tbuckley/cabot-search huggingface dataset:
Citrus Consumption and Risk of Cutaneous Malignant Melanoma
Authors: Shaowei Wu, Jiali Han, Diane Feskanich, Eunyoung Cho, Meir J. Stampfer, Walter C. Willett, Abrar A. Qureshi
Journal: Journal of Clinical Oncology (2015)

Purpose Citrus products are widely consumed foods that are rich in psoralens and furocoumarins, a group of naturally occurring chemicals with potential photocarcinogenic properties. We prospectively evaluated the risk of cutaneous malignant melanoma associated with citrus consumption. Methods A total of 63,810 women in the Nurses' Health Study (1984 to 2010) and 41,622 men in the Health Professionals Follow-Up Study (1986 to 2010) were included. Dietary information was repeatedly assessed every 2 to 4 years during follow-up. Incident melanoma cases were identified through self-report and confirmed by pathologic records. Results Over 24 to 26 years of follow-up, we documented 1,840 incident melanomas. After adjustment for other risk factors, the pooled multivariable hazard ratios for melanoma were 1.00 for overall citrus consumption &lt; twice per week (reference), 1.10 (95% CI, 0.94 to 1.30) for two to four times per week, 1.26 (95% CI, 1.08 to 1.47) for five to six times per week, 1.27 (95% CI, 1.09 to 1.49) for once to 1.5 times per day, and 1.36 (95% CI, 1.14 to 1.63) for ≥ 1.6 times per day (P trend &lt; .001). Among individual citrus products, grapefruit showed the most apparent association with risk of melanoma, which was independent of other lifestyle and dietary factors. The pooled multivariable hazard ratio for melanoma comparing the extreme consumption categories of grapefruit (≥ three times per week v never) was 1.41 (95% CI, 1.10 to 1.82; P trend &lt; .001). Conclusion Citrus consumption was associated with an increased risk of malignant melanoma in two cohorts of women and men. Nevertheless, further investigation is needed to confirm our findings and explore related health implications.
A PATHOLOGIST'S ODYSSEY
Authors: Morris J. Karnovsky
Journal: Annual Review of Pathology Mechanisms of Disease (2006)

I am honored to write the prefatory chapter for the inaugural volume of the Annual Review of Pathology: Mechanisms of Disease. This publishing venture signals that pathology takes its rightful place alongside the other biomedical sciences. I thought it may be of interest to some to delineate how a circuitous path led me into a career in experimental pathology and to give some of the flavor of a past era in experimental approaches. Thus, my title.
The α-Receptor for Platelet-Derived Growth Factor Confers Bone-Metastatic Potential to Prostate Cancer Cells by Ligand- and Dimerization-Independent Mechanisms
Authors: Mike R. Russell, Qingxin Liu, Hetian Lei, Andrius Kazlauskas, Alessandro Fatatis
Journal: Cancer Research (2010)

Prostate adenocarcinoma is the second leading cause of cancer death among men, due primarily to the fact that the majority of prostate cancers will eventually spread to the skeleton. Metastatic dissemination requires a complex series of coordinated events that result in cells that escape from the primary tumor into the circulation and eventually colonize a distant organ. The ability of these cells to evolve into macroscopic metastases depends strongly on their compatibility with, and ability to utilize, this new microenvironment. We previously showed that bone-metastatic prostate cancer cells exposed to human bone marrow respond by activation of cell survival pathways, such as phosphoinositide 3-kinase/Akt, and that these events are mediated by the alpha-receptor for platelet-derived growth factor (PDGFRalpha). Our studies and others have shown that PDGFRalpha may be activated by mechanisms independent of PDGF ligand binding. Here, we provide conclusive evidence that soluble components of human bone marrow can activate PDGFRalpha through a mechanism that does not require the canonical binding of PDGF ligand(s) to the receptor. In particular, we found that dimerization of PDGFRalpha monomers is not induced by human bone marrow, but this does not prevent receptor phosphorylation and downstream signaling from occurring. To establish the relevance of this phenomenon in vivo, we used a PDGFRalpha mutant lacking the extracellular ligand-binding domain. Our studies show that this truncated PDGFRalpha is able to restore bone-metastatic potential of prostate cancer cells as effectively as the full-length form of the receptor.
Molecular Pathways: Adipose Inflammation as a Mediator of Obesity-Associated Cancer
Authors: Louise R. Howe, Kotha Subbaramaiah, Clifford A. Hudis, Andrew J. Dannenberg
Journal: Clinical Cancer Research (2013)

The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-κB signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1β, and TNFα. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the rate-limiting enzyme for estrogen synthesis. Notably, this obesity-inflammation-aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor-positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. Clin Cancer Res; 19(22); 6074-83. ©2013 AACR.
Effect of nasal allergen challenge on serotonin, substance P and vasoactive intestinal peptide in plasma and nasal secretions
Authors: P. Tønnesen, I. Hindberg, O. B. Schaffalitzky de Muckadell, N. Mygind
Journal: Allergy (1988)

We have studied the changes in concentration of serotonin, substance P, and vasoactive intestinal peptide (VIP) in plasma following a nasal allergen provocation in 14 grass pollen-allergic subjects; in five the urinary excretion of serotonin and 5-hydroxy-indolyl-acetic acid (5-HIAA) was also measured. In addition, the concentration of serotonin and substance P was measured in nasal secretions following nasal challenge with allergen and methacholine. The results showed an allergen-induced increase in free plasma serotonin (P less than 0.01) and no change in platelet serotonin, urinary serotonin and urinary 5-HIAA. The plasma substance P level tended to fall (P greater than 0.1), while plasma VIP increased significantly (P less than 0.02). In nasal secretions, there were measurable levels of serotonin in all samples and of substance P in all but one. There was no difference between the concentrations of serotonin and substance P in secretions collected after allergen challenge and after methacholine challenge. For both substances, the secretion median value was comparable to that of plasma. Symptom reduction by topical and systemic pretreatment with a serotonin- and VIP-antagonist before nasal allergen provocation is necessary to define the role of these two agents in allergic rhinitis.
Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages
Authors: A. M. Wood, C. Bassford, D. Webster, P. Newby, P. Rajesh, R. A. Stockley, D. R. Thickett
Journal: Thorax (2011)

<h3>Background</h3> Vitamin D-binding protein (DBP) genetic polymorphisms have been associated with chronic obstructive pulmonary disease (COPD). DBP has an indirect role in macrophage activation; thus it was hypothesised that DBP is present in the airway and contributes to lung disease by this mechanism. <h3>Methods</h3> 471 PiZZ subjects with α1-antitrypsin deficiency (AATD) were genotyped for tag single nucleotide polymorphisms (SNPs) covering the DBP gene (<i>GC</i>), together with known functional variants, prior to seeking association with COPD phenotypes. 140 subjects with usual COPD and 480 controls were available for replication. Vitamin D and DBP levels were measured by tandem mass spectrometry and ELISA, respectively, in serum and DBP in the sol phase of sputum in a subset of 60 patients. Concentrations were related to phenotype and to alveolar macrophage activation. <h3>Results</h3> rs2070741 was associated with airway bacterial colonisation (p=0.04) and bronchiectasis (p=0.01), as was rs7041 (p=0.03) which also influenced vitamin D concentrations (p=0.01). The <i>GC2</i> variant predisposed to bronchiectasis in AATD (p=0.04) and protected against COPD (p=0.05); the latter association was replicated in usual COPD versus controls (p=0.04). Circulating DBP related inversely to forced expiratory volume in 1 s (FEV<sub>1</sub>) (p=0.02), in direct contrast to vitamin D, where deficiency related to low FEV<sub>1</sub> (p=0.04). Sol DBP related directly to alveolar macrophage activation (p=0.004). <h3>Conclusions</h3> The genetic association of DBP with COPD may be mediated by effects on macrophage activation, since DBP relates to FEV<sub>1</sub>, and affects macrophage activation. Vitamin D effects may be independent of this, relating more strongly to innate immunity.
Reliability and validity of three pain provocation tests used for the diagnosis of chronic proximal hamstring tendinopathy
Authors: Angelo Cacchio, Fabrizio Borra, Gabriele Severini, Andrea Foglia, Frank Musarra, Nicola Taddio, Fosco De Paulis
Journal: British Journal of Sports Medicine (2012)

Background The clinical assessment of chronic proximal hamstring tendinopathy (PHT) in athletes is a challenge to sports medicine. To be able to compare the results of research and treatments, the methods used to diagnose and evaluate PHT must be clearly defined and reproducible. Objective To assess the reliability and validity of three pain provocation tests used for the diagnosis of PHT. Methods Ninety-two athletes with (N=46) and without (N=46) PHT were examined by one physician and two physiotherapists, who were trained in the examination techniques before the study. The examiners were blinded to the symptoms and identity of the athletes. The three pain provocation tests examined were the Puranen–Orava, bent-knee stretch and modified bent-knee stretch tests. Intraclass correlation coefficients (ICCs) based on the repeated measures analysis of variance were used to analyse the intraexaminer and interexaminer reliability, while sensitivity, specificity, predictive values and likelihood ratios were used to determine the validity of the three tests. Results The ICC values in all three tests revealed a high correlation (range 0.82 to 0.88) for the interexaminer reliability and a high-to-very high correlation (range 0.87 to 0.93) for the intraexaminer reliability. All three tests displayed a moderate-to-high validity, with the highest degree of validity being yielded by the modified bent-knee stretch test. Conclusion All three pain provocation tests proved to be of potential value in assessing chronic PHT in athletes. However, we recommend that they be used in conjunction with other objective measures, such as MRI.
Early Stage Lung Cancer—New Approaches to Evaluation and Treatment: Conference Summary Statement
Authors: Thomas J. Lynch, Jeffrey A. Bogart, Walter J. Curran, Malcolm M. DeCamp, David R. Gandara, Glenwood Goss, Claudia I. Henschke, James R. Jett, Bruce E. Johnson, Karen L. Kelly, Thierry Le Chevalier, James L. Mulshine, Giorgio V. Scagliotti, Joan H. Schiller, Alice Shaw, Nick Thatcher, Everett E. Vokes, Douglas E. Wood, Carol Hart
Journal: Clinical Cancer Research (2005)

“Early Stage Lung Cancer—New Approaches to Evaluation and Treatment,” held in Cambridge, MA, October 1 — 2, 2004, was convened to present and discuss recent study findings on the detection, staging, and treatment of stage I to III non–small cell lung cancer (NSCLC). This small
OC-055 What is the true incidence of metachronous colorectal liver metastases? evidence from the UK FACS (follow-up after colorectal surgery) trial (ISRCTN: 41458548)
Authors: S Pugh, A Fuller, P Rose, R Perera-Salazar, J Mellor, S George, D Mant, J Primrose
Journal: Gut (2012)

<h3>Introduction</h3> Detecting patients with resectable metachronous colorectal liver metastases and performing potentially curative surgery is commonly cited as a reason for following up patients with completely resected colorectal cancer. However, the actual incidence of metachronous metastasis in fully staged and optimally treated colorectal cancer patients is not known with certainty. The FACS trial, the UK national trial on colorectal cancer follow-up, provided an opportunity to address this question. <h3>Methods</h3> Patients were recruited to the trial following potentially curative resection of the primary colorectal cancer (Dukes9 stages A–C, (I–III)). Complete evaluation by CT chest, abdomen and pelvis and a normal CEA (carcinoembryonic antigen) after surgery or adjuvant chemotherapy were prerequisites to trial entry. Patients were randomised in a 2×2 trial design of intensive imaging vs minimal CT imaging and CEA vs no CEA measurement. Follow-up data including site of recurrence and further surgery has been collected prospectively. An observational analysis has been performed on the entire cohort at a median follow-up of 54 months. <h3>Results</h3> A total of 1260 patients were recruited of which 22% were in Dukes9 stage A (I), 48% stage B (II), and 30% stage C (III) (remainder awaiting data clarification). At follow-up 85.6% of patients were alive without recurrence (stage A 90.9%, stage B 86.7%, stage C 80.4%). Of the 178 recurrences the majority were loco-regional or at multiple sites. Liver metastases were found in 72 (40% of patients with recurrence) and 45 (25%) had liver only disease. A potentially curative liver resection was performed in 35 patients (20%). Thus at a median follow-up of 54 months 5.7% of the study cohort had metachronous metastases in the liver. In 3.6% of the cohort the disease was confined to the liver and 2.8% went on to have a potentially curative liver resection. <h3>Conclusion</h3> These preliminary data demonstrate that the incidence of metachronous liver metastasis in fully staged patients with colorectal cancer appears to be low. Furthermore due to the often multi-site nature of the recurrence only a small proportion of patients can be cured. Thus very intensive follow-up strategies to detect colorectal liver metastases are unlikely to be cost effective. These data emphasise the importance of fully staging the liver at the time of treatment of the primary disease. <h3>Competing interests</h3> None declared.
Risk Model Predictive of Severe Anemia Requiring RBC Transfusion After Chemotherapy in Pediatric Solid Tumor Patients
Authors: Perrine Marec-Berard, Jean Yves Blay, Matthias Schell, Murielle Buclon, Corrine Demaret, Isabelle Ray-Coquard
Journal: Journal of Clinical Oncology (2003)

Severe anemias requiring RBC transfusions is a frequent complication of chemotherapy. A model elaborated by Ray-Coquard et al in adults pointed to three independent risk factors for RBC transfusion: performance status (PS) more than 1, hemoglobin less than 12 g/dL, and prechemotherapy absolute lymphocyte count (ALC) < or = 700/microL. This model is tested on a pediatric population.One hundred nineteen children with solid tumors consecutively admitted for conventional chemotherapy throughout 1 year were included. The study end point was the RBC-transfusion risk in the month following chemotherapy. Only one course was considered for each patient. Age, sex, number of courses, platinum-containing regimens, PS, and hemoglobin and lymphocyte count at day 1 were tested in univariate and multivariate analyses.Thirty-one (26%) of 119 children required RBC transfusion within 31 days of chemotherapy. Three factors correlated to transfusion risk in the univariate analysis: PS more than 1 (P <.001), hemoglobin less than 12 g/dL (P =.007), and pretreatment ALC < or = 700/microL (P <.001). In the multivariate analysis, hemoglobin less than 12 g/dL, PS more than 1, and ALC < or = 700/microL were identified as independent factors predicting RBC transfusion. The calculated probability of receiving RBC transfusion within 31 days of chemotherapy was high with three risk factors (96%), intermediate with two risk factors (53% to 77%), low with one risk factor (10% to 26%), and very low when no risk factor was present (2%). The difference of transfusion needs was significant (P <.001).The risk model elaborated for adults may also segregate children at high risk of postchemotherapy RBC transfusion, thus facilitating assessment of risk of transfusion and/or prophylactic erythropoietin support.
Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse
Authors: Deepti Nair, Shelley X. L. Zhang, Vijay Ramesh, Fahed Hakim, Navita Kaushal, Yang Wang, David Gozal
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Sleep fragmentation (SF) is one of the major characteristics of sleep apnea, and has been implicated in its morbid consequences, which encompass excessive daytime sleepiness and neurocognitive impairments. We hypothesized that absence of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is neuroprotective in SF-induced cognitive impairments.To examine whether increased NADPH oxidase activity may play a role in SF-induced central nervous system dysfunction.The effect of chronic SF during the sleep-predominant period on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters was assessed in mice lacking NADPH oxidase activity (gp91phox-(/Y)) and wild-type littermates.SF for 15 days was not associated with differences in sleep duration, sleep state distribution, or sleep latency in both gp91phox-(/Y) and control mice. However, on a standard place training task, gp91phox-(/Y) mice displayed normal learning and were protected from the spatial learning deficits observed in wild-type littermates exposed to SF. Moreover, anxiety levels were increased in wild-type mice exposed to SF, whereas no changes emerged in gp91phox-(/Y) mice. Additionally, wild-type mice, but not gp91phox-(/Y) mice, had significantly elevated NADPH oxidase gene expression and activity, and in malondialdehyde and 8-oxo-2'-deoxyguanosine levels in cortical and hippocampal lysates after SF exposures.This work substantiates an important role for NADPH oxidase in hippocampal memory impairments induced by SF, modeling sleep apnea. Targeting NADPH oxidase, therefore, is expected to minimize hippocampal impairments from both intermittent hypoxia and SF associated with the disease.
Incremental Prognostic Value of Post-Stress Left Ventricular Ejection Fraction and Volume by Gated Myocardial Perfusion Single Photon Emission Computed Tomography
Authors: Tali Sharir, Guido Germano, Paul B. Kavanagh, Shenhan Lai, Ishac Cohen, Howard C. Lewin, John D. Friedman, Michael J. Zellweger, Daniel S. Berman
Journal: Circulation (1999)

Background —The incremental prognostic value of post-stress left ventricular ejection fraction (EF) and volume over perfusion has not been investigated. Methods and Results —We identified 1680 consecutive patients who underwent rest Tl-201/stress Tc-99m sestamibi gated single photon emission computed tomography (SPECT) and who were followed-up for 569±106 days. Receiver-operator characteristics analysis defined an EF&lt;45%, an end-systolic volume (ESV) &gt;70 mL, and an end-diastolic volume &gt;120 mL as optimal thresholds, yielding moderate sensitivity and high specificity in the prediction of cardiac death. Patients with an EF≥45% had mortality rates &lt;1%/year, despite severe perfusion abnormalities, whereas patients with an EF&lt;45% had high mortality rates, even with only mild/moderate perfusion abnormalities (9.2%/year; P &lt;0.00001). Similarly, an ESV≤70 mL was related to a low cardiac death rate (&lt;1.2%/year), even for patients with severe perfusion abnormalities, whereas patients with an ESV&gt;70 mL and only mild/moderate perfusion abnormalities had high death rates (8.2%/year; P &lt;0.00001). Patients with an EF&lt;45% and an ESV≤70 mL had low cardiac death rates (1.7%/year); those with an EF&lt;45% but an ESV&gt;70 mL had high death rates (7.9%/year; P &lt;0.02). Multivariate Cox proportional hazards regression showed that perfusion variables and ESV were independent predictors of overall coronary events, whereas EF and ESV demonstrated incremental prognostic values over prescan and perfusion information in predicting cardiac death and cardiac death or myocardial infarction. Conclusions —Post-stress EF and ESV by gated-SPECT have incremental prognostic values over prescan and perfusion information in predicting cardiac death, and they provide clinically useful risk stratification.
Determinants of intention to get vaccinated against novel (pandemic) influenza A H1N1 among health-care workers in a nationwide survey
Authors: Helena C. Maltezou, Xanthi Dedoukou, Stavros Patrinos, Antonios Maragos, Sophia Poufta, Panagiotis Gargalianos, Marios Lazanas
Journal: Journal of Infection (2010)
PCSK9 impedes hepatitis C virus infection<i>in vitro</i>and modulates liver CD81 expression
Authors: Patrick Labonté, Syntia Begley, Carl Guévin, Marie-Claude Asselin, Nasha Nassoury, Gaétan Mayer, Annik Prat, Nabil G. Seidah
Journal: Hepatology (2009)

Abstract Human PCSK9 is known to enhance the degradation of membrane-bound receptors such as the hepatocyte low-density lipoprotein receptor (LDLR), ApoER2, and very low-density lipoprotein receptor. Because the LDLR is suspected to be involved in hepatitis C virus (HCV) entry, we also tested whether PCSK9 can affect the levels of CD81, a major HCV receptor. Interestingly, stable expression of PCSK9 or a more active membrane-bound form of the protein (PCSK9-ACE2) resulted in a marked reduction in CD81 and LDLR expression. Therefore, we analyzed the antiviral effect of PCSK9 in vitro using the HCV genotype 2a (JFH1) virus. The results clearly demonstrated that cells expressing PCSK9 or PCSK9-ACE2, but not the ACE2 control protein, were resistant to HCV infection. Furthermore, addition of purified soluble PCSK9 to cell culture supernatant impeded HCV infection in a dose-dependent manner. As expected, HuH7 cells expressing PCSK9-ACE2 were also resistant to infection by HCV pseudoparticles. In addition, we showed that CD81 cell surface expression is modulated by PCSK9 in an LDLR-independent manner. Finally, in the liver of single Pcsk9 and double ( Pcsk9 + Ldlr ) knockout mice, both LDLR and/or CD81 protein expression levels were significantly reduced, but not those of transferrin and scavenger receptor class B type 1. Conclusion : Our results demonstrate an antiviral effect of the circulating liver PCSK9 on HCV in cells and show that PCSK9 down-regulates the level of mouse liver CD81 expression in vivo . Therefore, we propose that the plasma level and/or activity of PCSK9 may modulate HCV infectivity in humans. (Hepatology 2009.)