tbuckley/cabot-search huggingface dataset:
CTLA-4 Blockade: Unveiling Immune Regulation
Authors: Glenn Dranoff
Journal: Journal of Clinical Oncology (2004)

To maintain tissue homeostasis under the duress of infection or injury, the immune system is endowed with a diverse repertoire of soluble and cellular effectors. The innate response, composed of granulocytes, macrophages, dendritic cells, natural killer cells, and complement, is rapidly triggered into action, detecting tissue disturbance through a set of germline-encoded pattern recognition receptors. The adaptive reaction, consisting of antibodyproducing B cells and T lymphocytes, is slower to develop, but manifests exquisite specificity and memory. These attributesreflecttherequirementforexpansionofrareclones harboring somatically rearranged immunoglobulin molecules or T-cell receptors specific for foreign proteins or processed peptides presented by major histocompatibility complex (MHC) molecules. These innate and adaptive responses are carefully orchestrated through soluble and membrane-bound regulators, resulting in the deployment of the most suitable effectors for containing the disorder, while minimizing tissue damage. Cancercellssimilarlyprovokeimmunerecognition.In one pathway, innate effectors detect tumor cells directly. 1 Natural killer cells and phagocytes express NKG2D moleculesthatfunctionasreceptorsforstress-relatedgenessuch
Autophagy suppresses tumorigenesis of hepatitis B virus‐associated hepatocellular carcinoma through degradation of microRNA‐224
Authors: Sheng-Hui Lan, Shan-Ying Wu, Roberto Zuchini, Xi-Zhang Lin, Ih-Jen Su, Ting-Fen Tsai, Yen-Ju Lin, Cheng-Tao Wu, Hsiao-Sheng Liu
Journal: Hepatology (2013)

In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study we determined that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time polymerase chain reaction and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224, and low-Smad4 showed significant correlation with HBV infection and a poor overall survival rate. Autophagy-mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model. A noncanonical pathway links autophagy, miR-224, Smad4, and HBV-associated HCC. These findings open a new avenue for the treatment of HCC.
Molecular Pathways: Mitogen-Activated Protein Kinase Pathway Mutations and Drug Resistance
Authors: Antonia L. Pritchard, Nicholas K. Hayward
Journal: Clinical Cancer Research (2013)

Abstract Receptor tyrosine kinases are a diverse family of transmembrane proteins that can activate multiple pathways upon ligation of the receptor, one of which is the series of mitogen-activated protein kinase (MAPK) signaling cascades. The MAPK pathways play critical roles in a wide variety of cancer types, from hematologic malignancies to solid tumors. Aberrations include altered expression levels and activation states of pathway components, which can sometimes be attributable to mutations in individual members. The V600E mutation of BRAF was initially described in 2002 and has been found at particularly high frequency in melanoma and certain subtypes of colorectal cancer. In the relatively short time since this discovery, a family of drugs has been developed that specifically target this mutated BRAF isoform, which, after results from phase I/II and III clinical trials, was granted U.S. Food and Drug Administration approval in August 2011. Although these drugs produce clinically meaningful increases in progression-free and overall survival, due to acquired resistance they have not improved mortality rates. New drugs targeting other members of the MAPK pathways are in clinical trials or advanced stages of development. It is hoped that combination therapies of these new drugs in conjunction with BRAF inhibitors will counteract the mechanisms of resistance and provide cures. The clinical implementation of next-generation sequencing is leading to a greater understanding of the genetic architecture of tumors, along with acquired mechanisms of drug resistance, which will guide the development of tumor-specific inhibitors and combination therapies in the future. Clin Cancer Res; 19(9); 2301–9. ©2013 AACR.
Sex-Related Differences in Bronchial Epithelial Changes Associated With Tobacco Smoking
Authors: S. Lam, J. C. leRiche, Y. Zheng, A. Coldman, C. MacAulay, E. Hawk, G. Kelloff, A. F. Gazdar
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Lung cancer is the most common cause of cancer death in North American women. Because smoking-related changes in the bronchial epithelium and in lung function have not been studied in detail in women, we used fluorescence bronchoscopy-directed biopsy to determine the prevalence of high-grade preinvasive lesions in former and current smokers of both sexes. METHODS: Spirometry, white-light bronchoscopy, and fluorescence bronchoscopy were performed in 189 women and 212 men older than 40 years of age who had smoked 20 pack-years or more (pack-years = number of packs of cigarettes smoked per day × number of years of smoking). RESULTS: Carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, and moderate dysplasia was found in 14% (all preinvasive lesions). Compared with men, women had a lower prevalence of high-grade preinvasive lesions in the observed airways (14% versus 31%; odds ratio = 0.18; 95% confidence interval = 0.04-0.88), and women with preinvasive lesions had fewer such lesions (two-sided P = .048). The prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking. Lung function was associated with the prevalence of preinvasive lesions, but the association was weaker in women than in men. If the presence of airflow obstruction was defined by an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) value of 70% or less, only 56% of the men and 44% of the women with preinvasive lesions had abnormal lung function. CONCLUSION: In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, it is important to consider the effect of sex and arbitrarily chosen lung function values on the prevalence of preinvasive airway lesions.
Urinary Excretion of Monocyte Chemoattractant Protein-1 in Autosomal Dominant Polycystic Kidney Disease
Authors: Danxia Zheng, Marieka Wolfe, Benjamin D. Cowley, Darren P. Wallace, Tamio Yamaguchi, Jared J. Grantham
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Autosomal dominant polycystic kidney disease (ADPKD) progresses to renal insufficiency in &gt;50% of patients and is characterized by interstitial inflammation and fibrosis in the end stage. In a rat model of ADPKD, monocytes accumulate within the renal interstitium in association with increased levels of monocyte chemoattractant protein-1 (MCP-1) in cyst mural cells and increased excretion of this chemokine into the urine. For determining the extent to which this chemokine is abnormally expressed in patients with ADPKD, a cross-section study was performed of MCP-1 in urine, serum, and cyst fluid and MCP-1 production by mural epithelial cells cultured from the cysts of human patients with ADPKD. Upper boundaries for urinary MCP-1 excretion (&gt;263 pg/mg creatinine) and serum creatinine concentration (&gt;1.5 mg/dl) determined in 19 normal individuals were used to sort 55 ADPKD patients into three groups. In group 1 (<i>n</i> = 13), urine MCP-1 excretion (136 ± 14 pg/mg creatinine) was not different from normal volunteers (152 ± 16 pg/mg); serum creatinine levels and urine total protein excretion were normal as well. In group 2 (<i>n</i> = 27), urine MCP-1 excretion was increased (525 ± 39 pg/mg creatinine), but serum creatinine levels and urine protein excretion were not different from normal. In group 3 (<i>n</i> = 15), urine MCP-1 excretion increased further (1221 ± 171 pg/mg), serum creatinine levels increased to 4.3 ± 0.8 mg/dl, and urine protein excretion rose to 0.64 ± 0.28 mg/mg creatinine. Serum MCP-1 levels of ADPKD patients (84 ± 9.9 pg/ml; <i>n</i> = 15) did not differ from normal. Levels of MCP-1 much higher than in serum or urine were found in cyst fluids obtained from nephrectomy specimens (range, 767 to 40,860 pg/ml; mean, 6434 ± 841 pg/ml; <i>n</i> = 73). Polarized, confluent cultures of ADPKD cyst epithelial cells secreted MCP-1 into the apical fluid to levels eightfold greater than in the basolateral medium. Similar results were obtained with tubule epithelial cells cultured from normal human renal cortex. On the basis of these results, it is concluded that urinary excretion of MCP-1 is increased in the majority of adult patients with ADPKD and that the source of some of this chemokine may be the mural epithelium of cysts. Furthermore, it seemed that urinary MCP-1 excretion may have increased in these ADPKD patients before appreciable increases in serum creatinine concentration or urine protein excretion were detected. It is reasonable to include urine MCP-1 excretion among candidate surrogate markers in controlled, longitudinal studies of ADPKD. E-mail: jgrantha@kumc.edu
Dietary Patterns and Risk of Incident Type 2 Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Jennifer A. Nettleton, Lyn M. Steffen, Hanyu Ni, Kiang Liu, David R. Jacobs
Journal: Diabetes Care (2008)

We characterized dietary patterns and their relation to incident type 2 diabetes in 5,011 participants from the Multi-Ethnic Study of Atherosclerosis (MESA).White, black, Hispanic, and Chinese adults, aged 45-84 years and free of cardiovascular disease and diabetes, completed food frequency questionnaires at baseline (2000-2002). Incident type 2 diabetes was defined at three follow-up exams (2002-2003, 2004-2005, and 2005-2007) as fasting glucose >126 mg/dl, self-reported type 2 diabetes, or use of diabetes medication. Two types of dietary patterns were studied: four empirically derived (principal components analysis) and one author-defined (low-risk food pattern) as the weighted sum of whole grains, vegetables, nuts/seeds, low-fat dairy, coffee (positively weighted), red meat, processed meat, high-fat dairy, and soda (negatively weighted).The empirically derived dietary pattern characterized by high intake of tomatoes, beans, refined grains, high-fat dairy, and red meat was associated with an 18% greater risk (hazard ratio per 1-score SD 1.18 [95% CI 1.06-1.32]; P(trend) = 0.004), whereas the empirically derived dietary pattern characterized by high intake of whole grains, fruit, nuts/seeds, green leafy vegetables, and low-fat dairy was associated with a 15% lower diabetes risk (0.85 [0.76-0.95]; P(trend) = 0.005). The low-risk food pattern was also inversely associated with diabetes risk (0.87 [0.81-0.99]; P(trend) = 0.04). Individual component food groups were not independently associated with diabetes risk. Associations were not modified by sex or race/ethnicity.Multiple food groups collectively influence type 2 diabetes risk beyond that of the individual food groups themselves.
The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption
Authors: Rainer Spanagel, Gurudutt Pendyala, Carolina Abarca, Tarek Zghoul, Carles Sanchis-Segura, Maria Chiara Magnone, Jesús Lascorz, Martin Depner, David Holzberg, Michael Soyka, Stefan Schreiber, Fumihiko Matsuda, Mark Lathrop, Gunter Schumann, Urs Albrecht
Journal: Nature Medicine (2004)
Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial
Authors: Susan O'Brien, Richard R Furman, Steven E Coutre, Jeff P Sharman, Jan A Burger, Kristie A Blum, Barbara Grant, Donald A Richards, Morton Coleman, William G Wierda, Jeffrey A Jones, Weiqiang Zhao, Nyla A Heerema, Amy J Johnson, Raquel Izumi, Ahmed Hamdy, Betty Y Chang, Thorsten Graef, Fong Clow, Joseph J Buggy, Danelle F James, John C Byrd
Journal: The Lancet Oncology (2013)
Proteinase content of mast cells of nasal mucosa; effects of natural allergen exposure and of local corticosteroid treatment
Authors: S. Juliusson, F. Aldenborg, L. Enerbäck
Journal: Allergy (1995)

The distribution and density of metachromatic cells (MCC) and mast cells containing chymase plus tryptase (MC TC ) or tryptase alone (MC T ) were studied in the nasal mucosa by dye‐binding methods and immuno‐histochemical analysis. Biopsies were obtained from 17 subjects with birch pollen allergy before and during the peak season and from nine healthy controls. Six patients were treated with an intranasal glucocorticosteroid before and during the season in an open study. Hay fever patients, even when asymptomatic, showed signs of mast cell system activation, exhibiting an increased number of mast cells in the nasal epithelium. Basophils, lacking immunohistochemically detectable tryptase, were not a major component of the mast cell response. MC T , most conspicuous in the epithelium, were found to be the most frequent mast‐cell type in the nasal mucosa of allergic, but not of normal, subjects. Only 33% of the epithelial, but 90% of the stromal, immunopositive cells in the atopic mucosa before as well as during the season were MCC. Intraepithelial MC T thus displayed a low capacity to stain metachromatically, indicating a relative deficiency of the glycosaminoglycan (heparin) component of the granules. Intraepithelial mast cells also appeared to be markedly sensitive to steroid treatment and aldehyde fixation. The findings suggest that the lack of chymase, the characteristic feature of MC T , may reflect a functional activation of the mast cells, rather than a stable phenotypic differentiation related to anatomic site.
Altered expression of alpha 4 beta 7, a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation.
Authors: J Meenan, J Spaans, T A Grool, S T Pals, G N Tytgat, S J van Deventer
Journal: Gut (1997)

Expression of alpha 4 beta 7 on memory T lymphocytes identifies a cell population that preferentially migrates to the gut. Detection of alpha 4 beta 7 on circulating lymphocytes may permit the identification of specific subsets trafficking between the circulation and the gut in inflammatory bowel diseases.Samples and clinical details were taken from patients with Crohn's disease (CD), ulcerative colitis (UC), diverticulitis/ infectious colitis, and healthy controls.Peripheral blood and lamina propria mononuclear cells were isolated. Cells were labelled with CD3, CD4, CD25, CD45RO or alpha 4 beta 7.Median levels of circulating total memory T cells (CD4+CD45RO+) were increased in CD (p < 0.01) and UC (p < 0.05). However, the proportion of systemic gut homing T cells (CD4+CD45RO+ alpha 4 beta 7+) was decreased in CD (p < 0.05), UC (p < 0.002), and inflammatory controls (p < 0.05). Levels of activated gut homing T cells (CD4+CD25+ alpha 4 beta 7+) were increased in CD (p < 0.01) and UC (p < 0.05). For both CD4+CD45RO+ and CD4+CD25+ cells, the proportion of lymphocytes coexpressing alpha 4 beta 7 was decreased compared with controls. In small and large intestine lamina propria, expression of alpha 4 beta 7+ on CD3+ cells was extensive, although it was decreased in CD (p < 0.03), UC (p < 0.05), and inflammatory controls (p < 0.05).Circulating and mucosal gut homing lymphocyte populations are changed in patients with colonic inflammation. This may arise due to a dilution effect from recruited naive T cells, or from integrin down regulation. Changes in general CD4+ lymphocyte populations mask more subtle variations in those cells with gut homing potential.
Public Health Medicine in Transition
Authors: Rosalind Stanwell-Smith, Deidre Hine
Journal: Journal of the Royal Society of Medicine (2001)

Public health medicine as a specialty in the UK was established in the nineteenth century with the introduction of medical officer of health posts by local authorities, the first being Dr William Duncan in Liverpool, 18471. In the early development of public health practice, doctors took a prominent part, but public health interventions have never been an exclusively medical prerogative. For example, the first Public Health Act of 1848 was instigated by Edwin Chadwick (1800-1890)2, secretary to the Poor Law Commission and later famous as a sanitarian. Today, many other disciplines are claiming a central role.
Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients
Authors: Nerea Varo, David Vicent, Peter Libby, Rebecca Nuzzo, Alfonso L. Calle-Pascual, María Rosa Bernal, Arturo Fernández-Cruz, Aristidis Veves, Petr Jarolim, Jose Javier Varo, Allison Goldfine, Edward Horton, Uwe Schönbeck
Journal: Circulation (2003)

Background— Considerable evidence implicates the proinflammatory cytokine CD40 ligand (CD40L) in atherosclerosis and accumulating data link type 1 and 2 diabetes, conditions associated with accelerated atherosclerosis, to inflammation. This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L (sCD40L) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation. Methods and Results— Subjects with type 1 (n=49) or type 2 diabetes (n=48) had higher ( P &lt;0.001) sCD40L plasma levels (6.56±3.27 and 6.67±2.90 ng/mL, respectively) compared with age-matched control groups (1.40±2.21 and 1.32±2.68 ng/mL, respectively). Multiple regression analysis demonstrated a significant ( P &lt;0.001) association between plasma sCD40L and type 1 as well as type 2 diabetes, independent of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, body mass index, gender, C-reactive protein, and soluble intracellular adhesion molecule-1. Furthermore, in a pilot study, administration of troglitazone (12 weeks, 600 mg/day), but not placebo, to type 2 diabetics (n=68) significantly ( P &lt;0.001) diminished sCD40L plasma levels by 29%. The thiazolidinedione lowered plasma sCD40L in type 2 diabetic patients with long-standing disease (&gt;3 years) with or without macrovascular complications (−34% and −29%, respectively) as well as in type 2 diabetic patients with more recent (&lt;3 years) onset of the disease (−27%; all P &lt;0.05). Conclusions— This study provides new evidence that individuals with type 1 or 2 diabetes have a proinflammatory state as indicated by elevated levels of plasma sCD40L. Troglitazone treatment of type 2 diabetic patients diminishes sCD40L levels, suggesting a novel antiinflammatory mechanism for limiting diabetes-associated arterial disease.
Cutaneous granulomatous reaction to injectable hyaluronic acid gel
Authors: M. Ghislanzoni, F. Bianchi, M. Barbareschi, E. Alessi
Journal: British Journal of Dermatology (2006)

Injectable hyaluronic acid (HA) derivatives are the most used reabsorbable dermal fillers for soft tissue augmentation today and their utilization is considered safe. We report a cutaneous granulomatous reaction that developed in a woman 5 weeks after the first treatment with a nonanimal HA derivative for the correction of facial wrinkling. We describe the clinicopathological findings and course of the cutaneous reaction. The adverse reaction showed clinical and histopathological characteristics comparable to the few previously reported cases. All cutaneous lesions spontaneously disappeared without scars within 3 months. We conclude that even nonanimal injectable HA derivatives can be associated with delayed granulomatous reactions. The patient should be informed of this potential long-term complication.
Bacterial α2-macroglobulins: colonization factors acquired by horizontal gene transfer from the metazoan genome?
Authors: Aidan Budd, Stephanie Blandin, Elena A Levashina, Toby J Gibson
Journal: Genome biology (2004)

Invasive bacteria are known to have captured and adapted eukaryotic host genes. They also readily acquire colonizing genes from other bacteria by horizontal gene transfer. Closely related species such as Helicobacter pylori and Helicobacter hepaticus, which exploit different host tissues, share almost none of their colonization genes. The protease inhibitor alpha2-macroglobulin provides a major metazoan defense against invasive bacteria, trapping attacking proteases required by parasites for successful invasion.Database searches with metazoan alpha2-macroglobulin sequences revealed homologous sequences in bacterial proteomes. The bacterial alpha2-macroglobulin phylogenetic distribution is patchy and violates the vertical descent model. Bacterial alpha2-macroglobulin genes are found in diverse clades, including purple bacteria (proteobacteria), fusobacteria, spirochetes, bacteroidetes, deinococcids, cyanobacteria, planctomycetes and thermotogae. Most bacterial species with bacterial alpha2-macroglobulin genes exploit higher eukaryotes (multicellular plants and animals) as hosts. Both pathogenically invasive and saprophytically colonizing species possess bacterial alpha2-macroglobulins, indicating that bacterial alpha2-macroglobulin is a colonization rather than a virulence factor.Metazoan alpha2-macroglobulins inhibit proteases of pathogens. The bacterial homologs may function in reverse to block host antimicrobial defenses. Alpha2-macroglobulin was probably acquired one or more times from metazoan hosts and has then spread widely through other colonizing bacterial species by more than 10 independent horizontal gene transfers. yfhM-like bacterial alpha2-macroglobulin genes are often found tightly linked with pbpC, encoding an atypical peptidoglycan transglycosylase, PBP1C, that does not function in vegetative peptidoglycan synthesis. We suggest that YfhM and PBP1C are coupled together as a periplasmic defense and repair system. Bacterial alpha2-macroglobulins might provide useful targets for enhancing vaccine efficacy in combating infections.