps from psychological causes3) is not well supported by experimental data, it cannot be dismissed.This review will examine reported associations between smoking and gastro- intestinal disease, and will particularly try to indicate where experimental support for a causative relationship exists. Malignant NeoplasmsCARCINOMA OF MOUTH AND PHARYNX Numerous anecdotal accounts exist to support the belief that smoking is a cause of cancer of lip and mouth4 especially when short-stemmed clay pipes are used.Unfortunately most studies group buccal and pharyngeal neo- plasms together, and sometimes add oesophageal ones as well.