tbuckley/cabot-search huggingface dataset:
Effect of a Nicotine Vaccine on Nicotine Binding to β<sub>2</sub>*-Nicotinic Acetylcholine Receptors In Vivo in Human Tobacco Smokers
Authors: Irina Esterlis, Jonas O. Hannestad, Evgenia Perkins, Frederic Bois, D. Cyril D’Souza, Rachel F. Tyndale, John P. Seibyl, Dorothy M. Hatsukami, Kelly P. Cosgrove, Stephanie S. O’Malley
Journal: American Journal of Psychiatry (2013)

Immunization with a nicotine conjugate vaccine (3′-AmNic-rEPA) significantly reduced nicotine's ability to enter the brain and bind to β2-containing nicotinic acetylcholine receptors (β2*-nAChRs) by sequestering nicotine in the blood. Healthy tobacco smokers experienced a 12.5% decrease in β2*-nAChR occupancy by nicotine after vaccination, which was associated with a 23.6% decrease in the amount of nicotine available to enter the brain, and significant reductions in cigarette use and craving.
Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis
Authors: Yun Zhang, Clara Dees, Christian Beyer, Neng-Yu Lin, Alfiya Distler, Pawel Zerr, Katrin Palumbo, Laura Susok, Alexander Kreuter, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Casein kinase II (CK2) is a constitutively active serine/threonine protein kinase that plays a key role in cellular transformation and tumorigenesis. The purpose of the study was to characterise whether CK2 contributes to the pathologic activation of fibroblasts in patients with SSc and to evaluate the antifibrotic potential of CK2 inhibition. <h3>Methods</h3> Activation of CK2, JAK2 and STAT3 in human skin and in experimental fibrosis was analysed by immunohistochemistry. CK2 signalling was inhibited by the selective CK2 inhibitor 4, 5, 6, 7-Tetrabromobenzotriazole (TBB). The mouse models of bleomycin-induced and TGFβ receptor I (TBR)-induced dermal fibrosis were used to evaluate the antifibrotic potential of specific CK2 inhibition in vivo. <h3>Result</h3> Increased expression of CK2 was detected in skin fibroblasts of SSc patients. Inhibition of CK2 by TBB abrogated the TGFβ-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGFβ on collagen release and myofibroblasts differentiation in cultured fibroblasts. Inhibition of CK2 prevented bleomycin-induced and TBR-induced skin fibrosis with decreased dermal thickening, lower myofibroblast counts and reduced accumulation of collagen. Treatment with TBB also induced regression of pre-established fibrosis. The antifibrotic effects of TBB were accompanied by reduced activation of JAK2/STAT3 signalling in vivo. <h3>Conclusions</h3> We provide evidence that CK2 is activated in SSc and contributes to fibroblast activation by regulating JAK2/STAT3 signalling. Inhibition of CK2 reduced the pro-fibrotic effects of TGFβ and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.
From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development
Authors: C. H. Lieu, A.-C. Tan, S. Leong, J. R. Diamond, S. G. Eckhardt
Journal: JNCI Journal of the National Cancer Institute (2013)

The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited.
Immunohistochemistry of minor salivary gland biopsy specimens from patients with Sjogren's syndrome with and without hepatitis C virus infection
Authors: J. Coll, G. Gambus, J. Corominas, S. Tomas, J.-I. Esteban, J. Guardia
Journal: Annals of the Rheumatic Diseases (1997)

OBJECTIVES To characterise phenotypically the minor salivary glands of patients with clinical and histological features of Sjögren's syndrome (SS) infected with hepatitis C virus (HCV). PATIENTS AND METHODS 75 consecutive patients with SS (31 primary SS, 44 secondary SS) diagnosed by preliminary European classification criteria. The presence of anti-HCV antibodies was detected by commercial third generation ELISA and by a second generation immunoblot assay. Presence of HCV genome in serum was determined by polymerase chain reaction analysis. Expression of CD3, CD4, CD8, CD20, HLA-DR, and CD25 molecules in lymphocytic and epithelial cells on minor salivary glands was detected by immunohistochemical assays. Expression of interferon γ and interleukin 4 cytokines was determined by in situ hybridisation. RESULTS Six of 31 primary SS (19%) and one of 44 secondary SS (2%) serum samples were positive for anti-HCV by ELISA. Three samples were positive, three indeterminate, and one sample corresponding to a secondary SS patient was negative by immunoblot. The three immunoblot positive serum samples were also HCV-RNA positive by PCR assay. The study of lymphocytic cells in the diffuse infiltrate of minor salivary glands showed a predominance of the CD3 lymphocytic population. A predominance of CD4 over CD8 T cells (ratio 2:1) was observed in HCV and non- HCV infected patients. The analysis of the lymphocytic focus showed that the HCV infected patients had a predominance of CD20 positive cells. Activation molecules ( CD-25 and HLA-DR ) were expressed in HCV and non-HCV infected patients in lymphocytic and epithelial cells, however epithelial cell expression of CD25 was low in HCV infected patients. As expected, a pronounced Th1 response was observed in the lymphocytic foci of HCV patients. CONCLUSIONS HCV infected patients may develop an autoimmune sialadenitis, similar to that described in primary SS.
Chemical Predictors of Wheeze among Farmer Pesticide Applicators in the Agricultural Health Study
Authors: JANE A. HOPPIN, DAVID M. UMBACH, STEPHANIE J. LONDON, MICHAEL C. R. ALAVANJA, DALE P. SANDLER
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Pesticides may contribute to respiratory symptoms among farmers. Using the Agricultural Health Study, a large cohort of certified pesticide applicators in Iowa and North Carolina, we explored the association between wheeze and pesticide use in the past year. Self-administered questionnaires contained items on 40 currently used pesticides and pesticide application practices. A total of 20,468 applicators, ranging in age from 16 to 88 years, provided complete information; 19% reported wheezing in the past year. Logistic regression models controlling for age, state, smoking, and history of asthma or atopy were used to evaluate associations between individual pesticides and wheeze. Among pesticides suspected to contribute to wheeze, paraquat, three organophosphates (parathion, malathion, and chlorpyrifos), and one thiocarbamate (S-ethyl-dipropylthiocarbamate [EPTC] ) had elevated odds ratios (OR). Parathion had the highest OR (1.5, 95% confidence interval [CI] 1.0, 2.2). Chlorpyrifos, EPTC, paraquat, and parathion demonstrated significant dose–response trends. The herbicides, atrazine and alachlor, but not 2,4-D, were associated with wheeze. Atrazine had a significant dose–response trend with participants applying atrazine more than 20 days/year having an OR of 1.5 (95% CI 1.2,1.9). Inclusion of crops and animals into these models did not significantly alter the observed OR. These associations, though small, suggest an independent role for specific pesticides in respiratory symptoms of farmers.
Increased circulating levels of α<sub>1</sub>-antitrypsin and calprotectin are associated with reduced gas diffusion in the lungs
Authors: I. Welle, P.S. Bakke, G.E. Eide, M.K. Fagerhol, E. Omenaas, A. Gulsvik
Journal: European Respiratory Journal (2001)

The aim was to examine the relationship of serum inflammatory markers to the level of single-breath diffusing capacity of carbon monoxide (T L,CO ). A stratified sample (n=1,121) of a Norwegian general population aged 18–73 yrs was examined. The inflammatory markers measured were calprotectin, a prominent protein in the cytosol fraction of neutrophil granulocytes, and α 1 -antitrypsin (α 1 -AT), the major inhibitor of neutrophil elastase in the lower respiratory system. Both markers have increased circulating levels in the course of an acute inflammatory reaction. Subjects with a T L,CO &lt;80% of predicted value had a higher level of both α 1 -AT (p=0.003) and calprotectin (p&lt;0.03) than those with a T L,CO &gt;100%. In multiple linear regression analyses, α 1 -AT was still significantly associated with T L,CO after adjusting for sex, age, smoking habits, haemoglobin, carboxyhaemoglobin, forced expiratory volume in one second and alveolar volume. In a similar analysis, no significant overall association was found between calprotectin and T L,CO , but in a stratified analysis, calprotectin was significantly related to T L,CO in females. However, no significant sex interaction in the relationship between the inflammatory markers and T L,CO was found. The findings suggest that increased levels of α 1 -antitrypsin and of calprotectin are risk factors for decreased diffusing capacity of carbon monoxide.
EMMPRIN Expression as a Prognostic Factor in Radiotherapy of Cervical Cancer
Authors: Xing-Zhu Ju, Jin-Ming Yang, Xiao-Yan Zhou, Zi-Ting Li, Xiao-Hua Wu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), a member of the immunoglobulin family and a glycoprotein enriched on the surface of many types of tumor cells, has been reported to be linked to invasion, metastasis, growth, and survival of malignant cells. Cervical cancer, the second most prevalent cancer in women worldwide and the fifth leading cause of cancer deaths, responds to radiotherapy variably, with 30% of cases recurring after therapy. The purpose of this study was to determine whether expression of EMMPRIN affects the response of cervical cancer to radiation therapy, and whether this membrane protein can be used as a prognostic marker for cervical cancer. Experimental Design: The retrospective cohort study included 82 patients with invasive cervical cancer referred to the Department of Gynecologic Oncology at The Cancer Hospital of Fudan University (Shanghai) between 1991 and 2000. These patients were treated with brachytherapy at a dose of 15 Gy at point A before radical hysterectomy. Expression of EMMPRIN in cervical tumor specimens was examined by immunohistochemistry staining before and after brachytherapy and scored for both staining intensity and percentage of tumor cells stained. EMMPRIN immunoreactivity and clinicopathologic data were analyzed with respect to survival end points using univariate and multivariate approaches. Results: The frequency of EMMPRIN overexpression was 52.4% in primary cervical cancer. After brachytherapy, EMMPRIN overexpression was significantly reduced (13.4%) compared with corresponding tumor before brachytherapy (P = 0.032). EMMPRIN expression was associated with pelvic lymph node metastasis (P = 0.026) and reduction in primary tumor volume following brachytherapy (P = 0.008). Although EMMPRIN expression before or after brachytherapy did not correlate with tumor-specific survival, but increased expression of EMMPRIN following brachytherapy tended to predict poor outcomes by univariate survival analysis (P = 0.0008). In addition, lymph vascular space invasion, deep stromal invasion, and lymph node metastasis were significantly associated with poor prognosis. In multivariate analysis, the independent prognostic factors for tumor-specific survival included the decreased expression of EMMPRIN after brachytherapy (P = 0.002; hazard ratio, 0.339; 95% confidence interval, 0.172-0.672) as well as lymph node metastasis (P = 0.044; hazard ratio, 2.053; 95% confidence interval, 1.020-4.133). Conclusion: Expression of EMMPRIN was associated with a decrease in the reduction of cervical tumor following brachytherapy, and increased EMMPRIN expression after brachytherapy seemed to be an important predictor of poor survival in this patient cohort. Our study suggests that expression of EMMPRIN confers resistance to radiotherapy. Therefore, EMMPRIN expression in cervical cancer may be regarded both as a prognostic factor and a therapeutic target.
2-Hydroxyestradiol Attenuates Renal Disease in Chronic Puromycin Aminonucleoside Nephropathy
Authors: Stevan P. Tofovic, Raghvendra Dubey, Eman M. Salah, Edwin K. Jackson
Journal: Journal of the American Society of Nephrology (2002)

It has been previously shown that 2-hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syndrome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 micro g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 micro mol/L; P < 0.001) inhibited serum (2.5%)-induced cell growth ((3)H-thymidine incorporation), collagen synthesis ((3)H-proline incorporation), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 micro mol/L) were not blocked by ICI182780 (50 micro mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg + 5 x 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P < 0.05) attenuated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor-beta (TGF-beta) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1(+) cells). 2-OHE had no effects on renal tubular cell TGF-beta, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infiltration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These effects are mediated by estrogen receptor-independent mechanisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis.
Decreased soluble tumour necrosis factor expression in spondylarthritis versus rheumatoid arthritis synovitis
Authors: N Yeremenko, C Ambarus, H Masdar, P P Tak, D L Baeten
Journal: Annals of the Rheumatic Diseases (2010)

Tumour necrosis factor (TNF) α is a pivotal mediator of synovial tissue inflammation in rheumatoid arthritis (RA) as well as in spondyloarthritis (SpA), as evidenced by the therapeutic effects of TNF blockade in both diseases. However, the levels of soluble TNF (sTNF) are strongly reduced in SpA versus RA synovial fluid (SF). Therefore we aimed to unravel the potential differences in TNF signalling between SpA and RA.

Synovial biopsies and SF were obtained from actively inflamed knee joints of RA and SpA patients. Soluble mediators in SF were analysed by ELISA. Synovial tissue expression …
In vivo validation of MRI vessel caliber index measurement methods with intravital optical microscopy in a U87 mouse brain tumor model
Authors: C. T. Farrar, W. S. Kamoun, C. D. Ley, Y. R. Kim, S. J. Kwon, G. Dai, B. R. Rosen, E. di Tomaso, R. K. Jain, A. G. Sorensen
Journal: Neuro-Oncology (2010)

The vessel caliber index (VCI), a magnetic resonance imaging biomarker of the average blood vessel diameter, is increasingly being used as a tool for assessing tumor angiogenesis and response to antiangiogenic therapy. However, although the VCI has been correlated with histological vessel diameters, good quantitative agreement with histology has been lacking. In addition, no VCI validation studies have been performed in vivo where the structural deformations frequently associated with histological tissue preparation are not present. This study employs intravital optical microscopy (IVM) measurements of cerebral blood vessel diameters in a mouse orthotopic glioma model to provide the first such in vivo validation. Two VCI correlation models, both a linear and a 3/2-power dependence on the ΔR2*/ΔR2 ratio, were compared with the IVM data. The linear VCI model, determined from steady-state susceptibility contrast (SSC) images, was found to be in excellent quantitative agreement with the intravitally determined VCI for separate tumor size matched groups of mice. In addition, preliminary data indicate that the VCI is independent of whether a dynamic susceptibility contrast or SSC measurement method is used.
Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial
Authors: Cem Gabay, Paul Emery, Ronald van Vollenhoven, Ara Dikranian, Rieke Alten, Karel Pavelka, Micki Klearman, David Musselman, Sunil Agarwal, Jennifer Green, Arthur Kavanaugh
Journal: The Lancet (2013)
Retrocalcaneal bursitis in juvenile chronic arthritis.
Authors: C Goldenstein-Schainberg, C Homsi, R M Rodrigues Pereira, W Cossermelli
Journal: Annals of the Rheumatic Diseases (1992)

Retrocalcaneal bursitis has been described in various adult rheumatic diseases and septic bursitis unrelated to previous bursal disease has been reported in children. The case is reported here of a girl with juvenile chronic arthritis who developed non-septic retrocalcaneal bursitis; the diagnosis was suggested by a combination of clinical and radiographic studies and was confirmed by ultrasonography.
Successful rapid discontinuation of immunosuppressive therapy at molecular relapse after allogeneic bone marrow transplantation in a pediatric patient with myelodysplastic syndrome
Authors: Kazushi Tamura, Takashi Kanazawa, Michiko Suzuki, Mikiko Koitabashi, Chitose Ogawa, Akihiro Morikawa
Journal: American Journal of Hematology (2006)

The success of allogeneic bone marrow transplantation (allo-BMT) in children with myelodysplastic syndrome (MDS) is mainly affected by relapse. The role of additional immunotherapy for pediatric patients with MDS relapsing after allo-BMT remains to be established. Because immunotherapy is generally more effective for patients who bear a low tumor burden, monitoring of minimal residual diseases (MRD) is essential for early diagnosis at molecular relapse. We report here that a patient with relapsed MDS after allo-BMT was successfully treated by the rapid discontinuation of immunosuppressive therapy at molecular relapse while monitoring Wilms tumor (WT1) gene expression levels. Quantitative analysis of WT1 gene expression appeared to be a useful tool to monitor MRD in the present case.
Pointing the Way to Informed Medical Decision Making: Test Characteristics of Clinical Breast Examination
Authors: Mary B. Barton, Joann G. Elmore
Journal: JNCI Journal of the National Cancer Institute (2009)

Clear-cut evidence that screening through clinical breast examination (CBE) alone can reduce breast cancer mortality has been elusive. Even if such evidence exists, it may never be discoverable in the current environment. Many clinicians in the United States perform CBE on patients ( 1 ), and in 2005, 65% of US women reported having had a screening CBE in the previous 2 years ( 2 ). Another recent study found that CBE was routinely performed along with screening mammography at eight (18%) of 45 mammography facilities surveyed in the United States ( 3 ). The most frequent justifi cation for performing CBE in developed countries, where high-quality mammography is widely available, is that CBE can detect lesions missed by mammography. Yet, there is a price to pay for this benefi t. Although the addition of CBE to mammography screening can increase the overall sensitivity of the examination ( 4 ), the cost of any improvement in sensitivity is a decrease in specifi city. In this issue of the Journal, Chiarelli et al. ( 5 ) have quantifi ed this cost in the Ontario Breast Screening Program in terms of the number of false-positive examinations for each additional cancer detected. The breast cancer screening program employed by the provincial program in Ontario permitted standardized information gathering on breast cancer screening, follow-up, and cancers diagnosed at nine regional cancer centers and 59 affi liated centers across the province. The data reported by Chiarelli et al. on 290 230 women
Predictive value of the exercise tolerance test for mortality in North American men: the Lipid Research Clinics Mortality Follow-up Study.
Authors: D J Gordon, L G Ekelund, J M Karon, J L Probstfield, C Rubenstein, L T Sheffield, L Weissfeld
Journal: Circulation (1986)

More than 3600 white men, from 30 to 79 years old and without a history of myocardial infarction, underwent submaximal treadmill exercise tolerance tests as part of their baseline evaluation for the Lipid Research Clinics Mortality Follow-up Study. The exercise test was conducted according to a common protocol and coded centrally; depression of the ST segment by at least 1 mm (visual coding) and/or 10 microV-sec (ST integral, computer coding) signified a positive test. Concurrent measurements of age, blood pressure, history of cigarette smoking, and plasma levels of lipids, lipoproteins, and glucose, as well as other coronary risk factors, were obtained. Cumulative mortality from cardiovascular disease was 11.9% (22/185) over 8.1 years mean follow-up among men with a positive exercise test vs 1.2% (36/2993) over 8.6 years mean follow-up among men with a negative test. Three-quarters (43) of these deaths were due to coronary heart disease. The relative risk for cardiovascular mortality associated with a positive exercise test was 9.3 before and 4.6 after age adjustment. Cardiovascular mortality rates were especially elevated (relative risk 15.6 before and 5.1 after age adjustment) among the 82 men whose exercise tests were adjusted "strongly" positive based on degree and timing of the ischemic electrocardiographic response. A positive exercise test was also moderately associated with noncardiovascular mortality; the relative risk for all-cause mortality was 7.2 before and 3.4 after age adjustment. The relative risk for cardiovascular mortality associated with a positive exercise test was not appreciably altered by covariance adjustment for known coronary risk factors other than age. A positive exercise test was a stronger predictor of cardiovascular death than were high plasma levels of low-density lipoprotein cholesterol, low plasma levels of high-density lipoprotein cholesterol, smoking, hyperglycemia, or hypertension. Its impact on risk of cardiovascular death was equivalent to that of a 17.4 year increment in age.